The Novel Soluble Guanylate Cyclase Activator PPCA Reverses Acute Hypoxia‐induced Pulmonary Hypertension in Dogs

Abstract

Nitric oxide (NO) plays a critical role in regulating pulmonary vascular tone. Impaired bioavilability of the NO receptor, soluble guanylate cyclase (sGC), and/or response to endogeneous NO has been implicated in the pathogenesis of pulmonary hypertension (PH). We hypothesize that activating sGC in a NO‐independent manner will provide a valuable therapy for patients with PH.We generated a novel NO‐independent type 2 sGC activator, PPCA, and tested it in a canine model of hypoxia‐induced pulmonary hypertension. Under normoxic conditions PPCA dose‐dependently (3–100 μg/kg, IV) decreased mean arterial pressure (MAP) and pulmonary arterial pressure (PAP) in anesthetized and catheterized beagle dogs (n=5). Following 20 minutes of hypoxia (10% O2), either saline or PPCA (15μg/kg, IV) was administered. PPCA significantly decreased PAP (−25.1±4.1%) vs. vehicle (−7.6±1.4%, P< 0.05), MAP (−16.1± 0.1%) vs. vehicle (−2.7±0.1%, P<0.05), PCWP and LVEDP. In addition, PPCA improved SaO2 and relieved labored breathing as compared to vehicle controls. In contrast, renal blood flow, LV dP/dtmax and cardiac output were not altered by PPCA. Early administration of PPCA (30μg/kg, IV) at 5 minutes after hypoxia completely blocked the hypoxic pulmonary vasoconstriction for over 80 minutes.These data suggest that activation of sGC by PPCA improves pulmonary hemodynamics and function in hypoxia‐induced pulmonary hypertension.