Published Online
on August 30, 2004

A more recent version of this article appeared on September 7, 2004

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Submitted on May 20, 2004
Revised on July 12, 2004
Accepted on July 15, 2004

Natriuretic Peptide Receptor-C Regulates Coronary Blood Flow and Prevents Myocardial Ischemia/Reperfusion Injury. Novel Cardioprotective Role for Endothelium-Derived C-Type Natriuretic Peptide

Adrian Hobbs PhD, Paul Foster PhD, Craig Prescott BMedSci, Ramona Scotland PhD, and Amrita Ahluwalia PhD^*

From the Wolfson Institute for Biomedical Research (A.H., R.S.), University College London, and Clinical Pharmacology (P.F., C.P., A.A.), William Harvey Research Institute, Barts and The London, Charterhouse Square, London, UK.

^* To whom correspondence should be addressed. E-mail: a.ahluwalia{at}qmul.ac.uk.

Background--Ischemia/reperfusion (I/R) injury complicates myocardial infarction and stroke by exacerbating tissue damage and increasing risk of mortality. We have recently identified C-type natriuretic peptide (CNP) as an endothelium-derived hyperpolarizing factor in the mesenteric resistance vasculature and described a novel signaling pathway involving activation of natriuretic peptide receptor C (NPR-C), which plays a pivotal role in the regulation of local blood flow. We tested the hypothesis that CNP/NPR-C signaling is a novel regulatory pathway governing coronary blood flow and protecting against I/R injury.

Methods and Results--CNP and (Cys18)-atrial natriuretic factor (4-23) amide (cANF^4-23) elicited dose-dependent decreases in coronary perfusion pressure (CPP) that were blocked by Ba²⁺ and ouabain in the isolated Langendorff rat heart. The endothelium-dependent vasodilator acetylcholine elicited the release of CNP from the coronary endothelium. CNP and cANF^4-23 reduced infarct size after 25 minutes of global ischemia and 120 minutes of reperfusion, maintaining CPP and left ventricular pressure at preischemic values. The vasorelaxant and protective activity of CNP and cANF^4-23 were enhanced in the absence of endothelium-derived nitric oxide.

Conclusion--Endothelium-derived CNP is involved in the regulation of the coronary circulation, and NPR-C activation underlies the vasorelaxant activity of this peptide. Moreover, this newly defined pathway represents a protective mechanism against I/R injury and a novel target for therapeutic intervention in ischemic cardiovascular disorders.

Key words: endothelium-derived factors • myocardial infarction • natriuretic peptides • cardiovascular diseases • ischemia

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