Natriuretic peptide receptor-C regulates coronary blood flow and prevents myocardial ischemia/reperfusion injury: novel cardioprotective role for endothelium-derived C-type natriuretic peptide.
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.


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 Ba(2+) 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.


CONCLUSIONS
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.
Hobbs
Adrian
A
Wolfson Institute for Biomedical Research, London, UK.
Foster
Paul
P
Prescott
Craig
C
Scotland
Ramona
R
Ahluwalia
Amrita
A
D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D009320:Atrial Natriuretic Factor / Q000494:pharmacology / Q000627:therapeutic use; D001464:Barium / Q000494:pharmacology; D003326:Coronary Circulation / Q000187:drug effects*; D004353:Drug Evaluation, Preclinical; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism; D008297:Male; D009203:Myocardial Infarction / Q000188:drug therapy / Q000473:pathology; D015428:Myocardial Reperfusion Injury / Q000517:prevention & control; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D020098:Natriuretic Peptide, C-Type / Q000378:metabolism / Q000494:pharmacology / Q000502:physiology* / Q000627:therapeutic use; D009569:Nitric Oxide / Q000502:physiology; D010042:Ouabain / Q000494:pharmacology; D010446:Peptide Fragments / Q000494:pharmacology / Q000627:therapeutic use; D051381:Rats; D017208:Rats, Wistar; D017461:Receptors, Atrial Natriuretic Factor / Q000187:drug effects / Q000502:physiology*; D015398:Signal Transduction; D014664:Vasodilation / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology / Q000627:therapeutic use
D010446:Peptide Fragments; D014665:Vasodilator Agents; C065367:atrial natriuretic factor (4-23)NH2, de-Gln(18)-de-Ser(19)-de-Gly(20,22)-de-Leu(21)-; D020098:Natriuretic Peptide, C-Type; D001464:Barium; D009569:Nitric Oxide; D010042:Ouabain; D009320:Atrial Natriuretic Factor; D017461:Receptors, Atrial Natriuretic Factor; C073616:atrial natriuretic factor receptor C; D000109:Acetylcholine; D019331:NG-Nitroarginine Methyl Ester