Fasudil inhibits the myogenic response in the fetal pulmonary circulation

Abstract

In addition to high pulmonary vascular resistance (PVR) and low pulmonary blood flow, the fetal pulmonary circulation is characterized by mechanisms that oppose vasodilation. Past work suggests that high myogenic tone contributes to high PVR and may contribute to autoregulation of blood flow in the fetal lung. Rho-kinase (ROCK) can mediate the myogenic response in the adult systemic circulation, but whether high ROCK activity contributes to the myogenic response and modulates time-dependent vasodilation in the developing lung circulation are unknown. We studied the effects of fasudil, a ROCK inhibitor, on the hemodynamic response during acute compression of the ductus arteriosus (DA) in chronically prepared, late-gestation fetal sheep. Acute DA compression simultaneously induces two opposing responses: 1) blood flow-induced vasodilation through increased shear stress that is mediated by NO release and 2) stretch-induced vasoconstriction (i.e., the myogenic response). The myogenic response was assessed during acute DA compression after treatment with Nω-nitro-l-arginine, an inhibitor of nitric oxide synthase, to block flow-induced vasodilation and unmask the myogenic response. Intrapulmonary fasudil infusion (100 μg over 10 min) did not enhance flow-induced vasodilation during brief DA compression but reduced the myogenic response by 90% ( P < 0.05). During prolonged DA compression, fasudil prevented the time-dependent decline in left pulmonary artery blood flow at 2 h (183 ± 29 vs. 110 ± 11 ml/min with and without fasudil, respectively; P < 0.001). We conclude that high ROCK activity opposes pulmonary vasodilation in utero and that the myogenic response maintains high PVR in the normal fetal lung through ROCK activation.