The Effect of Riociguat on Gas Exchange,Exercise Performance,and Pulmonary Artery Pressure During Acute Altitude Exposure

Introduction

Impairment of exercise performance during altitude exposure results in hypoxemia and decreased oxygen delivery to exercising muscles. Hypoxic pulmonary vasoconstriction (HPV) and ventilation/perfusion (V_A/Q) mismatch further contribute to hypoxemia. Therefore, if pharmacologic blockade could attenuate HPV, then V_A/Q matching, arterial PO₂, and exercise performance might improve. The nitric oxide (NO) pathway has been targeted in this context with sildenafil, but NO is limited at high altitude, which may explain the variable effectiveness of this approach. Riociguat is a soluble guanylate cyclase stimulator that does not require NO for its action.

Objective

To examine the acute effect of riociguat on pulmonary artery pressure, arterial oxygenation, and exercise performance at 15,000 feet simulated altitude.

Methods

Subjects instrumented with radial and pulmonary artery (PA) catheters performed incremental exercise tests on a bicycle ergometer at a simulated altitude of 15,000 feet before and after administration of 1 mg riociguat. The following parameters were measured: mean and PA pressures, pulmonary vascular resistance (PVR), systemic vascular resistance (SVR), heart rate (HR), cardiac output, arterial and mixed venous O₂ saturation, alveolar-arterial PO₂ difference, oxygen consumption (VO₂), and arterial O₂ delivery (DO₂). Statistical analysis was performed using a generalized estimating equation model, and the effect of riociguat on outcome was examined, accounting for exercise impact.

Results

Preliminary results (N = 11 subjects) demonstrated decreased PVR (P = .014), while DO₂ and cardiac output were increased (P < .01) at rest and at 50 W of exercise intensity after administration of riociguat. There was no statistically significant effect on mean arterial or PA pressures, arterial O₂ saturation, alveolar-arterial PO₂ difference, or VO₂.

Conclusion

We conclude that at 15,000 feet simulated altitude, a one-time dose of 1 mg riociguat appears to decrease pulmonary vascular resistance while increasing peripheral O₂ delivery and cardiac output at rest and low exercise levels.

Funding

WMS Hackett-Auerbach Grant (2014).