Efficacy Study of Riociguat and Its Effects on Exercise Performance and Pulmonary Artery Pressure at High Altitude
Efficacy Study of Riociguat and Its Effects on Exercise Performance and Pulmonary Artery Pressure at High Altitude
During ascent to high altitude there is a physiologic response to hypoxia that results in an
 elevated pulmonary arterial pressure associated with decreased exercise performance,
 altitude-induced pulmonary hypertension, and high altitude pulmonary edema (HAPE). Riociguat
 is a novel agent from Bayer Pharmaceuticals that has already demonstrated effectiveness in
 the treatment of pulmonary hypertension, and it may prove to be beneficial in cases of
 altitude-induced pulmonary hypertension or HAPE. This research study, composed of 20 healthy
 volunteers ages 18-40 years, will attempt to mimic the decreased oxygen supply and elevated
 pulmonary artery pressures found in conditions of high altitude, allowing observation of the
 effects of riociguat and exercise on pulmonary arterial pressure, arterial oxygenation, and
 exercise performance. Prior to entering the hypobaric chamber, subjects will have radial
 arterial lines and pulmonary artery catheters placed to obtain arterial and pulmonary artery
 pressure measurements. Subjects will then enter the hypobaric chamber and perform exercise
 tolerance tests at a simulated altitude of 15,000 feet on an electrically braked ergometer
 (exercise bike) before and after administration of riociguat. If, after administration of
 riociguat and exposure to a simulated altitude of 15,000 feet, the exercise performance is
 improved and observed pulmonary artery pressures are lower than those measurements seen prior
 to administration of riociguat, this could lead to development of a prophylactic and/or
 treatment strategy for HAPE and high-altitude pulmonary hypertension. Statistical analysis
 will compare the variables of pulmonary artery pressure, radial arterial pressure,
 ventilation rate, cardiac output, PaO2, and work rate at exhaustion before and after
 administration of the drug riociguat. The investigator's hypothesis is that riociguat will
 decrease pulmonary artery pressure and improve gas exchange and exercise performance at
 altitude.
Background and Significance:

 Impairment of exercise performance during hypoxemia due to altitude exposure or lung disease
 is caused primarily by reduced oxygen delivery to the exercising muscles, due to the
 reduction in arterial oxygen content. This reduction in arterial oxygen content is due to
 reduced alveolar PO2 and ventilation/perfusion (VA/Q) mismatch, and to some extent alveolar
 to end-capillary diffusion impairment. Ultimately, hypoxemia results in secondary diffuse
 pulmonary vasoconstriction (hypoxic pulmonary vasoconstriction, HPV), which in turn causes
 pulmonary hypertension. This secondary pulmonary hypertension is believed to worsen VA/Q
 mismatch, further reducing the PO2, suggesting that pharmacologic blockade of HPV could
 increase PO2 (e.g. during altitude exposure) and thus improve exercise performance. Reduction
 in pulmonary artery pressure (PAP) in individuals susceptible to high altitude pulmonary
 edema (HAPE) could also facilitate both prevention and treatment of HAPE.

 Sildenafil is commonly used to treat pulmonary hypertension, including pulmonary hypertension
 that occurs due to altitude exposure, with variable success in treating cases of
 altitude-induced pulmonary hypertension and HAPE. Sildenafil works via blockade of blocks
 phosphodiesterase-5 (PDE-5) in pulmonary arterioles, causing an increase in cGMP. When cGMP
 is activated by nitric oxide (NO) it induces vasodilatation, and indeed, sildenafil
 administration during altitude exposure does increase arterial oxygenation slightly. However,
 attempting to block HPV with sildenafil by using a pathway that requires NO can only be
 realized if there is sufficient NO available to produce cGMP. During hypoxia endogenous
 levels of NO are depleted due to impaired endothelial NO synthesis. This may explain the
 inconsistent effects of sildenafil when used to improve oxygenation and performance at
 altitude.

 Endogenous concentration of unbound NO is actually quite low, and most of the biological
 effects of NO are mediated through formation of S-nitrosothiols (SNOs) such as
 S-nitrosohemoglobin (SNO-Hb). NO binds to hemoglobin in a PO2-dependent manner, forming
 SNO-Hb so that when PO2 is low, NO-Hb binding is less avid and SNO-Hb is depleted. Depletion
 of SNO-Hb during hypoxia has been proposed as a mechanism that augments HPV, and indeed
 hypoxia has been shown to induce low levels of SNO-Hb. It is quite possible that the
 reduction in available endogenous NO and depletion of SNO-Hb during hypoxia limits the effect
 of the cGMP mechanism by which sildenafil works. Thus, an agent which can activate cGMP
 during periods of hypoxia when NO and SNO-Hb are depleted should be more effective in
 treating altitude-induced pulmonary hypertension.

 Riociguat is a stimulator of soluble guanylate cyclase that bypasses the NO pathway and is
 currently approved by the FDA for treatment of pulmonary hypertension. Riociguat exhibits a
 dual mode of action that i.) stabilizes the reduced form of the nitrosyl-heme complex,
 enhancing the NO-cGMP signaling pathway in the absence of endogenous NO and ii.) acts in
 synergy with endogenous NO by increasing sGC sensitivity to NO. Essentially, riociguat
 stimulates sGC to produce cGMP in the absence of NO, and it is a mechanism by which pulmonary
 vascular resistance could be attenuated during altitude-induced pulmonary hypertension. It
 has recently been shown to augment exercise performance and decrease pulmonary artery
 pressure in both primary pulmonary hypertension and pulmonary arterial hypertension (PAH) due
 to chronic thromboembolic disease. Lowering pulmonary artery pressure could improve pulmonary
 gas exchange and performance at altitude, which has significant implications for those living
 at altitude, conducting military operations, altitude trekkers and high-altitude rescue
 teams. Direct stimulation of sGC also represents a promising alternative therapeutic strategy
 for those susceptible to high altitude pulmonary edema (HAPE) when current treatment
 modalities of nifedipine and sildenafil are ineffective and oxygen is unavailable. By itself
 or in combination with sildenafil, riociguat could produce a significant advance in exercise
 performance during altitude exposure and provide a substantial improvement over the current
 therapeutic options in the prevention and treatment of HAPE.

 Design and Procedures:

 This investigation will consist of 20 normal subjects. Medical screening will exclude cardiac
 and pulmonary disease, pregnancy and sickle cell disease/trait in African Americans.

 Subjects will be instrumented with radial arterial lines and pulmonary artery catheters and
 will perform a VO2 max test on a bicycle ergometer in a hypobaric chamber at a simulated
 altitude of 15,000 feet.

 Following the VO2 max test, subjects will return to ground level for a 3-hour rest period. At
 90 minutes subjects will be administered riociguat 0.5 mg or 1.0 mg orally. Once study
 subjects are at therapeutic levels of riociguat (30 to 90 minutes after oral administration),
 they will repeat the VO2 max test at 15,000 feet. The dosing of riociguat will start at the
 lowest recommended individual dose (0.5 mg) for the first three subjects. If there are no
 side effects and no clinically important difference in either PAP (5 mmHg decrease in mean
 PAP) or PaO2 (5 mmHg increase) during exercise, then for the remaining subjects the dose will
 be increased to 1.0 mg.

 During the incremental exercise test arterial and mixed blood samples will be analyzed for
 PO2, PCO2, pH, O2 saturation and hemoglobin. Exhaled gas will be collected continuously and
 analyzed for O2 and CO2 concentrations and exhaled volume. Cardiac output will be calculated
 using Fick. Pulmonary and systemic vascular resistances will be calculated from the cardiac
 output and intravascular pressures.

 Outcome measures will be VO2max, maximum mechanical work rate, pulmonary and systemic
 arterial pressures, cardiac output, oxygen delivery and arterial blood gases.

 Benefits:

 Further understanding of the mechanism of hypoxic pulmonary vasoconstriction will aid in
 prognosis and treatment in conditions of increased pulmonary vascular resistance such as
 congenital heart disease, pulmonary arterial hypertension, and COPD, in addition to
 high-altitude pulmonary hypertension and high-altitude pulmonary edema (HAPE). Furthermore,
 the current treatment modalities for HAPE have demonstrated variable and/or limited
 effectiveness, so riociguat could potentially be used to prevent or treat HAPE in susceptible
 individuals. Additionally, riociguat could substantially improve exercise performance in
 those who must operate in conditions of high-altitude, such as those conducting military
 operations or working in high-altitude rescue teams.
Inclusion Criteria:

 -  Healthy males and females

 -  Non-smoking

 -  Non-pregnant females

 -  Ages 18 - 40 years old

 Exclusion Criteria:

 -  Serious pulmonary or cardiovascular comorbidities

 -  Pregnant women

 -  VO2max < 35 mL/kg per minute

 -  Sickle cell trait or disease

 -  Smokers

 -  Lung disease

 -  Hypertension

 -  Cardiac disease and left bundle branch block

 -  Taking nitrates, nitric oxide donors (such as amyl nitrite), and phosphodiesterase
 (PDE) inhibitors (including specific PDE-5 inhibitors, such as sildenafil, tadalafil,
 or vardenafil, or non-specific PDE inhibitors, such as dipyridamole or theophylline).