Abstract 3629: Inhibition of Smooth Muscle Myosin, a Novel Therapeutic Approach for Pulmonary Hypertension
In contrast to the therapy of systemic hypertension, there are relatively few approaches available to treat pulmonary hypertension. The goal of the present study was to examine the extent to which a new approach, inhibition of smooth muscle myosin by CK-2019165 (CK-165) ameliorated pulmonary hypertension. Six domestic female pigs were surgically instrumented with a Transonic flow probe around the main pulmonary artery and catheters placed in the pulmonary artery, descending aorta, and right and left atria to measure systemic and pulmonary vascular dynamics. One week after surgery, pulmonary hypertension was induced by hypoxia, i.e., breathing at reduced FIO2 (0.10), or infusion of the thromboxane analog (U-46619, 0.1microg/kg/min, i.v.), which increased (p<0.01) pulmonary artery pressure to 29±1 and 35±1 mmHg, respectively, from a baseline of 18±1 mmHg, resulting in a doubling of pulmonary vascular resistance. CK-165 at a dose of 4 mg/kg, i.v. reduced (p<0.01) pulmonary vascular resistance by 22±3 and 32±6% from their baseline levels in the hypoxia and thromboxane models, respectively, while mean arterial pressure also fell and heart rate rose slightly. When CK-165 was delivered via inhalation, in the hypoxia model, pulmonary vascular resistance fell similarly, by 23±3%, while mean arterial pressure and heart rate were unchanged. We also matched the peak pulmonary vasodilator responses induced by i.v. injection of CK-165 with those elicited by a NO donor, sodium nitroprusside (SNP). In these experiments the duration of vasodilation was relatively longer with CK-165 than with SNP. These results demonstrate that inhibition of smooth muscle myosin may be a novel therapeutic target for treatment of pulmonary hypertension.