Release of C-type natriuretic peptide accounts for the biological activity of endothelium-derived hyperpolarizing factor.
Endothelial cells in most vascular beds release a factor that hyperpolarizes the underlying smooth muscle, produces vasodilatation, and plays a fundamental role in the regulation of local blood flow and systemic blood pressure. The identity of this endothelium-derived hyperpolarizing factor (EDHF), which is neither NO nor prostacyclin, remains obscure. Herein, we demonstrate that in mesenteric resistance arteries, release of C-type natriuretic peptide (CNP) accounts for the biological activity of EDHF. Both produce identical smooth muscle hyperpolarizations that are attenuated in the presence of high [K(+)], the G(i) G protein (G(i)) inhibitor pertussis toxin, the G protein-gated inwardly rectifying K(+) channel inhibitor tertiapin, and a combination of Ba(2+) (inwardly rectifying K(+) channel blocker) plus ouabain (Na(+)K(+)-ATPase inhibitor). Responses to EDHF and CNP are unaffected by the natriuretic peptide receptor (NPR)-AB antagonist HS-142-1, but mimicked by the selective NPR-C agonist, cANF(4-23). EDHF-dependent relaxation is concomitant with liberation of endothelial CNP; in the presence of the myoendothelial gap-junction inhibitor 18alpha-glycyrrhetinic acid or after endothelial denudation, CNP release and EDHF responses are profoundly suppressed. These data demonstrate that acetylcholine-evoked release of endothelial CNP activates NPR-C on vascular smooth muscle that via a G(i) coupling promotes Ba(2+)ouabain-sensitive hyperpolarization. Thus, we have revealed the identity of EDHF and established a pivotal role for endothelial-derived CNP in the regulation of vascular tone and blood flow.
Chauhan
Sharmila D
SD
Department of Clinical Pharmacology, St. Bart's and Royal London School of Medicine, Charterhouse Square, London EC1M 6BQ, United Kingdom.
Nilsson
Holger
H
Ahluwalia
Amrita
A
Hobbs
Adrian J
AJ
D000818:Animals; D001685:Biological Factors / Q000378:metabolism / Q000502:physiology*; D004305:Dose-Response Relationship, Drug; D004594:Electrophysiology; D004730:Endothelium, Vascular / Q000378:metabolism*; D008297:Male; D008954:Models, Biological; D009126:Muscle Relaxation; D032389:Myocytes, Smooth Muscle / Q000166:cytology; D020098:Natriuretic Peptide, C-Type / Q000737:chemistry* / Q000378:metabolism; D017434:Protein Structure, Tertiary; D051381:Rats; D017207:Rats, Sprague-Dawley; D000254:Sodium-Potassium-Exchanging ATPase / Q000037:antagonists & inhibitors; D013997:Time Factors
D001685:Biological Factors; C067410:endothelium-dependent hyperpolarization factor; D020098:Natriuretic Peptide, C-Type; D000254:Sodium-Potassium-Exchanging ATPase