The Effect of Riociguat on Gas Exchange, Exercise Performance, and Pulmonary Artery Pressure During Acute Altitude Exposure
Description:
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.
Condition:
Hypertension, Pulmonary
Treatment:
Riociguat
Start Date:
January 2014
Sponsor:
Richard Moon
For More Information:
https://clinicaltrials.gov/show/NCT02024386