American Society of Exercise Physiologists



Exercise Performance

PHOSPHODIESERTERASE 5 INHIBITORS (SILDENAFIL) to Enhance Altitude EXERCISE Performance?

Robert W Gotshall1

1Health and Exercise Science/Colorado State University, Fort Collins, USA

ABSTRACT

Gotshall RW. Phosphodiesterase 5 Inhibitors (Sildenafil) to Enhance Altitude Exercise Performance? JEPonline 2007;10(3):14-24. Exercise performance is reduced by both acute and chronic exposure to hypobaric hypoxia (altitude). Recently, phosphodiesterase (PDE5) 5 inhibitors have been shown to reduce hypoxic pulmonary vasoconstriction (HPV), and to improve altitude exercise performance. This review provides the background for the concept that HPV potentially plays a role in reduced altitude exercise performance. Additionally, this review critically analyzes the limited number of studies to-date that have used PDE5 inhibitors during acute hypoxia and with hypobaric hypoxia to evaluate exercise performance. Finally, the review addresses interesting physiological and pathophysiological questions that arise from the use of PDE5 inhibition during hypoxic conditions. For example: can PDE5 inhibition reduce the incidence and/or severity of high altitude pulmonary edema and other serious altitude illnesses? How does relieving HPV with PDE5 inhibition result in improved altitude performance?

Key Words: Hypoxia, hypoxic pulmonary vasoconstriction, sildenafil, acclimatization, altitude illness

TABLE OF CONTENTS

ABSTRACT------------------------------------------------------------------------------------------------------------ 1

1. INTRODUCTION ------------------------------------------------------------------------------------------------- 2

2. Phosphodiesterase 5 Inhibitors------------------------------------------------------------------ 3

3. PDE5 INHIBITORS AND HYPOXIC PULMONARY VASOCONSTRICTION (HPV) ------------ 3

4. PDE5 INHIBITORS AND HYPOXIC/ALTITUDE EXERCISE PERFORMANCE ----------------- 4

4.1 HPV Relief and Exercise Performance----------------------------------------------------------- 4

5. SUMMARY---------------------------------------------------------------------------------------------------------- 8

REFERENCES-------------------------------------------------------------------------------------------------------- 9

INTRODUCTION

Reduced submaximal and maximal exercise tolerance during both acute altitude (hypobaric hypoxia) exposure and after altitude acclimatization have long been the subject of interest for scientists and those who sojourn to altitude (1,2,1,3). The principal goals of this longstanding interest are the attempt to understand the underlying physiology and to produce a “treatment” that will return altitude performance back toward sea level performance. Physiologically, the main limiting factor(s) for performance at altitude remains unclear (4), but involves some aspect(s) of the pulmonary, cardiovascular and muscular adaptations to altitude (4). The decrement in performance with acute and chronic altitude exposure for low-altitude residents is well demonstrated by the classic decline in VO2max associated with ascent to altitude (1) (Figure 1, adapted from Fulco et al. (1)). One important physiological challenge induced by hypoxia and associated with ascent to altitude is hypoxic pulmonary vasoconstriction (HPV) (5). HPV may reduce exercise performance by increasing pulmonary arterial pressure, increasing right ventricular afterload and decreasing or limiting cardiac output. Additionally, HPV potentially exacerbates the decrements in oxygen saturation and delivery by causing heterogeneous or “patchy” pulmonary vasoconstriction leading to an uncoupling of ventilation-perfusion. Therefore, reducing HPV in hypoxia or sojourn to altitude might improve cardiac output, oxygen diffusion and delivery thereby enhancing exercise performance. Another issue regarding HPV and increased pulmonary arterial pressure at altitude is the recognized casual relationship of HPV to the development of high-altitude pulmonary edema (HAPE), and therefore the potential of alleviating HPV for prevention and treatment of HAPE (6,7,8).

Several recent investigations have evaluated alleviating HPV during hypoxia or altitude exposure with sildenafil (a phosphodiesterase 5 inhibitor) to determine the effect on exercise performance. The purpose of this review is to critically analyze these investigations using sildenafil with regard to: 1) potential “treatment” for altitude-induced hypo-performance; 2) magnitude of effect; 3) new insights as to altitude physiology; and, (4) potential risks associated with the treatment. This review is timely because of the public interest in immediately extrapolating research results and employing treatments without fully understanding benefits and risks.

Phosphodiesterase 5 Inhibitors

Phosphodiesterase 5 (PDE5) inhibitors have transformed the treatment of erectile dysfunction (ED) (9). PDE5 inhibition leads to accumulation and increased activity of cyclic guanosine monophosphate (cGMP), which enhances the vascular dilatory actions of nitric oxide (10). Sildenafil citrate [Viagra™] was the first PDE5 inhibitor agent developed for men with ED. Other PDE5 inhibitor drugs (tadalafil [Cialis™] and vardenafil [Levitra™]) are now on the market. Sildenafil began as a potential alternative agent to oral nitrates for treatment of stable angina pectoris; but its short half life and modest nitrate-like hemodynamic effects were not seen as a clinical advantage over nitrates. The development of sildenafil for ED began after men taking sildenafil reported improved erections. However, the original vasodilator and subsequent hemodynamic properties of PDE5 inhibitors have now resulted in renewed interest in PED5 inhibitors to treat other vascular conditions, such as pulmonary hypertension (11,12,13). Subsequently, the success of sildenafil in treating pulmonary hypertension has led to investigations of sildenafil in resolving hypoxic pulmonary vasoconstriction (HPV) associated with ascent to altitude (14).

PDE5 INHIBITORS AND HYPOXIC PULMONARY VASOCONSTRICTION (HPV)

Clinically, PDE5 inhibitors, and specifically sildenafil (11,15,16,17,18,19,20) and vardenafil (21), have demonstrated potency in relieving pulmonary hypertension through vasodilation of pulmonary arteries. This efficacy led to the proposed use of PDE5 inhibitors in acute hypoxia-induced pulmonary vasoconstriction in healthy subjects (14,22,23,24,25).

Zhao et al. (14) were the first to investigate PDE5 inhibition (sildenafil) administration in healthy subjects at rest to determine the effect on acute HPV. Ten healthy male volunteers aged 18 to 27 were evaluated in a randomized double-blind study (at 760 meters above sea level). Pulmonary artery pressures (PAP) were determined via a Swan-Ganz catheter. Oxygen saturations (O2SAT) were determined by pulse oximeter, along with heart rate (HR) and blood pressure (BP) Sildenafil (100mg) or placebo was administered one hour prior to the hypoxic exposure (FIO2 = 0.11 for 30 minutes). The results are summarized in Table 1.

Table 1. Summary of Data from Zhen et al. (14).

|Baseline |Hypoxia + Placebo |Baseline |Hypoxia + Sildenafil | |O2SAT % |99 |65 |99 |65 | |PAP

systolic ,mm Hg |

25 |

39 |

27 |

30 | | mean, mm Hg |16 |25 |16 |18 | | | | | | | |Systemic BP

systolic, mm Hg |112 |110 |112 |106 | | diastolic, mm Hg |67 |59 |69 |58 | |HR, bpm |67 |95 |62 |82 | |

Red text indicates significantly different from hypoxia + placebo.

Thus, in this study, sildenafil did not alter O2SAT but did reduce the PAP to normoxic baseline values. The reduction in HR with sildenafil most likely reflects the reduced PAP effect on homodynamics as Sildenafil did not alter systemic pressures.

Interestingly, in this same study (14), mice were used to examine the chronic effects of hypoxia and sildenafil. Sildenafil was again effective in reducing, but not normalizing, the pulmonary pressures; and also attenuated the right ventricular hypertrophy and pulmonary vascular remodeling associated with chronic hypoxia and increased PAP.

More recently, Preston and colleagues (19) used a healthy rat model to investigate acute and chronic HPV and PDE5 inhibition, along with atrial natriuretic peptide (ANP). Both PDE5 inhibition and ANP act to increase intracellular cGMP, a second messenger that mediates pulmonary vascular relaxation. Thus, both interventions were expected to increase cGMP and blunt HPV. These results demonstrated effectiveness of both sildenafil and ANP on reducing HPV, with a synergistic effect when the two compounds were combined (19). Chronic dosing (21 days) of rats with sildenafil during chronic hypoxia (0.5 atm) exposure was effective in reducing HPV.

These studies, along with others (22,23,24,25), indicate PDE5 inhibition to be effective in ameliorating HPV in animals and humans. These studies addressed HPV in resting subjects. The question of importance to this review is the effectiveness of relieving HPV and improving exercise performance during hypoxia.

PDE5 INHIBITORS AND HYPOXIC/ALTITUDE EXERCISE PERFORMANCE

HPV Relief and Exercise Performance

In 2005, Ghofrani et al. (26) examined the influence of PDE5 inhibition on HPV and exercise performance during both acute hypoxia at sea level and chronic hypobaric hypoxia at the base camp on Mount Everest. In a randomized, placebo-controlled, crossover design, healthy altitude-experienced subjects underwent hypoxic resting and exercise testing at low altitude (acute hypoxia) and again after 8 days traveling to and during 6 days at 5245 m (chronic hypobaric hypoxia).

Systolic pulmonary arterial pressure was measured using Doppler echocardiography along with arterial oxygen saturation, and cardiac output (gas-rebreathing). For the acute studies, hypoxia was induced by mask using an FIO2 of 10% for two hours. Measurements at rest and during incremental cycle (semi-supine) ergometer exercise to maximum were obtained. PDE5 inhibition was accomplished with 50 mg of sildenafil 2 hours prior to resting and exercise measurements. The data are significant and are summarized in the figures 2 and 3 that are adapted from their data (26). These two figures demonstrate that in both acute and chronic hypoxia, sildenafil reduced HPV and improved exercise performance. Oxygen saturations during exercise were improved by sildenafil during acute hypoxia, but not at altitude. Underlying these physiological effects was a positive improvement in maximal cardiac output in both hypoxic conditions. While the mechanism of improved work capacity is not clearly defined, it is strongly suggestive that ameliorating HPV reduces right heart afterload and improves maximal cardiac output. This represents a new emerging concept in understanding reduced exercise performance at altitude.

Of note is the fact that sildenafil (at this dose) did not restore either pulmonary artery pressures or work capacity to normoxic levels in either hypoxic condition. However, the improvements in work capacity of about 32% on average during acute hypoxia and of 11% at altitude are functionally important. While non-pulmonary effects of sildenafil may have contributed to the results demonstrated, systemic pressures were unaffected. The potential impact of sildenafil on normoxic exercise was not determined in this study.

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One question that arises from this study is the relative effect of sildenafil at lower altitudes than the extremes investigated. Most sojourns occur at lower altitudes than the extremes of 5,400 m. In contrast, what would the effect be at the very extreme altitudes above 5,400 m where exercise capacity is dramatically reduced? Six to eight days at altitude represents acute acclimatization. What effect would PDE5 inhibition have after chronic acclimatization (>6 weeks)? In addition, the issue of whether or not improving HPV at altitude can improve ventilation-perfusion mismatch and thereby SaO2, either at rest or with exercise, remains open. In this study by Ghofrani et al. (26), there was improved exercise SaO2 with sildenafil, but primarily only during acute hypoxia.

Richalet et al. (27) addressed the issue of ventilation-perfusion mismatch at altitude, and oxygenation at altitude, using sildenafil to relieve HPV. Additionally, they measured exercise performance. Twelve healthy, unacclimatized, moderately trained, male subjects participated in sea level (60 m) control and six-day altitude (4,350 m) exposure. The design was a randomized double-blind placebo-controlled study. The dose of sildenafil used was 40 mg. Pulmonary artery pressure was assessed with Doppler echocardiography. Cardiac output was calculated from both Doppler echocardiography and impedance cardiographic measurements. Treatment was initiated after altitude control measures upon arrival at altitude and was taken three times per day thereafter until the conclusion of the experiment.

During resting conditions at altitude, sildenafil improved SaO2 and PaO2 by day 3 through day 6, but not to sea level values. Additionally, sildenafil lowered pulmonary artery pressures, from day 2 through day 6, to sea level values. Maximal oxygen uptake was decreased during altitude and improved with sildenafil, by about 29%. As shown in figure 5 (adapted from Richalet et al. (27)) maximal oxygen uptake improved with acclimatization, and sildenafil significantly improved VO2 max on each day of measurement. Cardiac outputs, rest or exercise, were not affected by treatment.

Submaximal exercise measurements were accomplished during the maximal tests and taken at the ventilatory threshold. Sildenafil significantly improved PaO2 values both at rest and during exercise. Cardiac outputs were not changed by treatment. Thus, in summary, sildenafil improved pulmonary hemodynamics, oxygenation and work capacity at altitude in this study, while systemic hemodynamics remained unaffected. Work capacity was not restored to sea level values, but was significantly improved with sildenafil. In comparing work capacity for day 2 versus day 5, sildenafil provided a greater improvement than did the acute acclimatization.

Two recent studies have examined the effects of sildenafil on exercise performance during acute hypoxia (28,29). In the first, Ricart et al. (28) exposed 14 healthy volunteers to simulated altitude of 5000 m in a hypobaric chamber over about a 90-minute period. Subjects served as their own control on different days. Sildenafil, or placebo, was administered orally as a 100 mg dose, 45 minutes prior to entering the altitude chamber. Echocardiography was used to measure pulmonary artery pressures and cardiac ejection fraction before and immediately after five minutes of exercise at ~50% of maximal exercise capacity. Sildenafil was effective at lowering pulmonary artery pressures during hypoxia (there was no effect during normoxia) at rest and immediately after exercise. SaO2 was not altered by sildenafil during normoxia or at rest in hypoxia. However, there was a slight but significant improvement in SaO2 during hypoxic exercise. There were no other remarkable findings. Thus, this study provides further support for sildenafil as an agent to reduce HPV. But, there are few data within this study to indicate the impact on exercise performance per se, other than a very small improvement in oxygen saturations during hypoxic exercise. The hypoxic exposures used were short (only 5 minutes prior to resting measurements) in comparison to other studies. Additionally, the exercise regimen was also very short (5 minutes) and the post-exercise measurements (supine) are not likely reflecting the true exercise hemodynamic picture.

The study by Hsu et al. (29) perhaps provides more useful information as to hemodynamic effects of sildenafil during hypoxia and exercise. Ten healthy subjects were randomly exercise tested during normoxia and during hypoxia (FIO2 = 0.128), before and again after 50 or 100 mg of sildenafil. Cycle ergometer exercise consisted of a set work rate (55% peak watts, adjusted for sea level (SL) and hypoxia peak watts) for one hour (SL) or 30 minutes (hypoxia), and followed by a time-trial performance test (10 km at SL, 6 km for hypoxia) on a stationary bike. Pulmonary, metabolic and cardiovascular measurements were determined throughout. Pulmonary artery pressures were not determined.

Sea level (normoxia) values at rest or with exercise were unchanged by either dose of sildenafil. Time trial times were likewise unchanged. Subjects did not desaturate hemoglobin during normoxic exercise. In contrast, during hypoxia, both doses of sildenafil had significant impact on oxygenation, cardiovascular, and performance measures. There were no apparent added benefits of 100 mg of sildenafil over the 50 mg dose, so results are presented for the 50 mg dose. With hypoxia, subjects did desaturate hemoglobin further during exercise. Sildenafil increased SaO2 both at rest and during exercise by about 5%. Exercise cardiac output was improved by about 20% with sildenafil.

Time trial performance for the 6 km during hypoxia was improved by about 15% with sildenafil (from about 12.8 minutes to 11 minutes). Based on the average data across all subjects, sildenafil provided significant performance benefits during hypoxia. Using the study data for the time trial, the pace at SL for 10 km was ~ 1.65 min/m. During hypoxia the pace dropped to ~ 2.13 min/m, and improved to ~1.83 min/m with sildenafil. This is a very good improvement in performance. Figure 6 summarizes some of the interesting performance data from this study (29).

Interestingly, six subjects in the study (29) did not improve their time trial performance (~1.0% improvement) during hypoxia with sildenafil, four subjects did improve (~39% improvement). Thus, there were those who responded to the sildenafil treatment, and those who did not, based on performance. The authors evaluated various variables during the set rate exercise period to determine any characteristics that would provide insight into this separation of responders and non-responders to sildenafil. Sildenafil responders had greater drug induced increases in cardiac output and stroke volume during the hypoxic set rate exercise. Responders also demonstrated greater hypoxia induced decrements in stroke volume at rest. This might imply greater HPV and reduced cardiac filling. Thus, perhaps, with the greater HPV, there was a greater hemodynamic response to sildenafil. However, HPV was not measured in this study. Future studies should make note that not all subjects may respond the same to sildenafil treatment.

SUMMARY

Table 2 presents summary information from the hypoxia/altitude studies giving an overview of the significant outcomes related to HPV and the exercise capacity effects of sildenafil. All differences are expressed as sildenafil from the placebo effect under the same conditions. All measured differences are during the exercise, unless noted otherwise.

Prior to these few studies regarding PDE5 inhibition and altitude exercise performance, the two major interventions that improved altitude exercise performance were supplemental oxygen and acclimatization. Based on the cited investigations, PDE5 inhibition has promise as an intervention for HPV and for the improvement of hypoxic/altitude exercise performance. In general, exercise

performance during both acute hypoxia and hypoxic/altitude exposures (for up to a week) has

benefited from PDE5 inhibition. Hypoxic pulmonary artery pressures have been lowered by PDE5

Table 2. Overview of sildenafil studies on cardiopulmonary variables and exercise capacity during hypoxia/altitude exposures.

Study |Exposure |Dosage |Exercise |Difference

PAP |Difference

O2SAT |Difference Cardiac Output |Difference

Work Capacity | |Ghofrani et al. (26) |6 da @ 5,245 m |50 mg,

2 h prior |Incremental cycling to max |-18% |0%

|+19% |+11%

(peak watts) | |Richalet et al. (27) |6 da @ 4,350 m |40 mg, 3x’s/da |Incremental cycling to max |-27%

*at rest |+9%

|0% |+29%

(VO2max) | |Ghofrani et al. (26) |10% FIO2 for 2 h |50 mg,

2 h prior |Incremental cycling to max |-16%

|+10%

|+16% |+32%

(peak watts) | |Ricart et al. (28) |5000 m hypobaric chamber for ~90 min |100 mg,

~1 h prior |50% max for 5 min; absolute workload same for normoxia and hypoxia |-12%

|+2%

|na |na | |Hsu et al. (29) |12% FIO2 for ~90 min |50 mg and 100 mg trials,

1 h prior; results for 50 mg here

|5 min cycling at 55% of max; and 10 km time trial |na |+5%

|+20% |+15%

(time trial performance) | |PAP, pulmonary artery pressure; O2SAT, arterial oxygen saturation.

inhibition both at rest and during exercise. Some indicators of oxygenation have shown improvement with PDE5 inhibition during hypoxic conditions, particularly during exercise. However, in all instances described in this review, exercise performance was not returned to normoxic values by PDE% inhibition. This is not remarkable as low PIO2 and PaO2 result in reduced driving forces for tissue diffusion of oxygen in hypoxic settings such as altitude. Improvement in exercise performance with PDE5 inhibition after acute altitude acclimatization was greater than the improvement seen in performance after acute altitude acclimatization alone. This observation demonstrates that even with acute altitude acclimatization, performance improvements can be expected with the proper intervention to improve cardiopulmonary function (and perhaps skeletal muscle function). Comparable studies from chronic altitude acclimatization studies remain to be conducted.

Several important issues for future study arise from these early data. What is the role of HPV in the reduction in human performance during hypoxia and sojourn to altitude? Both acute HPV and chronic HPV during periods of altitude acclimatization are of interest. Additionally, both pulmonary and cardiovascular effects of HPV under these hypoxic circumstances are important to understand in order to elucidate underlying mechanisms of action. Ventilation-perfusion matching and diffusion capacity have potential to be altered during HPV. Cardiac output may be suppressed by the high pulmonary pressures and right heart function limited by chronic exposure to hypoxia. The use of PDE5 inhibition may provide a tool to elucidate the contributions of HPV to cardiac function at altitude. Additionally, the systemic effects of PDE5 during these hypoxic conditions should be determined, especially during exercise. Limited skeletal muscle blood flow with exercise during chronic altitude exposure has been proposed as an important contributor to reduced exercise capacity at altitude(30). Will PDE5 inhibition improve blood flow distribution under these circumstances?

With specific regard to the use of PDE5 inhibition, dose and dosing regimens are issues to be optimized. Will other PDE5 inhibitors with longer half lives (e.g. tadalafil) be more effective? What role will PDE5 inhibition play in reducing or eliminating altitude illnesses such as acute mountain sickness, high altitude pulmonary edema, or high altitude cerebral edema(31)?

PDE5 inhibitors are regulated medications and have potential serious side effects. Thus, use is not recommended without a physician’s prescription. Considering the wide availability of PDE5 inhibitors without a prescription, special care in unmonitored use must be taken. For mountaineers and hikers, acclimatization remains the best proven way to reduce altitude illnesses and to improve altitude performance to date. PDE5 inhibition provides a novel tool for researchers to investigate hypoxia/altitude physiology and pathophysiology to help unravel some of the remaining mysteries.

Address for correspondence: Robert W. Gotshall, Ph.D., Department of Health and Exercise Science, Colorado State University, Fort Collins, Colorado, US, 80523-1582. Phone (970) 491-6374, FAX: (970)491-0445; Email. gotshall@cahs.colostate.edu.

REFERENCES

1. Fulco CS, Rock PB and Cymerman A. Maximal and submaximal exercise performance at altitude. Aviat Space Environ Med 1998;69:793-801.

2. Wehrlin JP and Hallen J. Linear decrease in VO2max and performance with increasing altitude in endurance athletes. Eur J Appl Physiol 2006;96:404-412.

3. Wagner PD, Sutton JR, Reeves JT, Cymerman A, Groves BM and Malconian MK. Operation Everest II: pulmonary gas exchange during a simulated ascent of Mt. Everest. J Appl Physiol 1987;63:2348-2359.

4. West JB. Limiting factors for exercise at extreme altitudes. Clin Physiol 1990;10:265-272.

5. Moudgil R, Michelakis ED and Archer SL. Hypoxic pulmonary vasoconstriction. J Appl Physiol 2005;98:390-403.

6. Kleinsasser A and Loeckinger A. Are sildenafil and theophylline effective in the prevention of high-altitude pulmonary edema? Med Hypotheses 2002;59:223-225.

7. Hackett P and Rennie D. High-altitude pulmonary edema. JAMA 2002;287:2275-2278.

8. Maggiorini M, Melot C, Pierre S, Pfeiffer F, Greve I, Sartori C, Lepori M, Hauser M, Scherrer U and Naeije R. High-altitude pulmonary edema is initially caused by an increase in capillary pressure. Circulation 2001;103:2078-2083.

9. DeBusk RF, Pepine CJ, Glasser DB, Shpilsky A, DeRiesthal H and Sweeney M. Efficacy and safety of sildenafil citrate in men with erectile dysfunction and stable coronary artery disease. Am J Cardiol 2004;93:147-153.

10. Wilkins MR and Wharton J. Progress in, and future prospects for, the treatment of primary pulmonary hypertension. Heart 2001;86:603-604.

11. Ghofrani HA, Osterloh IH and Grimminger F. Sildenafil: from angina to erectile dysfunction to pulmonary hypertension and beyond. Nat Rev Drug Discov 2006;5:689-702.

12. Singh TP, Rohit M, Grover A, Malhotra S and Vijayvergiya R. A randomized, placebo-controlled, double-blind, crossover study to evaluate the efficacy of oral sildenafil therapy in severe pulmonary artery hypertension. Am Heart J 2006;151:851-855.

13. Galie N, Ghofrani HA, Torbicki A, Barst RJ, Rubin LJ, Badesch D, Fleming T, Parpia T, Burgess G, Branzi A, Grimminger F, Kurzyna M and Simonneau G. Sildenafil citrate therapy for pulmonary arterial hypertension. N Engl J Med 2005;353:2148-2157.

14. Zhao L, Mason NA, Morrell NW, Kojonazarov B, Sadykov A, Maripov A, Mirrakhimov MM, Aldashev A and Wilkins MR. Sildenafil inhibits hypoxia-induced pulmonary hypertension. Circulation 2001;104:424-428.

15. Karatza AA, Bush A and Magee AG. Safety and efficacy of Sildenafil therapy in children with pulmonary hypertension. Int J Cardiol 2005;100:267-273.

16. Malhotra S and Punia VP. Oral Sildenafil in the management of primary pulmonary hypertension. J Assoc Physicians India 2004;52:670-672.

17. Montgomery GS, Sagel SD, Taylor AL and Abman SH. Effects of sildenafil on pulmonary hypertension and exercise tolerance in severe cystic fibrosis-related lung disease. Pediatr Pulmonol 2006;41:383-385.

18. Preston IR, Klinger JR, Houtches J, Nelson D, Farber HW and Hill NS. Acute and chronic effects of sildenafil in patients with pulmonary arterial hypertension. Respir Med 2005;99:1501-1510.

19. Preston IR, Hill NS, Gambardella LS, Warburton RR and Klinger JR. Synergistic effects of ANP and sildenafil on cGMP levels and amelioration of acute hypoxic pulmonary hypertension. Exp Biol Med (Maywood ) 2004;229:920-925.

20. Tsai BM, Turrentine MW, Sheridan BC, Wang M, Fiore AC, Brown JW and Meldrum DR. Differential effects of phosphodiesterase-5 inhibitors on hypoxic pulmonary vasoconstriction and pulmonary artery cytokine expression. Ann Thorac Surg 2006;81:272-278.

21. Aizawa K, Hanaoka T, Kasai H, Kogashi K, Kumazaki S, Koyama J, Tsutsui H, Yazaki Y, Watanabe N, Kinoshita O and Ikeda U. Long-term vardenafil therapy improves hemodynamics in patients with pulmonary hypertension. Hypertens Res 2006;29:123-128.

22. Aldashev AA, Kojonazarov BK, Amatov TA, Sooronbaev TM, Mirrakhimov MM, Morrell NW, Wharton J and Wilkins MR. Phosphodiesterase type 5 and high altitude pulmonary hypertension. Thorax 2005;60:683-687.

23. Fesler P, Pagnamenta A, Rondelet B, Kerbaul F and Naeije R. Effects of sildenafil on hypoxic pulmonary vascular function in dogs. J Appl Physiol 2006;101:1085-1090.

24. Hanasato N, Oka M, Muramatsu M, Nishino M, Adachi H and Fukuchi Y. E-4010, a selective phosphodiesterase 5 inhibitor, attenuates hypoxic pulmonary hypertension in rats. Am J Physiol 1999;277:L225-L232.

25. Zhao L, Mason NA, Strange JW, Walker H and Wilkins MR. Beneficial effects of phosphodiesterase 5 inhibition in pulmonary hypertension are influenced by natriuretic Peptide activity. Circulation 2003;107:234-237.

26. Ghofrani HA, Reichenberger F, Kohstall MG, Mrosek EH, Seeger T, Olschewski H, Seeger W and Grimminger F. Sildenafil increased exercise capacity during hypoxia at low altitudes and at Mount Everest base camp: a randomized, double-blind, placebo-controlled crossover trial. Ann Intern Med 2004;141:169-177.

27. Richalet JP, Gratadour P, Robach P, Pham I, Dechaux M, Joncquiert-Latarjet A, Mollard P, Brugniaux J and Cornolo J. Sildenafil inhibits altitude-induced hypoxemia and pulmonary hypertension. Am J Respir Crit Care Med 2005;171:275-281.

28. Ricart A, Maristany J, Fort N, Leal C, Pages T and Viscor G. Effects of sildenafil on the human response to acute hypoxia and exercise. High Alt Med Biol 2005;6:43-49.

29. Hsu AR, Barnholt KE, Grundmann NK, Lin JH, McCallum SW and Friedlander AL. Sildenafil improves cardiac output and exercise performance during acute hypoxia, but not normoxia. J Appl Physiol 2006;2031-2040.

30. Calbet JA, Boushel R, Radegran G, Sondergaard H, Wagner PD and Saltin B. Determinants of maximal oxygen uptake in severe acute hypoxia. Am J Physiol Regul Integr Comp Physiol 2003;284:R291-R303.

31. Chan CW, Hoar H, Pattinson K, Bradwell AR, Wright AD and Imray CH. Effect of sildenafil and acclimatization on cerebral oxygenation at altitude. Clin Sci (Lond) 2005;109:319-324.

Disclaimer

The opinions expressed in JEPonline are those of the authors and are not attributable to JEPonline, the editorial staff or ASEP.

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Journal of Exercise Physiologyonline

(JEPonline)

Volume 10 Number 3 June 2007

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Managing Editor

Robert Robergs, Ph.D.

Editor-in-Chief

Jon Linderman, Ph.D.

Review Board

Todd Astorino, Ph.D.

Julien Baker, Ph.D.

Tommy Boone, Ph.D.

Lance Dalleck, Ph.D.

Dan Drury, DPE.

Hermann Engels, Ph.D.

Eric Goulet, M.Sc.

Robert Gotshall, Ph.D.

Knight-Maloney, Mellisaa, Ph.D.

Len Kravitz, Ph.D.

James Laskin, Ph.D.

Jon Linderman, Ph.D.

Melissa Knight-Maloney, Ph.D.

Derek Marks, Ph.D.

Cristine Mermier, Ph.D.

Daryl Parker, Ph.D.

Robert Robergs, Ph.D.

Brent Ruby, Ph.D.

Jason Siegler, Ph.D.

Greg Tardie, Ph.D.

Lesley White, Ph.D.

Chantal Vella, Ph.D.

Thomas Walker, Ph.D.

Ben Zhou, Ph.D.

Official Research Journal of The American Society of Exercise Physiologists (ASEP)

ISSN 1097-9751

Figure 1. Percent decrease in maximal oxygen uptake with gain in altitude.

Figure 2. Pulmonary artery pressures.

Figure 3. Oxygen saturations and exercise capacity.

!"#$ Figure 5. Changes in VO2 max with day at altitude on placebo or sildenafil treatment. (D2, altitude day 2; D5, altitude day 5; SL, return to seal level.)

Figure 6. Percent change in hypoxic exercise performance variables (time trial and set rate exercise), sildenafil vs. placebo.

* indicates significance.

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