Inhibition of smooth muscle myosin as a novel therapeutic target for hypertension.

Abstract

We examined a novel therapeutic approach for hypertension, a small-molecule direct inhibitor of smooth muscle myosin, CK-2018448 (CK-448), which is an N,N'-alkylurea (U.S. Patent Publication 2009-0275537 A1) in conscious dogs with renal hypertension and compared its efficacy with that of a calcium channel blocker, amlodipine. Dogs were instrumented with a miniature left ventricular pressure gauge, an aortic pressure catheter, and ultrasonic flow probes in the ascending aorta and renal and iliac arteries for measurement of cardiac output and regional blood flow. In the hypertensive state, mean arterial pressure increased from 101 ± 3.8 to 142 ± 1.9 mm Hg. At the doses selected, CK-448 and amlodipine increased cardiac output similarly (30 ± 11% versus 33 ± 6.4%) and similarly reduced mean arterial pressure (-22 ± 3.6% versus -16 ± 3.4%) and total peripheral resistance (-36 ± 5.9% versus -37 ± 5.8%). CK-448 had the greatest vasodilator effect in the renal bed, where renal blood flow increased by 46 ± 9.0%, versus 11 ± 3.4% for amlodipine (p < 0.01). CK-488 produced significantly less vasodilation in the limb, where iliac blood flow did not change; in contrast, it rose by 48 ± 12% with amlodipine (p < 0.01). The minimal effects on limb blood flow could limit the development of peripheral edema, an adverse side effect of Ca(2+) channel blockers. In addition, in a rodent model of hypertension, oral administration of a smooth muscle myosin inhibitor resulted in a sustained antihypertensive effect. Thus, the smooth muscle myosin inhibitor's preferential effect on renal blood flow makes this drug mechanism particularly appealing, because many patients with hypertension have renal insufficiency, and patients with heart failure could benefit from afterload reduction coupled with enhanced renal blood flow.

• Authors: Xin Zhao, David Ho, Patricio Abarzúa, Sunil K Dhar, Xi Wang, Zhiheng Jia, Malar Pannirselvam, David J Morgans, Fady I Malik, Stephen F Vatner
• Journal: The Journal of pharmacology and experimental therapeutics (J Pharmacol Exp Ther) Vol. 339 Issue 1 Pg. 307-12 (Oct 2011) ISSN: 1521-0103 [Electronic] United States
• PMID: 21784887 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antihypertensive Agents
• CK 2018448
• Amlodipine
• Urea
• Myosins

Topics

• Amlodipine (pharmacology)
• Animals
• Antihypertensive Agents (pharmacology)
• Blood Pressure (drug effects)
• Cardiac Output (drug effects)
• Dogs
• Female
• Hemodynamics (drug effects)
• Hypertension (drug therapy)
• Iliac Artery (drug effects)
• Injections, Intravenous
• Muscle, Smooth (drug effects)
• Myosins (antagonists & inhibitors)
• Rats
• Rats, Inbred SHR
• Regional Blood Flow (drug effects)
• Renal Circulation (drug effects)
• Urea (analogs & derivatives, pharmacology)
• Vascular Resistance (drug effects)