| Inhibition of smooth muscle myosin as a novel therapeutic target for hypertension. | |
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MedLine Citation:
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PMID: 21784887 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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. |
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Authors:
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Xin Zhao; David Ho; Patricio Abarzúa; Sunil K Dhar; Xi Wang; Zhiheng Jia; Malar Pannirselvam; David J Morgans; Fady I Malik; Stephen F Vatner |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't Date: 2011-07-22 |
Journal Detail:
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Title: The Journal of pharmacology and experimental therapeutics Volume: 339 ISSN: 1521-0103 ISO Abbreviation: J. Pharmacol. Exp. Ther. Publication Date: 2011 Oct |
Date Detail:
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Created Date: 2011-09-20 Completed Date: 2011-11-22 Revised Date: 2012-05-15 |
Medline Journal Info:
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Nlm Unique ID: 0376362 Medline TA: J Pharmacol Exp Ther Country: United States |
Other Details:
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Languages: eng Pagination: 307-12 Citation Subset: IM |
Affiliation:
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Department of Cell Biology and Molecular Medicine and the Cardiovascular Research Institute, University of Medicine and Dentistry of New Jersey, New Jersey Medical School, Newark, New Jersey 07103, USA. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Amlodipine
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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 |
| Grant Support | |
ID/Acronym/Agency:
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AG0--27211--04/AG/NIA NIH HHS; HL0--69020-10/HL/NHLBI NIH HHS; HL0-33107-27/HL/NHLBI NIH HHS; HL0-69752-07/HL/NHLBI NIH HHS; HL0-93481-02/HL/NHLBI NIH HHS; HL10-1420-01/HL/NHLBI NIH HHS; HL10-2472-01/HL/NHLBI NIH HHS; R01 HL093481/HL/NHLBI NIH HHS; R01 HL106511/HL/NHLBI NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Antihypertensive Agents; 0/CK 2018448; 57-13-6/Urea; 88150-42-9/Amlodipine; EC 3.6.4.1/Myosins |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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