NEP inhibitors enhance C-type natriuretic peptide-induced relaxation in porcine isolated coronary artery.
C-type natriuretic peptide (CNP), a local regulator of vascular tone and cell proliferation, is eliminated from the circulation via NPR-C receptors and neutral endopeptidase enzyme (NEP, EC. 3.4.24.11). The increased contractility of coronary arteries in different cardiovascular diseases made us study the possible enhancement of vasodilator capacity of exogenously added CNP with concomitant NEP inhibition on porcine coronary arteries in vitro. CNP (0.006-1.4 microM) concentration dependently relaxed the U46619 (0.07-0.4 microM) precontracted preparations in an almost equally effective manner in the presence and absence of functional endothelium with maximum effects of about 40%. The combined NEP/endothelin-converting enzyme inhibitor (NEP/ECE inhibitor), phosphoramidon (10 microM) or the specific inhibitor of the NEP, thiorphan (10 microM) resulted in an enhanced magnitude of CNP-induced relaxation without significant change in the EC50 both on endothelium intact and endothelium deprived preparations. The inhibition of endothelin receptors by PD 142893 (10 microM) enhanced the relaxing effect of CNP in the presence but not in the absence of functional endothelium indicating a functional antagonism between CNP and endothelin. Our results suggest that inhibition of CNP degradation may endue this endogenous peptide with therapeutic potency in cardiovascular diseases.
Márton
Zoltán
Z
Department of Pharmacology and Pharmacotherapy, University of Szeged, H-6701, Szeged, Dóm tér 12, Hungary.
Pataricza
János
J
Krassói
Irén
I
Varró
András
A
Papp
Julius Gyula
JG
D000818:Animals; D003331:Coronary Vessels / Q000187:drug effects*; D006020:Glycopeptides / Q000494:pharmacology; D066298:In Vitro Techniques; D007537:Isometric Contraction / Q000187:drug effects; D009126:Muscle Relaxation / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects*; D020098:Natriuretic Peptide, C-Type / Q000494:pharmacology*; D015260:Neprilysin / Q000037:antagonists & inhibitors*; D009842:Oligopeptides / Q000494:pharmacology; D011480:Protease Inhibitors / Q000494:pharmacology*; D013552:Swine; D015244:Thiorphan / Q000494:pharmacology
D006020:Glycopeptides; D009842:Oligopeptides; D011480:Protease Inhibitors; D020098:Natriuretic Peptide, C-Type; C076213:PD 142893; D015244:Thiorphan; D015260:Neprilysin; C008890:phosphoramidon