Efficacy Study of Riociguat and Its Effects on Exercise Performance and Pulmonary Artery Pressure at High 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.