Abstract 5077: Inhibition of Smooth Muscle Myosin, a Novel Anti-Hypertensive Strategy

Abstract

Inhibition of smooth muscle myosin is a novel mechanism to reduce vascular smooth muscle tone and may represent a new antihypertensive class. The goal of this study was to examine the effects of a smooth muscle myosin inhibitor, CK-2018448 (CK-448), in conscious dogs at baseline and in the hypertensive state. Hypertension was induced by wrapping one kidney combined with renal artery stenosis in 5 dogs instrumented with a left ventricular (LV) pressure gauge, Transonic flow probes on the ascending aorta, coronary, renal and iliac arteries, and pressure catheters in the aorta and left atrium. One week after surgery, when the dogs were still normotensive, CK-448 (2– 6 mg/kg, iv bolus) produced dose-dependent decreases in mean arterial pressure (MAP) and total peripheral vascular resistance (TPR) and increases in cardiac output, LV dP/dt and heart rate; the latter were nearly eliminated by autonomic blockade. The changes in TPR and regional vascular resistance after administration of CK-448 (6 mg/kg, iv) were compared with those of the calcium channel blocker, amlodipine (0.5 mg/kg, iv) at doses inducing similar reductions in TPR (Table ). The pattern of regional vasodilation in the kidney and limb was different for the 2 drugs; the greatest vasodilation for amlodipine was in the limb, whereas for CK-448 it was the kidney. When hypertension developed 2– 4 weeks later, baseline MAP rose from 101±4 to 158±7 mmHg and TPR from 27±3 to 100±10 mmHg/L/min. The effect of CK-448 on TPR was more than in the normotensive state and there was a similar preferential renal vasodilation with CK-448, i.e., it increased renal blood flow by 76% (t = 3 min), which was twice the increase in the iliac bed. Thus, the smooth muscle myosin inhibitor and a calcium channel blocker elicited different patterns of regional vasodilation. The renal vasodilation induced by CK-448 could have additional salutary effects in hypertension, which is often accompanied by renal insufficiency.