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Cls795.dviClinical Science (2005) 109, 319–324 (Printed in Great Britain)
Effect of sildenafil and acclimatization on Colin W. M. CHAN∗, Helen HOAR∗, Kyle PATTINSON†, Arthur R. BRADWELL∗,
Alexander D. WRIGHT∗, Christopher H. E. IMRAY‡ and
the Birmingham Medical Research Expeditionary Society∗
∗Immunodiagnostics Research Laboratory, The Medical School, University of Birmingham, Vincent Drive, Edgbaston,Birmingham B15 2TT, U.K., †Nuffield Department of Anaesthetics, University of Oxford, The John Radcliffe Hospital,Headley Way, Oxford OX3 9DU, U.K., and ‡County Vascular Unit, University Hospitals Coventry and WarwickshireNHS Trust, Clifford Bridge Road, Coventry CV2 2DX, U.K.
Phosphodiesterase-5 inhibitors decrease hypoxic pulmonary vasoconstriction under hypobarichypoxia, but are not known to affect cerebral blood flow or oxygenation. The present study wasdesigned to evaluate the effect of sildenafil on cerebral haemodynamics during acute exposureto altitude and after acclimatization. Ten subjects were studied 1 and 3 days after rapid ascent to3480 m before and for two consecutive hours after taking sildenafil (50 mg). Before acclimatization,HR (heart rate) rose at 1 h (76.3 + P < 0.05) and had returned to baseline at 2 h (71.3 + − 1.1 beats/min; P > 0.05). Mean BP (blood pres- − 2.5 (P < 0.001) at 1 h and 89.8 + (P < 0.0001) at 2 h, whereas SaO2 (arterial oxygen saturation) increased from 83.9 + − 0.4 % (P < 0.0001) at 1 h and 85.0 + − 0.5 % (P < 0.01) at 2 h. MCAV [MCA (middle cerebral artery) velocity] and PETCO2 (end-tidal partial pressure of CO2) were unchanged,but rSO2 (regional cerebral oxygen saturation) rose progressively at 1 h (62.7 + − 0.9 %; P < 0.0001) compared with baseline (59.3 + ization, resting rSO2 and RMCA (MCA resistance) increased and oxygen delivery fell. Changes inHR and mean BP after sildenafil were similar to day 1, but SaO2 did not change. However, rSO2increased [61.7 + − 1.0 % (P < 0.0001) at 1 h and 64.0 + at 2h], despite a reduction in MCAV [65.3 + − 1.7 cm/s (P < 0.0001) at 2 h] and PETCO2 [4.1 + 0.04 kPa at 2 h (P < 0.01)]. These observations suggest that sildenafil improves cerebral oxygen-ation at altitude. Whereas the early changes before acclimatization may be largely pulmonary inorigin, the later observations may be a direct cerebral effect which warrants further study.
cerebral autoregulatory responses which provide stableDo2 (oxygen delivery), particularly by increasing cerebral Increasing numbers of people travel to or work at altitude and risk development of AMS (acute mountain sickness) Acute hypobaric hypoxia also affects the pulmonary . The brain is sensitive to relatively minor fluctuations circulation resulting in pulmonary hypertension and this in cerebral oxygenation and is normally protected by may be associated with high-altitude pulmonary oedema.
Key words: acclimatization, altitude, cerebral regional oxygen saturation, hypoxia, middle cerebral artery velocity, phos-
phodiesterase-5, sildenafil (Viagra®).
Abbreviations: AMS, acute mountain sickness; BP, blood pressure; Do2, oxygen delivery; HR, heart rate; MCA, middle
cerebral artery; MCAV, MCA velocity; NIRS, near-IR spectroscopy; NO, nitric oxide; eNOS, endothelial NO synthase; PDE5,
phosphodiesterase-5; Petco2, end-tidal partial pressure of CO2; RMCA, MCA resistance; rSo2, regional cerebral oxygen saturation;
Sao2, arterial oxygen saturation.
Correspondence: Dr Colin W. M. Chan (email [email protected]).
There has been recent interest in the use of sildenafil, was administered orally following baseline measurements a selective PDE5 (phosphodiesterase-5) inhibitor, which and repeat measurements made after 1 h at 150 m and at has been shown to be effective in reducing pulmonary 1 and 2 h at 3480 m. HR (heart rate), BP (blood pressure), hypertension. Sildenafil has variable vasodilating effects Sao2 (arterial oxygen saturation), Petco2 (end-tidal par- on different vascular beds attributable to the differential tial pressure of CO2), rSo2 (regional cerebral oxygen sat- expression of PDE5 in the endothelium of blood vessels uration) and MCAV (MCA velocity) were recorded with throughout the body. The presence of other synergistic five measurements made at each time point. Subjects were factors is postulated to play a role as well, e.g. the pres- not taking nitrates or any other cardiovascular drugs.
ence of NO (nitric oxide) released from non-cholinergic The side-effect profile was evaluated by direct question- non-adrenergic penile nerve endings, which has been ing of subjects upon completion of the experiment at utilized in the treatment of erectile dysfunction. The pro- 3480 m. The presence of AMS was scored using the Lake found effect of sildenafil in abolishing the rise in pul- Louise self-completed questionnaire .
monary artery pressure during acute hypoxia-induced The Research and Ethics Committee of the South pulmonary hypertension in human and eNOS (endo- Birmingham Health Authority granted approval for the thelial NO synthase)-deficient mice experiments has studies, and subjects gave written informed consent.
raised the potential therapeutic value of sildenafil and itsanalogues . Furthermore, it has been suggested that Cerebral NIRS (near-IR spectroscopy)
sildenafil might prove to be of therapeutic benefit to In the pilot study, continuous non-invasive cerebral NIRS travellers and indigenous populations not well adapted was performed at 150 m using a Critikon 2020 cerebral to altitude in the prevention of pulmonary hypertension redox spectroscope (Johnson and Johnson Medical Ltd).
The dual detector sensor position was standardized to a It has been assumed that PDE5 is distributed widely point over the right fronto-parietal region with sensor throughout the vasculature, including the cerebral vas- margins 3 cm from the midline and 3 cm above the supra- cular bed. Thus sildenafil induces headache and aggrav- orbital crest taking care to avoid the sagittal sinus. A Blue- ates migraine at sea level, suggesting a vasodilatory effect line Tubifast bandage (Seton Healthcare Group) was used despite no demonstrable change having been shown in to keep the sensor in place, and maintained a standard MCA (middle cerebral artery) diameter [4,5]. Immuno- probe pressure. rSo2was derived from the equation: localization studies have demonstrated PDE5 within neu-ronal tissue in rat Purkinje fibres , but the enzyme rSo2 = (oxygenated haemoglobin/total haemoglobin) has not been specifically identified within cerebral blood vessels. To date, sildenafil has not been shown to affectcerebral perfusion. Given its potential value in reducing In the main study at 3480 m, an Invos Adult Cerebral altitude related pulmonary hypertension, we sought to Oximeter (Somanetics; Somanetic Corporation) was used evaluate the effect of sildenafil on cerebral blood flow to measure cerebral oxygenation. Bilateral frontal probes and oxygenation on acute ascent to high altitude and after were positioned and kept in place using Blue-line Tubifast Transcranial Doppler
MATERIALS AND METHODS
Continuous transcranial Doppler assessment of MCAVwas measured by one of two experienced operators using Two studies were performed. The first was a pilot experi- a 2 MHz pulsed-wave, range-gated Doppler ultrasound ment undertaken to assess the cerebrovascular changes at (MultiDop T1; DWL Elektronische Systeme). The right 150 m (Birmingham, United Kingdom) produced by sil- MCA was identified by recognition of the characteristic denafil on six healthy male subjects (age 34–60 years). The waveform and typical flow velocity profile, and was aim of the main study was to evaluate the time depen- insonated at 45–60 mm through the temporal bone dency and acclimatization response to sildenafil and was window. The MCA time-averaged mean velocity (MCAV; carried out in ten healthy subjects (seven male and three female; age 30–65 years) at 1 and 3 days after acute ascentby cable car to 3480 m (Refugio Guide del Cervino,Aosta, Italy). Barometric pressures were 99.1 kPa in Measurement of SaO2, PETCO2, HR and BP
Birmingham, and 66.2 kPa and 66.4 kPa on days 1 and 3 Sao2 and HR were monitored using an Ohmeda Biox respectively, at 3480 m. Five subjects were common to 3740 Pulse Oximeter. Mean BP and Petco2 were mea- sured using a Datex-Ohmeda S/5 portable critical caremonitor. Data were logged either manually (BP, Petco2, Study protocol
HR and Sao2) or input via a multichannel I/O port to Subjects were rested in the supine position for 5 min prior the hard drive of the transcranial Doppler for subsequent to any measurements. Sildenafil (50 mg; Viagra®, Pfizer) Time course effect of sildenafil on systemic parameters and cerebral haemodynamics on days 1 and 3 after arrival
− S.E.M., n = 10. ∗P < 0.05, ∗∗P < 0.01, ∗∗∗P < 0.001 and ∗∗∗∗P < 0.0001 compared with the pre-sildenafil value, as determined by a paired Student t-test. ††P < 0.01 and ††††P < 0.0001 between the 1 and 2 h time points, as determined by a paired Student t-test. ‡‡‡‡P < 0.0001 comparedwith the pre-sildenafil values on day 1, as determined by an unpaired Student t-test.
Estimated cerebral DO2 and RMCA
continued to fall at 2 h. Sao2 increased at 1 h and remained (MCA resistance)
so during the second hour. Petco2 remained unchanged.
MCAV did not change significantly after sildenafil on 2 to the brain is proportional to the product of arterial oxygen content and brain blood flow. Since the day 1 (Figure 1B), but cerebral oxygenation improved at haemoglobin concentration is unlikely to have altered 1 h and continued to rise at 2 h (Figure 1A). The calculated within 3 days and the barometric pressure remained Do2 (Figure 1C) and RMCA (Figure 1D) did not change.
virtually unchanged, an estimate of the cerebral Do On day 3, HR rose at 1 h and then returned to the baseline level at 2 h. Mean BP fell at 1 h and remained soat 2 h. Although Sao2 did not alter at 1 or 2 h compared with pre-sildenafil values, there was a small fall in Petco2 at 2 h. The mean MCAV fell and cerebral oxygenation increased. The calculated Do2 at all time points on day 3 RMCA (resistance units) = mean arterial BP/MCAV.
was reduced compared with day 1 (P < 0.01; Figure 1C).
Following sildenafil, Do2 fell at 2 h on day 3 (35.5 + 2 and RMCA were calculated for individual subjects − 1.2 units; P < 0.05). The baseline RMCA was higher Statistics
− 0.1 units respectively; P < 0.05), but this difference Statistical and graphical analyses were performed using was abolished with sildenafil at 1 and 2 h (Figure 1D).
StatView 5.01 (SAS Institute Inc.) and Deltagraph 5 (SPSS The main side-effect noted was facial flushing in seven Inc. and Red Rock Software) by unpaired and paired subjects of whom five felt that this was mild and the Student’s t tests based on the parametric distribution of remaining two considered this moderately severe. Head- data. Results are expressed as mean values with data ache was noted in three subjects (two subjects had mild − 1 S.D. P values <0.05 were symptoms and one moderately severe but not incapacit- ating). Three subjects experienced mild nasal congestionand two subjects noticed bloodshot eyes although none experienced photophobia. One subject had mildindigestion and one other had mild transient postural In the pilot study, there were no changes in HR DISCUSSION
− 1.4%) before and 1 h after sildenafil Sildenafil is a cGMP-specific phosphodiesterase inhibitor that causes selective vasodilatation through a reduction of On the first day of the main study, there was one intracellular calcium in vascular smooth muscle. This is subject who had a Lake Louise symptom score of 3. There effected by inhibiting PDE5, which prevents the break- was no recorded AMS on day 3. The responses to silden- down of pre-existing cGMP, the second messenger in afil on days 1 and 3 are shown in Table 1. On day 1, there the NO pathway. The presence of raised levels of NO was a rise in the mean HR at 1 h, which then returned to is a prerequisite for PDE5 inhibitors such as sildenafil the baseline level at 2 h. Mean BP was reduced at 1 h and to work, as demonstrated by the prolongation of erectile Effect of acclimatization and sildenafil on rSO2 (A), MCAV (B), DO2 (C) and RMCA (D)
− S.E.M. (single-ended error bars); n = 10. ∗P < 0.01 comparing values at day 1 and day 3 at specified time points; ∗∗P < 0.05 comparing pre-sildenafil with the 2 h time point on day 3; and ∗∗∗P < 0.05 comparing the pre-sildenafil time point on day 1 with that at day 3. Statistical analyses on rSO2and MCAV are shown in Table 1.
function when non-cholinergic non-adrenergic (nitrox- conditions for cerebral hypoxia and have found this idergic) penile nerves are stimulated .
measure to be sensitive and reproducible as well as robust Although the reduction in systemic BP due to the vaso- dilatory effect of sildenafil is modest , there is a signi- A comparison between the rSo2 and MCAV curves ficant reduction in pulmonary arterial pressure in cases in response to sildenafil for 1 day (unacclimatized) and of pulmonary hypertension , presumably due to the 3 days (acclimatized) is shown in Figure 1. On day one, background increase in NO in the pulmonary vasculature sildenafil caused a progressive improvement in cerebral secondary to chronic hypoxia. Thus far, sildenafil has oxygenation at 1 and 2 h. There is a similar rise at 1 h on not been demonstrated to have an effect on cerebral day 3, but this effect appears to plateau at 2 h. This blood flow by transcranial Doppler nor are there any improvement, however, does not appear to be dependent data on the effect of sildenafil on cerebral oxygenation as on cerebral blood flow as there is no change in MCAV on measured by NIRS. The effect of sildenafil on the cerebral day 1 and, paradoxically, a reduction in MCAV on day 3.
vasculature has been postulated but not demonstrated The calculated Do2 (Figure 1C) demonstrates the effect previously . The present study describes the effect of of acclimatization. Do2 is proportionate to the MCAV sildenafil on cerebral blood flow and oxygenation at sea and the Do2 profile follows the changes in MCAV with level and 3480 m. The absence of any change in cerebral sildenafil. The reduction in MCAV on day 3 is likely to oxygenation and blood flow at sea level is consistent with be secondary to the overall improvement in Sao2 and possibly a decrease in Petco2 with acclimatization. At Transcranial Doppler insonation of the MCA is high altitude, the cerebral circulation is exposed to various accurate and reliable in the measurement of cerebral blood competing influences: arterial hypoxaemia is a potent flow  and has been shown to be robust in assessing cerebral vasodilator, whereas arterial hypocapnia is a cerebral haemodynamics under high-altitude conditions potent vasoconstrictor . Both these effects are reflec- . MCAV as measured by transcranial Doppler has a ted in RMCA (Figure 1D) and are modulated by acclimat- linear relationship with cerebral blood flow within a wide ization. In the present study there was an increase in range of flow values as measured by the 133Xe clearance RMCA and a decrease in Do2 with acclimatization that technique . Furthermore, MCAV measurements was overcome by sildenafil. On acute exposure to high under conditions of acute hypobaric hypoxia have been altitude, hypoxia-induced cerebral vasodilatation appears validated against sea-level measurements and are an ac- to override the vasoconstrictor effects of hypocapnia curate indicator of cerebral blood flow and Do2 .
but, by day 3, improved peripheral oxygenation with We have used previously cerebral NIRS under hypobaric acclimatization increased RMCA. In the present field study, an indirect measure of Do2 has been made by calculating Under conditions of high-altitude hypoxia, sildenafil the product of Sao2 and MCAV which are both non- has a positive influence on cerebral oxygenation and an invasive measurements. Calculated Do2 did not take into attenuation of cerebral blood flow. However, our present account any changes in plasma volume that may have study was not designed to establish any therapeutic bene- occurred at altitude, thus changes in Do2 after sildenafil fit from improved cerebral oxygenation. The mechanism by which these effects take place is not currently known The different profiles in the time-course experiment and will need to be investigated further. These findings suggest that there may be multiple mechanisms at work may influence our knowledge of PDE5 localization and and the observed effects of sildenafil when acclimatized direct further studies towards a potentially therapeutic may be intracranial rather than systemic. It may be pos- role for PDE5 inhibitors in the management of cerebral tulated that the improvement in cerebral oxygenation with sildenafil on day 1 may be due, in part, to an in-crease in Sao2. Despite the improvement in Sao2 due to ACKNOWLEDGMENTS
acclimatization, the response to sildenafil on day 3 is notcorrelated with any change in Sao2. This suggests that the We are grateful for the technical assistance of ScanMed improvement in cerebral oxygenation is predominantly Ltd, Datex-Ohmeda for the loan of the S/5 portable intracranial. NIRS provides a measure of the proportion critical care monitor, and to Selly Oak Hospital, of oxygenated blood in the cerebral capillaries. It does Birmingham, U.K. for the loan of a back-up Critikon not distinguish how much is in the arterial or venous part of the capillary bed. The proportion of total blood in thecerebral capillaries has been estimated at 28 % arterial REFERENCES
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Received 26 January 2005/5 April 2005; accepted 3 May 2005Published as Immediate Publication 3 May 2005, doi:10.1042/CS20050036
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