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A literature review: the effects of magnetic field exposure on blood flow and blood vessels in the microvasculature

A Literature Review: The Effects of Magnetic Julia C. McKay,1,2 Frank S. Prato,1,2,3 and Alex W. Thomas1,2,3* 1Bioelectromagnetics, Imaging Program, Lawson Health Research Institute, 2Faculty of Medicine and Dentistry, Department of Medical Biophysics, The University of Western Ontario, London, Ontario, Canada 3Department of Nuclear Medicine, St. Joseph’s Health Care, London, Ontario, Canada The effect of magnetic field (MF) exposure on microcirculation and microvasculature is not clear orwidely explored. In the limited body of data that exists, there are contradictions as to the effects of MFson blood perfusion and pressure. Approximately half of the cited studies indicate a vasodilatory effectof MFs; the remaining half indicate that MFs could trigger either vasodilation or vasoconstrictiondepending on initial vessel tone. Few studies indicate that MFs cause a decrease in perfusion or noeffect. There is a further lack of investigation into the cellular effects of MFs on microcirculation andmicrovasculature. The role of nitric oxide (NO) in mediating microcirculatory MF effects has beenminimally explored and results are mixed, with four studies supporting an increase in NO activity, onesupporting a biphasic effect, and five indicating no effect. MF effects on angiogenesis are alsoreported: seven studies supporting an increase and two a decrease. Possible reasons for thesecontradictions are explored. This review also considers the effects of magnetic resonance imaging(MRI) and anesthetics on microcirculation. Recommendations for future work include studies aimedat the cellular/mechanistic level, studies involving perfusion measurements both during and post-exposure, studies testing the effect of MFs on anesthetics, and investigation into the microcirculatoryeffects of MRI. Bioelectromagnetics 28:81–98, 2007.
Key words: blood flow; perfusion; blood pressure; nitric oxide; angiogenesis Johnson, 2005; Segal, 2005; Verdant and De Backer,2005].
As our knowledge of human physiology increases A greater understanding of this vascular network and medical diagnosis and treatment becomes more has, and likely will in the future, lead to advances in sophisticated, the scale at which research is targeted tissue regeneration, pain control, circulatory disorders, becomes more minute. In today’s society, the need for and much more. In fact, several attempts have been research involving microstructures within the body andcellular physiology has become increasingly important, as integration of discovery often requires a mechanistic Grant sponsor: Lawson Health Research Institute Internal framework. Currently, there is much interest surround- Research Fund; Grant sponsor: Canadian Institutes of Health Microcirculation is the flow of blood through the *Correspondence to: Alex W. Thomas, Lawson Health Research microvasculature: the arterioles, capillaries, and ven- Institute (Imaging, Office E4-141), London, Ont., Canada N6A 4V2.
ules. It is these vessels that nourish the body’s tissues and organs. Two important functions of the micro-circulatory system are to alter blood flow according to Received for review 26 July 2005; Final revision received 30 May the varying metabolic requirements of the tissues it serves and to stabilize blood flow and pressure by making local regulatory adjustments [Zweifach, 1977; Published online 26 September 2006 in Wiley InterScience Neeman and Dafni, 2003; Pittman, 2005; Popel and made to explore the parameters of microcirculation and and microvasculature, and ‘‘perfusion’’ will refer to microvasculature when tissue and/or blood vessels have blood flow through the vessels that serve an organ or been exposed to a magnetic field (MF). Recently, MFs tissue, that is, the microvasculature. ‘‘Microcircula- have been shown to have positive effects on numerous tion’’ will therefore be considered as both blood flow human systems. For instance, it is documented that MF and perfusion. ‘‘Microvasculature’’ will refer to the exposure can provide analgesia, decrease healing time microcirculatory blood vessels (arterioles, capillaries, for fractures, increase the speed of nerve regeneration, act as a treatment for depression, and provide other This review describes reported effects (and non- medical benefits [Bassett, 1989; Rubik, 2002; Shupak, effects) of any form of MF on blood vessels and blood 2003; Eccles, 2005; Carpenter, 2006]. Increased flow in the microcirculatory systems of experimental knowledge of the influence of MFs on microvascular animals and humans. The experiments presented in this function may have significant therapeutic potential.
review use MFs of varying parameters (varying At the moment, there is limited research exploring strengths, static, time-varying, pulsed, etc.). This the potential of magnetism on blood perfusion; undertaking was prompted by the emerging body of however, if an association between MFs and micro- literature dealing with this topic and the inconsistencies circulation is found, there may be a number of clinical in reported effects. As noted by Cook et al. [2002] in a benefits. As an example, MF therapy could be useful for review on human cognition and electrophysiology, the reperfusion of ischemic tissue or during sepsis.
the MF literature is littered with contradictory evidence.
When blood flow to a tissue becomes blocked or We highlight the importance of considering the reduced, necrosis will eventually occur. Local exposure particular MF parameters that are used in a study, of a MF could potentially result in blood vessel as well as the model tested. It is our aim to relaxation [Smith et al., 2004] and increased blood provide an overview of all published research in flow. Another emerging body of data suggests that MF English (up to May 2006, as represented in PubMed exposure affects the microcirculation and microvascu- ( and ISI Web of Knowledge lature by pushing the system to maintain dynamic (http://isiwebofknowledge)) involving the effects of equilibrium through biphasic responses [Ohkubo and MF exposure on microcirculation and microvascula- Okano, 2004]. This type of biphasic effect could trigger ture. Studies addressing MF effects on a cellular level a biological system to return to its optimum state.
are also included to provide insight into the possible Although there is evidence suggesting that MF mechanisms of action on the vasculature. This review exposure has positive applications for circulatory also considers the use of anesthetics in studies testing problems, not all studies support this notion. Some the effect of MFs and the MFs used in magnetic researchers have found no effect of MFs on blood flow [Mayrovitz et al., 2001, 2005; Haarala et al., 2003].
Not only do the overall findings within this field of research need clarification, but does the terminology.
The terms ‘‘blood flow’’ and ‘‘perfusion’’ are often usedinterchangeably within studies and their exact defini- There are numerous processes and chemicals tions vary. It would appear that the definitions of ‘‘blood within the microcirculatory system that can be flow’’ and ‘‘perfusion’’ are often characterized as influenced by MF exposure. Most research involving method-dependent definitions. There are many ways the effect of MFs on microcirculation and micro- of measuring blood flow/perfusion; therefore, the vasculature has focused on static magnetic fields definition of blood flow/perfusion in one experiment (SMFs); however, the MF parameters that have been might not be the same in another (e.g., the use of used vary between studies, as do other aspects of the radioactive microspheres to measure tissue blood flow experimental designs. Such parameters include field in ml/min2/g [Sinha et al., 2003; Anetzberger et al., intensity, static versus time changing field, field 2004], versus a protocol that measures blood flow only frequency, pulsed versus non-pulsed field (e.g., duty in tissues with an active sodium/potassium ATPase cycle), localization of exposure, and duration of pump [Gruwel et al., 1997]). In some research, actual exposure. When comparing studies, these variables blood flow parameters are considered (e.g., laser must be kept in mind. The research findings below are Doppler flowmetry), whereas in other research infer- ences are made based on observed vessel effects(changes in vessel diameter, vessel growth). In this review, ‘‘blood flow’’ will be considered as the flow of The effect of SMF exposure on blood velocity was blood through any vessel, that is, large arteries/veins assessed in a study by Xu et al. [2001]. Peak blood velocity in the tibialis anterior muscle of mice was baroreceptor sensitivity and microcirculation were measured using a fluorescence epi-illumination system unaffected. This led the author to suggest that the (a fluorescence microscope, charge-coupled device verapamil counteracted the SMF and that the site of camera, video time generator, tape recorder, and display action of the SMF on the microcirculation was the Ca2þ monitor). It was reported that whole body exposure to a 1 mT SMF for a duration of 10 min led to a 20–45% increase in blood velocity over a period of 45 min post- [Gmitrov, 2005] in sedated rabbits under changing exposure. No significant increase was noted during the geomagnetic field conditions. Blood pressure and exposure period. When the mice were exposed to a microcirculation were also measured using micro- 10 mT SMF, blood velocity was increased by 15% photoelectric plethysmography. A negative correlation immediately after the initiation of the MF and 45% was found between geomagnetic disturbance and immediately after the end of exposure. A 0.3 mT SMF both microcirculation and baroreflex sensitivity, and a did not have any effect. When an electromagnetic field positive correlation was found between microcircula- (EMF) (50 Hz) of 1 mT was tested, blood velocity was tion and baroreflex sensitivity. That is, on days with significantly increased by 27.6% from baseline; intense geomagnetic activity, both microcirculation and whereas when a 0.3 mT (50 Hz) MF was used, no geomagnetic activity were decreased. This study significant change in blood velocity was observed.
further suggests that geomagnetic fields directly modify These results suggest that a 1 mT MF may be the microcirculatory responses rather than general sys- threshold for altering hemodynamics for both SMFs temic responses. These findings may have serious and 50 Hz EMFs. This study clearly demonstrates that implications for individuals with ischemic diseases various microcirculatory effects are possible depending during periods of intense geomagnetic activity.
Using a similar animal model as Gmitrov [2004], Gmitrov et al. [2002] investigated changes in Ohkubo and Xu [1997] reported the effects of a 1, 5, and blood flow within the cutaneous tissue of the rabbit ear 10 mT SMF. The mean amplitude of microphotoelectric lobe. A rabbit ear chamber (a transparent acryl-resin plethysmography was taken to represent vasomotion chamber) was attached to the ear lobe and then placed within the microvasculature. A rabbit ear chamber was under an intravital microscope that allows for the attached to the ear lobe of conscious rabbits and quantification and observation of moving particles.
then placed under a microscope. Throughout the 10 min Blood flow measurement by microphotoelectric ple- exposure period, the SMF induced changes in thysmography, a simple procedure which provides vasomotion in a non-dose dependent manner. When relative changes in microcirculation in cutaneous the initial vessel diameter was less than a certain value, tissues based on the light absorption of hemoglobin, MF exposure caused an increase in vessel diameter occurred pre-, during, and post-exposure. They found (vasodilation). In contrast, when the initial vessel that SMF exposure (0.25 T, 40 min exposure) led to a diameter was greater than a certain value, the 20–40% increase in microcirculation. Blood flow was MF exposure caused a decrease in vessel diameter significantly increased starting 10 min into the exposure (vasoconstriction). Based on these results (and more to through to 20 min post-exposure compared to sham follow), it would appear that the initial state of the vessel is of importance when considering MF effects on In a similar experiment, the effects of a 0.35 T microcirculation and microvasculature.
SMF on microcirculation and the arterial baroreflex (reflexes initiated by receptors in the aortic arch that studies. Okano et al. [1999] reported biphasic effects alter peripheral vasomotion) of conscious rabbits were (activation/inhibition) of a 1 mT SMF on cutaneous investigated [Gmitrov, 2004]. As was done previously, a microvasculature of conscious rabbits using micro- rabbit ear chamber was attached to the ear lobe of photoelectric plethysmography and intravital micro- sedated rabbits and then placed under a microscope.
scopy. When they pharmacologically induced high Relative blood flow was assessed non-invasively using vascular tone using norepinephrine to cause vaso- microphotoelectric plethysmography. The SMF sig- constriction, the SMF exposure led to increased vaso- nificantly increased baroreceptor sensitivity, heart rate, motion and caused vasodilation. In contrast, when they mean arterial pressure, and blood flow. Verapamil, a induced low vascular tone using acetylcholine to cause Ca2þ channel blocker, decreased the sensitivity of the vasodilation, the SMF exposure led to decreased baroreflex. Vasodilation occurred both after SMF and vasomotion and caused vasoconstriction.
after verapamil exposure, applied separately. The In a later experiment by Okano and Ohkubo highlight of their findings was that when the SMF [2001], their previous work on cutaneous microvascu- and verapamil were applied simultaneously, the lature of conscious rabbits was extended (1 mT SMF, 30 min exposure). This study focused on blood pressure hypotension caused by the drug. A 10 mT SMF did changes associated with SMF exposure. When blood not have any effect. They concluded that a 25 mT SMF pressure was increased using a nitric oxide synthase could potentially reduce hypotension in vivo.
(NOS) inhibitor (vasoconstrictor), exposure to a SMF Recently, Morris and Skalak [2005] have reported caused a significant decrease in blood pressure during similar findings to Okano et al. [1999, 2005a] and and post-exposure, and led to vasodilation. This led to a Okano and Ohkubo [2001, 2003a,b]. Using the significant increase in blood flow, measured using microvessels of rat skeletal muscle, they found that a microphotoelectric plethysmography, after 10 min of SMF (70 mT for 15 min exposure) had a restorative exposure through to 40 min post-exposure. Alterna- effect on microvascular tone. That is, when vessels had tively, when blood pressure was decreased using a Ca2þ high tone (constricted), the SMF acted to reduce tone, channel blocker (vasodilator), the SMF caused a and when the vessels had low tone (dilated), the SMF significant increase in blood pressure during and post- increased tone. This response was amplified when the exposure, and led to vasoconstriction. This led to a vessels had an initial diameter of less than 30 mm significant decrease in blood flow for 10 min during (transverse vessels). Intravital microscopy was used to assess vessel tone. The researchers also attempted to The ability of a SMF (5.5 mT, 30 min exposure) to detect any response pattern among vessel networks alter blood pressure was again tested on conscious (adjacent vessels, vessel hierarchy, parent/daughter rabbits with pharmacologically induced hypertension vessels); however, nothing was identified. In a similar [Okano and Ohkubo, 2003a]. Norepinephrine or a NOS conclusion to the above researchers, Morris and Skalak inhibitor was used to induce vasoconstriction. For the [2005] noted that if a network of vessels is resting at an group that received the norepinephrine, the SMF average tone when SMF exposure occurs, then it is increased the mean blood flow in the ear lobe (measured possible that no response to the SMF may be observed.
by microphotoelectric plethysmography) after 10 min Similarly, if a sample of vessels with heterogeneous of exposure through to 50 min post-exposure. Likewise, tone is exposed to a SMF, it is possible that no net for the group that received the NOS inhibitor, the SMF effect will be observed due to the homeostatic action of increased the mean blood flow after 20 min of exposure through to 20 min post-exposure. The SMF also Okano and Ohkubo [2005a] confirmed the results reduced both the norepinephrine-induced and NOS of Morris and Skalak [2005] when they observed the inhibitor-induced high blood pressure 60–100 min biphasic and restorative effect of a SMF (5.5 mT) on post-exposure. When a SMF-exposed group with no microvascular tone and blood pressure in conscious pharmacological treatment was compared to a sham rabbits after 30 min of exposure to the neck. Blood exposure group with no pharmacological treatment, no pressure and vascular tone were pharmacologically This effect was further tested on genetically Ca2þ channel blocker (hypertension) or nicardipine hypertensive rats [Okano and Ohkubo, 2003b]. At (hypotension). The reduction in cutaneous ear lobe 7 weeks of age, the rats were continuously exposed to a microcirculation (measured using microphotoelectric SMF (10 or 25 mT) for 12 weeks. Throughout the 3rd to plethysmography) upon application of norepinephrine 5th weeks of SMF exposure, significant antipressor was significantly attenuated 20–80 min post-exposure effects on mean blood pressure were found using the to the SMF. A similar, but opposite, SMF effect was tail-cuff method. No differences in mean blood pressure observed upon application of nicardipine. By contrast, were found between the two MF intensities that were neither of these effects were observed when the SMF tested. Hormone analysis revealed that the 10 mT SMF exposure occurred in the pelvic region. The SMF also (at 5 weeks of exposure) reduced angiotensin II by had an antipressor effect on blood pressure 40–70 min 65.3% and aldosterone by 39.6%. The 25 mT SMF (at post-exposure to the neck when it was increased by 5 weeks of exposure) reduced angiotensin II by 63.8% norepinephrine, and the opposite effect 30–50 min and aldosterone by 36.6%. These reductions disap- post-exposure to the neck when blood pressure was reduced by nicardipine. No effects were observed The homeostatic effects of a SMF were again during or after SMF exposure to the pelvis. The reinforced by Okano et al. [2005a] when they used SMF further increased the norepinephrine-reduced reserpine (dilate vessels) to induce hypotension and baroreflex sensitivity 40–60 min post-exposure to the deplete catecholamine reserves in rats. Blood pressure was assessed using the tail-cuff method. The SMF Okano and Ohkubo [2005b] thereafter tested the exposure (25 mT, 12 week exposure) significantly effect of a stronger SMF (180 mT) implanted in the neck reduced the effect of the reserpine, reducing the of spontaneously hypertensive rats. Hypertensive rats that were exposed to the SMF (14 weeks) had a mean Similarly, no significant effect of an 85 mT MF on blood pressure reduction (tail-cuff measurements) of human skin blood flow was found using laser Doppler 3.8% in comparison to controls during the 5th–8th flowmetry [Mayrovitz et al., 2005]. When subjects weeks of exposure. The SMF also inhibited the decrease took a deep and rapid inspiration, sympathetic reflexes in baroreflex sensitivity that was observed in sham led to transient vasoconstriction in the skin micro- animals during the 5th–8th weeks of exposure. When vasculature (inspiratory gasp reflex). MF exposure nicardipine (Ca2þ channel blocker) was administered to for 20 min did not affect the magnitude of this decrease blood pressure, the application of the SMF further enhanced this decrease in mean blood pressure deviates from ‘‘normal’’ resting conditions, the authors by 6.9% during weeks 1–8 of exposure. These results suggested that the extent that a tissue/vessel deviates suggested that the SMF synergistically antagonized from normality may affect the effect of a MF.
Ca2þ influx through Ca2þ channels. It was also In another experiment, however, Mayrovitz and postulated through theoretical calculations that a PEMF Groseclose [2005] did find an effect of a 0.4 T SMF on modulated by changing heart rate may be effective in skin microcirculation of human subjects. A sham magnet was placed under the 2nd finger and another The effect of high-intensity SMFs, such as those placed under the 4th finger for a period of 15 min. Next, fields used in MRI, has also been investigated. Ichioka a sham magnet was again placed under the 4th finger et al. [1998] examined the effect of an 8 T SMF on and an active magnet (of either polarity) was placed peripheral hemodynamics. They performed an in vivo under the 2nd finger for 15 min. This process was experiment measuring microvascular and hemody- repeated for another 15 min using a magnet of the namic data in the dorsal skin of a rat using intravital opposite polarity under the 2nd finger. A significant microscopy. After 20 min of whole body exposure to the reduction in skin blood flow using laser Doppler SMF, the MF exposure was stopped. At this time point, flowimetry was reported after three 15 min exposure vasodilation was apparent and skin microcirculation intervals using magnets of either polarity. Polarity of the had increased by 17% at 1 through to 5 min post- exposure. At 10 min post-exposure, blood flow hadreturned to baseline. The authors suggested that the increase in blood flow post-exposure was due to Few researchers have examined the use of pulsed hyperaemia following reduced flow during the MF electromagnetic fields (PEMFs) on microcirculation exposure. Follow-up work in 2000 by Ichioka et al.
and mircovasculature. Smith et al. [2004] used a PEMF again involved whole body exposure of a rat to a strong (positive rate of change of 18.8 T/s; negative rate of static field of 8 T for 20 min. In contrast to their previous 8 T/s) to examine acute changes in arteriole diameter in study, blood flow assessment occurred during exposure.
the cremaster muscle of the rat using intravital micro- The authors reported that skin microcirculation, scopy. The particular PEMF that was used is clinically measured using laser Doppler flowmetry (a technique useful for the healing of non-union fractures. Their based on the Doppler shift of low power laser light experiment revealed that a 2 min local exposure to the scattered by moving erythrocytes), decreased from PEMF led to a 9% increase in arteriole diameter.
baseline, and upon cessation of the exposure, blood flow Subsequent exposure to the same PEMF for 60 min led returned to baseline values after 20 min. Although the to an 8.7% increase in arteriolar diameter. Temperature post-exposure results seem to conflict with the bulk of and systemic hemodynamics were ruled out as the studies cited, as well as their study in 1998, the field confounding variables, and no differences were found strength that was tested is substantially higher than most A study by Schuhfried et al. [2005] also explored Some MF exposure studies have been performed the effect of two low frequency PEMFs on the using human subjects. For instance, human exposure to cutaneous microcirculation of human volunteers. A a 0.1 T permanent magnet resulted in no change in skin low-dose PEMF (0.1 mT, 30 Hz, Bemer specific signal), blood perfusion [Mayrovitz et al., 2001]. Laser Doppler high-dose PEMF (8.4 mT, 10 Hz, sine wave pulses), and flowmetry and imaging both indicated that no differ- sham MF were each randomly applied to the entire foot ences in microcirculation existed between groups that (double-blind) for one 30 min exposure session each received either 36 min of sham or MF exposure.
separated by 1 week intervals. A laser Doppler probe Perfusion measurements were made before and during was placed on the dorsum of the foot and measurements exposure. These authors emphasized that the lack of were made prior to each PEMF exposure, every 5 min MF effect may have been a result of studying during the half-hour exposure period, and then 5 and healthy subjects with ‘‘normal, unstressed circulation’’.
10 min post-exposure. There were no reported changes in microcirculation (or skin temperature) after either the MF exposure, blood perfusion had significantly PEMF exposure session. Schuhfried et al. [2005] note increased in the exposed arm (by 29%) and perfusion that the lack of effect may be due to the single, short- was unchanged in the control arm. Importantly, the term application of the PEMF; however, Smith et al.
researchers also measured skin temperature in both [2004] had a comparably short exposure period and did arms: starting at 5 min into the MF exposure, skin find an effect of a PEMF on microcirculation. Other temperature on the exposed arm was significantly PEMF parameters did however differ, as did the tested higher than on the control arm. It was not clear to these researchers whether it was the temperature increase that A number of studies have examined radiofre- caused in the increase in perfusion or whether the quency MFs on microcirculation and microvasculature.
increase in temperature was a result of MF effect on One of the first reports of non-thermal vasodilation by muscle blood flow. Further use of this pulse sequence electromagnetic radiation was made by Miura and (27.12 MHz, 600 pulses/s, 0.1 mT) indicated that it was Okada [1991]. They exposed the arterioles in the web of effective in increasing blood perfusion in peri-ulcer skin a frog to radiofrequency burst-type EMF radiation of microcirculation of diabetic patients [Mayrovitz and various parameters. Dilation was measured using a Larsen, 1995]. A number of these patients also had video microscope gauge. Vasodilation occurred slowly lower extremity arterial disease. A laser Doppler probe (in arterioles that had been constricted by norepinephr- was placed on the peri-ulcer skin of either the toe or foot ine and in non-stimulated vessels), reached a plateau (subjects had an ulcer in one of these two locations) and after 60 min of MF exposure, and then continued also on the contralateral limb. The coil generating the for 40–100 min after MF exposure was ceased. A MF was placed directly above the ulcer. It was found 10–100 MHz frequency (compared to 1 MHz), 50% that during the last 5 min of the 45 min exposure period burst time (compared to 10, 30, 70, 90, 100%), and perfusion had significantly increased at the peri-ulcer 10 kHz burst rate (compared to 102, 103, 105, 106 Hz) site compared to the control limb site. There was no produced the greatest vasodilatory effect. These other corresponding increase in skin temperature. Another burst times and burst rates also produced vasodilation; important finding of this experiment was that prior to however, significance levels were not included in the MF exposure the ulcer site had higher perfusion and study. It was also found that the concentration Ca2þ in blood volume than the non-ulcerated site, yet the MF the perfusion solution (Ringer’s solution) influenced the was still able to induce further increases. These extent of vasodilation (low Ca2þ increased vaso- researchers suggested that new microvessel recruitment dilation). Inhibiting Ca2þ-ATPase eliminated the MF- is likely responsible for the increases in perfusion and induced vasodilation. It was concluded that the MF volume after exposure since there was no change in effect involved modulation of Ca2þ outflow through the cell membrane or an increase in Ca2þ uptake by the Addressing the concern over the safety of cellular phone use, Monfecola et al. [2003] examined the effect Another early study, by Ueno et al. [1986], of non-ionizing electromagnetic radiation (3 Â 108 to reported a decrease in human skin microcirculation 3 Â 1011 Hz) on cutaneous microcirculation of human when exposed for 60 s to an alternating MF (32 and volunteers. They reported that blood flow (in the ear 48 mT, 3.8 kHz). A rapid decrease in blood flow, skin), measured using laser Doppler flowmetry, was measured using laser Doppler flowimetry, was observed increased by 131.74% from baseline when the cellular 6–8 s after the start of exposure, and values returned to phone was turned on and pressed against the ear. When normal after 10 s. The authors suggested that the body the cellular phone was turned on, pressed against the responds to MF exposure with a ‘‘defense’’ or ‘‘escape’’ ear, and was receiving a signal, the blood flow was reaction, namely, vasoconstriction of the vessels in the increased by 157.67% from the baseline. This increase skin. Ueno et al. [1986] concluded that the MF effect is in blood flow could not solely be attributed to a thermal mediated by the nervous system, specifically, the effect due to skin contact with the phone; when the cortico-hypothalamico-bulbar system.
subjects had the phone pressed against their ear and the Similarly, Mayrovitz and Larsen [1992] inves- phone turned off, there was only a 61.38% increase in tigated the effect of a PEMF (27.12 MHz, 600 pulses/s) blood flow from baseline. The authors concluded that on human skin microcirculation. A laser Doppler probe the electromagnetic radiation from cellular phones does was placed on both forearms of healthy volunteers, and indeed lead to a significant modification of micro- the coil producing the MF was placed directly above the circulation in the cutaneous tissue of the ear.
probe on one forearm. The values obtained during the This appears to correspond with the early results 45 min exposure period were compared to the 20 min of obtained by Miura and Okada [1991] involving RF baseline measurements. It was found that 40 min into MFs. Similarly, Huber et al. [2002] reported that a 900 MHz pulse-modulated EMF used in cellular phones led to an increase in regional cerebral blood flow.
sodium or urethane, and the other half, conscious Subjects were exposed unilaterally (only the left side) to subjects. An overview of the results of these studies can the MF for 30 min while sitting with their heads between two antennas. Ten min after this exposure, theconscious human subjects received a positron emissiontomography (PET) scan. Blood flow was increased in the dorsolateral prefrontal cortex only on the side ipsilateral to exposure. This region of the brain is The mechanisms by which MFs exert their effects are still relatively unknown. There are various theories In contrast to the previous two findings, Haarala to account for the microcirculatory changes following et al. [2003] concluded that a pulsed radio-frequency EMF associated with mobile phones (902 MHz, pulse The biological effects of MFs have often been rate 217 Hz) did not have an effect on regional cerebral linked to nitric oxide (NO). For instance, Kavaliers blood flow in the brain area exposed to the maximum et al. [1998] found that NO and NOS were implicated EMF. Human subjects had a phone fastened to one in the effects of extremely low frequency (ELF) MFs side of their head and were exposed to the EMF for on opioid-induced analgesia in land snails. Many 45 min while being imaged by a PET scanner for believe that NO may also be the molecule responsible 90 min. It is, however, possible that EMF effects for the changes in vessel diameter following MF may have occurred in other regions of the brain.
Tsurita et al. [2000] also reported that an EMFused in cellular phones (1439 MHz time divisionmultiple access) did not produce an effect in their experiment. Non-anesthetized rats were exposed to the An investigation by Okano et al. [2005b] indicates EMF for 1 h a day (for either 2 or 4 weeks) by that the homeostatic effect of MFs might influence NO being confined in tube with their heads directed toward pathways. When genetically hypertensive rats were the exposure apparatus. After 2 or 4 weeks, rats were exposed to a SMF (1 or 5 mT) for 12 weeks, blood placed under anesthesia (diethylether and sodium pressure, the concentration of NO metabolites, angio- pentobarbital) and staining methods were employed to tensin II, and aldosterone were reduced. Specifically, determine the effect of MF exposure on the perme- exposure to the SMF reduced blood pressure during ability of the blood-brain-barrier (BBB). No changes weeks 3–6. Hypertensive rats are known to have were found after 2 or 4 weeks. These MF-exposed increased levels of NO metabolites, likely due to the rats were compared to sham-exposed rats and also to upregulation of NOS. Exposure to the 5 mT SMF for rats that had not been confined within the exposure 6 weeks significantly reduced the concentration of NO metabolites by 73.2%. The 1 mT SMF did not have an It would appear that ten studies (four using a SMF, effect on the NO metabolites. At 3 weeks, the 5 mT SMF six using a time-varying MF) support the finding that reduced angiotensin II by 51.1% and aldosterone by MFs act to increase blood flow, and three (two using a 40.2%, and at 6 weeks reduced angiotensin II by 58.2% SMF, one using a RF MF) support a negative finding.
and aldosterone by 72.2%. Similar significant reduc- Ten studies, all using a SMF, found a homeostatic effect tions in angiotensin II and aldosterone were seen with of MF exposure. Four studies found no effect. There the 1 mT field. At 12 weeks, all effects on the NO does not appear to be a clear pattern in terms of why one metabolites, angiotensin II, and aldosterone disap- experiment produces an increase and another, a decrease in blood flow/pressure. Conflicting effects Other research by these investigators, however, were found using MFs of similar parameters; however, reports a lack of change in measured NO upon MF different subjects types and test sites (e.g., skin, muscle, exposure. Okano et al. [2005a] used a SMF (10 and tail vessels) were used. All of the studies that reported a 25 mT) to counter reserpine-induced hypotension in rats.
decrease in blood flow/pressure used healthy subjects, They reported that the SMF did significantly counter the so this decrease was not a result of an initially high reserpine-induced effects; however, this effect was not blood flow/pressure or a diseased state. Two of these mediated by NO. They found no significant differences studies used conscious subjects and one used anesthe- in the concentration of NO metabolites between any tized subjects (urethane). In the studies that reported tested groups. In another experiment, Okano and an increase in blood flow/pressure, all studies used Ohkubo [2005a] reported similar findings. After expos- healthy subjects (both humans and animals). Half used ing conscious rabbits to a 5.5 mT SMF for 30 min, they TABLE 1. MF Effects on Microcirculation and Microvasculature 0.3, 1, and 10 mT (SMF); 0.3 Anesthetized mice (tibialis (" blood flow) (post-exposure);when # vascular tone:vasoconstriction (# blood flow)(during and post-exposure) " blood flow (during andpost-exposure); when # vasculartone: " BP and # blood flow(during exposure) 1 and 5 mT (SMF); 12 weeks Conscious hypertensive rats 5.5 mT (SMF); 30 min whole Conscious rabbits (cutaneous only); when # vascular tone: " BPand # blood flow (post-exposure toneck only); when # baroreflexsensitivity: " baroreflex sensitivity(post-exposure) When " vascular tone: # vascular tone (post-exposure); when # vasculartone: " vascular tone(post-exposure) Conscious humans (cutaneous No effect (during exposure) Conscious humans (cutaneous No effect (during exposure) " baroreflex regulation(post-exposure) Mayrovitz and Groseclose [2005] 0.4 T (SMF); three 15 min Conscious humans (cutaneous # Blood flow (during exposure) Conscious humans (cutaneous No effect of PEMF " Arteriolar diameter (post-exposure) EMF (32 and 48 mT, 3.8 kHz Conscious humans (cutaneous # Blood flow (during exposure) Burst-type EMF (10 MHz RF, Anesthetized albino frogs " Blood flow (last 5 min of exposure) " Blood flow (last 5 min of exposure) EMF (900 MHz RF); 30 min Conscious humans (brain) EMF (902 MHz RF); 45 min Conscious humans (brain) EMF (3 Â 108 to 3 Â 1011 Hz Conscious humans EMF: Electromagnetic fields. EMFs are waves composed of both electric and magnetic fields.
PEMF: Pulsed electromagnetic field. A MF that is pulsed on and off at a specific frequency and intensity.
RF: Radiofrequency. Frequency ¼ 3 kHz–300 GHz.
SMF: Static magnetic field. A direct current MF that does not vary with time (0 Hz) and has an infinitely long wavelength.
Note: It is not clear from the articles cited whether the MF strengths listed for the AC fields are peak or rms values.
reported biphasic effects on pharmacologically modified MF of 1.6 mT (1 Hz). In spite of their results, Mnaimneh vessel tone and blood pressure, but no changes in NO et al. [1996] made note that MFs could potentially metabolites. They suggested that the site of SMF modify a NO-dependent reaction that is independent of, interaction may be biochemical mechanisms involving or ‘‘down-stream’’ from, NO formation.
baroreflex sensitivity and signal transduction pathwaysinvolving Ca2þ.
The above findings were partially elucidated when spontaneously hypertensive rats were exposed to a Noda et al. [2000] proposed that PEMFs may exert 180 mT SMF (magnet implanted in neck) for 14 weeks their effects by affecting the activity of NOS. In their [Okano and Ohkubo, 2005b]. The SMF enhanced the experiment, rat brain tissue was divided up into seven hypotensive effect of nicardipine and caused a further regions and each sample was homogenized. Next, they increase in NO metabolites during the 6th–8th week passed a 0.1 mT pulsed DC (direct current) field through of exposure compared to rats that also received each of the homogenized brain samples for 1 h. A nicardipine but were exposed to a sham MF. Thus, the significant increase in NOS activity was found in the synergistic effect of the SMF appeared to be related to cerebellum only and not in the other six regions tested.
NO. The SMF alone (without nicardipine), however, Likewise, Yoshikawa et al. [2000] found that when mice did not induce any change in NO metabolite concen- were injected with lipopolysaccharide (a bacterial stressor) for the induction of inducible nitric oxide Mnaimneh et al. [1996] also reported that synthase (iNOS), exposure to an EMF (0.1 mT, 60 Hz) inducible NO production in macrophages taken from for 5.5 h enhanced the generation of NO in the liver.
mice was not increased by the particular MF parameters Exposure to the EMF alone, with no lipopolysacchar- that they used. They tested a SMF of 1, 10, 50, and ide, did not result in an increase in NO generation.
100 mT (plus an ambient 50 Hz MF) and a sinusoidal Yoshikawa et al. [2000] suggested that EMFs may exert their effects by extending the life of free radicals and Sponges containing either prostaglandin E1 or fetal altering signal transduction pathways involved with calf serum were placed on the membranes to induce angiogenesis; phosphate buffered solution was used as a Miura et al. [1993] used tissue from rat cerebellum negative control. Two days after real or sham exposure to determine whether the vasodilation due to radio- for 3 h, the membranes were examined for the presence frequency burst-type EMF radiation that they had of new microvessels. Both sham groups that were treated observed in previous studies was related to NO synthesis.
with either prostaglandin E1 or fetal calf serum exhibited They studied the cerebellum since NO synthase is a strong angiogenic response. The SMF-exposed groups, predominant in this region. The authors concluded that however, exhibited reduced angiogenesis with fewer new after 30 min of exposure to a 2.65 mT MF with a 10 MHz vessels developing towards the sponges.
frequency and a 10 kHz burst rate, NO did gradually The above effect, however, has not been consis- increase to a maximal value after 20 min cessation of tently replicated. In a study involving the use of MFs to exposure. This effect was near abolished using a NOS treat ulcers not responsive to conventional treatments, inhibitor. Cyclic guanosine monophosphate (cGMP) was exposure led to an increase in the superficial vascular also increased when tissue was exposed to EMF network of the skin [Can˜edo-Dorantes et al., 2002].
radiation. When a cGMP inhibitor was used, the effect They used a SMF (approximately 52 mT) combined with an ELF MF (3.7 mT, 60 Hz) that consisted of A lack of effect on NO was found when a PEMF frequencies that could interact with peripheral blood (0.4 mT, 120 Hz, sinusoidal) was tested by Kim et al.
mononuclear cells (cells that promote the healing [2002]. They found no differences between a control of ulcers). The MF exposure was localized to one arm and PEMF-exposed group in neuronal NOS (nNOS) 2–3 h/day 3 times a week. After the exposure, it was expression in an injured recurrent rat laryngeal nerve.
found that 69% of the 42 chronic arterial and venous It is clear that conflicting evidence involving MFs leg ulcers were cured or substantially healed. The and NO has been obtained. The limited studies that have improvement in the arterial ulcers was partly attributed been performed measure NO in various tissues and to an increase in the superficial vascular network (after use MFs of varying strengths and frequencies. It is 4–8 weeks of treatment), and the improvement in the therefore difficult to make any conclusions on this venous ulcers was partly attributed to reduced/elimi- subject. The role of NO as a mediator for the biological nated edema (after 3–6 weeks of treatment). This study, effects of MF exposure is uncertain. More research is however, used a before-after design that did not compare MF treatment to a control. It is therefore Other radicals within the body, in addition to NO, difficult to ascertain whether the effects on vasculariza- may be influenced by MF exposure. Specifically, it is tion and reduction of edema are enhanced by the MF or known that high concentrations of reactive oxygen are simply a result of time or some other factor.
species are involved with reperfusion injury, which is An ELF MF (50 Hz, 8 mT peak) was used in an the harm that occurs to tissue when blood flow is attempt to improve the healing of skin wounds surgically reestablished after ischemia. It has been found that created on the backs of rats [Ottani et al., 1988]. Thirty stress proteins protect tissue from this type of injury and minutes of MF exposure immediately after surgery and that MF exposure can induce a stress response that also every 12 h thereafter for 42 days, led to a greater and exerts a protective effect [DiCarlo et al., 1999; Carmody faster rate of healing. Specifically, the exposed animals et al., 2000]. In light of this interaction, it is plausible had developed a new vascular network on the 6th day that MFs could interact with other radicals as well.
after surgery; whereas, this occurred in the controls12 days post-surgery. At the 12 days post-surgery mark for the exposed animals, a rich capillary network had Some research indicates that MFs can influence formed. These differences were evaluated by light and vessel growth and development. For instance, some electron microscopy. Increased angiogenesis in response research on ulcers and MF therapy has partly linked the to a PEMF (0.1 mT, 15 Hz) was also observed enhanced healing of wounds to effects on microcirculation in vitro using human umbilical vein and bovine aortic and microvasculature. Any study that involves MF effects endothelial cells [Yen-Patton et al., 1988]. A wound on microvessel growth or development has been included model was created by raking a comb across a monolayer in this section. Studies are organized by modality (SMFs of endothelial cells. As a result of the continuous PEMF exposure, there was a 20–40% significant increase in A SMF (0.2 T) was applied to the chorioallantoic the growth rate of the endothelial cells, and these membranes of chick embryos for 3 h to test the effect of cells appeared more elongated in appearance, forming exposure on angiogenesis [Ruggiero et al., 2004].
10–30% more ‘‘sprouts’’ than controls. When a 2nd set of human umbilical vein endothelial cells were disrupted umbilical vein endothelial cells were exposed to the MF and separated from each other, PEMF exposure led to for 7–10 days, there was sevenfold increase in the degree vascularization within hours; this took 1–2 months with of cell tubulization compared to sham-exposed cells.
non-exposed cells. The stages of neovascularization that There was also a significant increase in the proliferation occurred in this experiment were similar to the stages that of PEMF-exposed endothelial cells. This increase was similar to what would be expected after a large dose of In another experiment, the effect of three PEMF vascular endothelial growth factor. An interesting finding waveforms on blood vessel growth in the ears of a rabbit of this experiment was that fibroblast and osteoblast cell model was investigated [Greenough, 1992]. A 15 Hz lines did not show the same proliferation as did the pulse burst waveform (6 h daily for 25 days) led to an endothelial cells. It was proposed that endothelial cells increased rate of vascular growth at day 24, but no are the main target for PEMFs by releasing proteins that significant changes in the maturation of the vessels upregulate angiogenesis. This is an important finding for compared to controls. The 2nd pulseform (72 Hz, single the healing of fractures, in that perhaps the MFs interact pulse, 1 h daily for 25 days) had no effect on the growth with vascularity instead of osteogenesis [Tepper et al., rate, but did significantly enhance the maturation of the 2004]. It was also found that when a gel that supports vessels at day 24. The 3rd pulseform (72 Hz, single vascular growth was implanted subcutaneously into pulse, 6 h daily) led to no significant effects.
mice, the PEMF exposure (8 h/day) stimulated signifi- Weber et al. [2004] tested the effects of a PEMF cantly more (more than twofold) vascular growth than (0.1 mT, 65-ms burst of 27.12 MHz sinusoidal waves) on did sham exposure after 3, 10, and 14 days.
angiogenesis using two different exposure lengths (8 or In contrast to the previous few studies, Williams 12 weeks). They created a groin composite flap in rats et al. [2001] found that a PEMF (10, 15, or 20 mT) by removing a portion of tail artery that was then reduced the vascularization of breast tumors implanted anastomosed to two other arteries. This arterial loop into mice. A half sinewave MF with 120 pulses/s was was placed over the abdominal wall and under the skin.
used. Seven days after tumor implantation, whole body Rats received MF exposure twice daily (exposures were MF treatment was initiated 10 min daily for 12 days.
at least 4 h apart) for 30 min each exposure. After either MF exposure led to a significantly greater degree of 8 or 12 weeks, rats underwent a 2nd surgery to ligate the expression of CD31 (platelet endothelial cell adhesion vessel that was initially responsible for blood flow to the molecule), a marker for blood vessels. Specifically, the composite flap. The tissue would then be supplied only group exposed to the 10 mT MF had a 39% decrease by the neoarterial loop. Five days later, the percentage in CD31 staining compared to controls, whereas the of flap survival was calculated. The group exposed to 15 mT group had a 68% decrease and the 20 mT group a the PEMF for 8 weeks had significant skin flap survival 62% decrease. These authors concluded that since whereas the skin flap in the control group did not there were no significant differences between the 15 and survive. The group exposed to the PEMF for 12 weeks 20 mT MF groups, that a biological window exists did not differ significantly from the control group. This research indicates that it is possible to accelerate It is inferred that additional vessel growth leads to greater circulation, although blood flow was not Roland et al. [2000] performed a similar experi- measured in any of the above experiments. Seven ment using a microsurgically transferred vessel in rats.
of these studies (one using a SMF and six using a time- An arterial loop, consisting of tail artery, was anasto- varying MF) reported an increase in angiogenesis and mosed to the femoral artery and was placed over the two reported a decrease (one using a SMF and the other groin musculature. A PEMF (0.01 or 0.2 mT, 2–20 ms a time-varying MF). Again, there do not appear to be pulses, 27.12 MHz) was applied twice daily for 30 min at any features that distinguish between these varying each exposure session. Surface area neovascularization results. An overview of the results of these studies can was measured after either 4, 8, or 12 weeks of MF exposure. At all time points, both MF-treated groupsexhibited significantly more neovascularization than the controls. There were no differences between the two MF-exposed groups. This study clearly indicates that under the correct conditions MF exposure canincrease blood vessel development and growth.
Most, if not all, in vivo animal experiments Tepper et al. [2004] also used a PEMF (1.2 mT, involving the effects of MF exposure on microcircula- 15 Hz, asymmetric 4.5 ms pulses) both in vitro and in tion and microvasculature are performed under anes- vivo to test its effect on angiogenesis. After human thesia. Not surprisingly, anesthetics can have a number 10 and 25 mT (SMF); 12 weeks Blood samples from 10 and 25 mT (SMF); 12 weeks Blood samples from normotensive Blood samples from rabbits (central No change in NO metabolites Can˜edo-Dorantes et al. [2002] 52 mT (SMF) þ 3.7 mT, Chorioallantoic membrane in chick # Angiogenesis exposure twice daily for 4, 8,or 12 weeks Human and bovine endothelial cells " Growth rate of endothelial (8 h/day whole body exposurefor 3, 10, or 14 days) (15 Hz, 6 h daily); enhancedvessel maturation (72 Hz,1 h daily) of effects on the various organ systems; the cardiovas- enhance inhibitory synaptic transmission. It is most cular and microcirculatory systems are no exception. It rapidly distributed to the tissues with the most has been shown by Longnecker and Harris [1980] vasculature (McCaughey et al., 1997, p 186). Propofol that in the laboratory anesthetics can skew results by is a cardiovascular depressant that causes a 20–30% altering regional blood flow, response to vasoactive reduction in systolic blood pressure and a 20% decrease chemicals, and response to neural input. In general, in systemic vascular resistance (Kaufman and Taberner, deep anesthesia leads to vasodilation of the arterioles 1996, p 71). In the peripheral system, propofol causes and venules, diminished response to vasoactive noticeable decrease in vascular resistance which compounds, and decreased erythrocyte velocity within leads to systemic hypotension (McCaughey et al., the capillaries [Longnecker and Harris, 1980]. To further confound matters, each anesthetic alters the Urethane is an anesthetic used in veterinary microcirculation in a slightly different manner.
medicine and animal experiments. It has minimal The choice of anesthetic agent used by researchers effects on the cardiovascular and respiratory systems is variable. In this review, the most popular choices were [Hara and Harris, 2002]. Urethane has, however, been ketamine, pentobarbital, and urethane. Another com- shown to decrease blood pressure by 30% and this effect monly used anesthetic is propofol. In an experiment by can last for 30 min [Longnecker and Harris, 1980].
Gustafsson et al. [1995], the effects of three popular Dilation by 15% occurs in the arterioles, particularly the anesthetics on skeletal muscle capillary and regional second-order arterioles (the first set of arterioles that blood flow were compared. This study indicated that branch off the central arteriole), and the venules appear ketamine maintained capillary perfusion the best, to be unaffected [Longnecker and Harris, 1980].
followed by pentobarbital and then propofol.
As mentioned previously, the studies compared in Ketamine is a dissociative anesthetic that is this review use a variety of anesthetics. This may or may restricted to veterinary use. It provides fast, intense not be problematic. In each study where experimental analgesia by inhibiting excitatory synaptic transmission groups (receiving MF exposure) were compared to a at N-methyl-D-aspartate (NMDA) receptors. Ketamine control group, all groups received the same anesthetic; imposes certain effects on the cardiovascular system, thus, any side effects from the anesthetic were including increased systemic and pulmonary arterial experienced by all groups and therefore should cancel blood pressure, heart rate, cardiac output, myocardial out. However, no experiments have been performed to determine whether the anesthetic’s mechanism of cardiac work (Weinberg, 1997, p 26). Studies involving action is affected in any way by the MF. In any changes in perfusion should take note that ketamine is a particular experiment where perfusion is affected by potent cerebral vasodilator that increases blood flow to MF exposure, there is no evidence to determine whether the brain and intracranial pressure (Weinberg, 1997, p it is the MF that is affecting the physiology associated 26). It should also be noted that ketamine causes with perfusion/blood flow or whether the MF has vasodilation in tissues that are primarily innervated by exacerbated or diminished a particular anesthetic side a-adrenoceptors, and in contrast, ketamine causes vaso- effect on perfusion. This point may simply be a fine constriction in tissues that are mainly innervated by detail, contributing little to an overall effect, or it could b-adrenoceptors (Vickers et al., 1984, p 63). Furthermore, become quite significant if MF therapy was 1 day to be in the peripheral system, ketamine is a vasodilator used in a clinical setting on non-anesthetized patients.
(Kaufman and Taberner, 1996, p 69) with arteriolar Also, if a particular anesthetic caused vasodilation or vasodilation of 25% [Longnecker and Harris, 1980].
vasoconstriction, it is possible that the true extent of a Pentobarbital belongs to the class of anesthetics MF effect on vessel diameter might not be realized since known as the barbiturates. The barbiturates cause a the vessel is already at its maximum or minimum decrease in systemic arterial pressure and cardiac output, and an increase in heart rate. They tend tolead to hypotension due to venodilation and the poolingof blood in the periphery (Weinberg, 1997, p 18).
Longnecker and Harris [1980] state that subcutaneousvenules dilate 15% and arterioles dilate 25%. The drop Research on the effects of MFs on microcircula- in blood pressure observed at large doses of barbiturates tion and microvasculature is limited, but growing. Not is due in part to direct effects on the musculature of only is research in this domain important for the arterioles (Vickers et al., 1984, p 102).
discovery of potential medical therapies, but also the Propofol is a rapid-acting anesthetic that interacts importance of establishing accurate safety standards with gamma-aminobutyric acid (GABAA) receptors to A common problem with pharmaceutical drugs is sound Doppler, and Doppler flowmetry should that they often exert their effects at sites within the body possibly be considered as alternative methods to MRI other than the target site [Goodwin and Meares, 2001].
Localization of a drug to a particular tissue is difficult to There are a number of potential reasons for the achieve. For instance, the popular drug Viagra1 variation in the reports of MF effects on micro- (sildenafil citrate), used for erectile dysfunction, circulation and microvasculature. The reviewed studies increases blood flow to the corpus carvernosum by vary in terms of a number of factors. For instance, some inhibiting phosphodiesterase type 5 (PDE-5) [Raja studies measure perfusion during exposure; others, and Nayak, 2004]. Unfortunately, this effect is not after exposure; and some, during both periods.
limited to the corpus carvernosum; PDE-5 is also Discrepancy between studies could be affected by this located in smooth muscle, skeletal muscle, and variable. Furthermore, the duration of exposure and platelets. Therefore, some side effects of Viagra1 type of MF exposure are no doubt confounding include hypotension and effects on the central nervous variables. In addition, various anesthetics and organs and muscoskeletal systems [Cheitlin et al., 1999]. A have been used in the current experiments. This is likely similar example would be the problem of isolating the to contribute to the observed differences as reported in drugs used for chemotherapy and radioimmunotherapy to the target organ/tumor site, without causing toxicity There are a number of recommendations for to other organs or metabolism or excretion by the liver future studies. Investigation into the effects of MFs on and kidneys [Goodwin and Meares, 2001]. The ability microcirculation and microvasculature is relatively new to alter microcirculation to a particular, isolated, site of and studies are scarce. As a result, limited data is the body would be a highly beneficial therapeutic available. For results to be widely accepted, more replication of current studies by independent research The importance of assessing safety standards on groups is needed to validate obtained results. At present, MF exposure and microcirculation/microvasculature there is controversy within the literature and this tends should be considered. For instance, if an individual was to weaken the effect of positive findings. Much of the taking medication to control hypotension and a skepticism surrounding the therapeutic action of MF particular MF was known to lead to vasodilation, it exposure is a result of the uncertainty of the implicated may not be in the best interest of the individual to be physiological mechanisms. Studies aimed at the exposed to the field. Additionally, it may be a cellular level will add more clarity and merit to current worthwhile effort to assess the effects of strong MF results. Further investigation into the possible role exposure, for example, during an MRI scan, on microcirculation. In functional magnetic resonance hyperpolarizing factor (EDHF), and Ca2þ is needed.
imaging (fMRI) of brain activity, use of the blood In addition, studies that reported a MF effect on oxygen level dependent (BOLD) signal is common. The microcirculation might simultaneously investigate differences in magnetic properties of oxygenated and potential cellular markers of the MF mechanism.
de-oxygenated hemoglobin, mainly within the micro- vasculature, are used to produce a signal. When fMRI is perfusion measurements during the exposure. In some used to measure related changes in blood flow, there is a experimental set-ups, it is difficult to take accurate possibility that the MFs themselves are causing, measurements during the MF exposure due to interfer- confounding, or contributing to, the change. It is largely ence of signals. In a number of the studies cited in assumed that such non-invasive imaging techniques are this review, perfusion measurements occur post-MF simply measuring blood flow, not altering it. However, exposure. More measurements during exposure may reports have been made suggesting that this may not be provide helpful information as to when a biological the case. BBB permeability in rats was increased for 1 h effect occurs. Research involving the effects of after a 23 min MRI scan at 0.15 T (SMF) [Prato et al., anesthetics on blood flow and blood vessels might also 1990]. Similarly, increased BBB permeability was seen be important and will add further insight into the precise in rats exposed to a clinically relevant MRI procedure: a mechanisms behind MF exposure. It may be useful to 1.5 and 1.89 T SMF [Prato et al., 1994]. Certain changes test a MF effect using different anesthetics and in the radiofrequency and gradient field caused a determine whether there are any differences in results.
decrease in BBB permeability. Clearly, it should not be Future investigation might also address the potential assumed that the MFs encountered during a MRI scan have no other effects on the body. Optical Broad classification of results may help delineate imaging techniques, such as near-infrared spectro- where, how, and why some studies report positive scopy, orthogonal polarization spectroscopy, ultra- findings and others report negative findings. The TABLE 3. Summary of MF Effects on Perfusion and Blood Pressure Okano et al. [1999]Okano and Ohkubo [2001] Miura and Okada [1991]Mayrovitz and Larsen [1995]Mayrovitz and Larsen [1992]Huber et al. [2002] aInitial state of subjects: genetically hypertensive rats.
bInitial state of subjects: pharmacologically induced hypertension.
cInitial state of subjects: pharmacologically induced hypotension.
TABLE 4. Summary of MF Cellular Effects Related to Perfusion Decreased nitric oxide activity No change in nitric oxide activity Other cellular effects Ruggiero et al. [2004]Roland et al. [2000]Yen-Patton et al. [1988] Tepper et al. [2004]Ottani et al. [1988]Williams et al. [2001]Greenough [1992] aInitial state of subjects: genetically hypertensive rats.
bInitial state of subjects: genetically hypotensive rats.
cInitial state of subjects: pharmacologically modulated blood pressure.
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