Endothelium-derived nitric oxide inhibits the relaxation of the porcine coronary artery to natriuretic peptides by desensitizing big conductance calcium-activated potassium channels of vascular smooth muscle

• Published in: The Journal of pharmacology and experimental therapeutics 2010-07, Vol.334 (1), p.223-231
• Main Authors: Liang, Chao Fan, Au, Alice Lai Shan, Leung, Susan Wai Sum, Ng, Kwok Fu Jacobus, Félétou, Michel, Kwan, Yiu Wa, Man, Ricky Ying Keung, Vanhoutte, Paul M
• Format: Article
• Language: English
• Subjects: Animals; Coronary Vessels - drug effects; Coronary Vessels - metabolism; Coronary Vessels - physiology; Cyclic GMP - biosynthesis; Endothelium, Vascular - drug effects; Endothelium, Vascular - metabolism; Endothelium, Vascular - physiology; Enzyme Inhibitors - pharmacology; Guanylate Cyclase - antagonists & inhibitors; In Vitro Techniques; Ion Channel Gating - drug effects; Large-Conductance Calcium-Activated Potassium Channels - antagonists & inhibitors; Muscle, Smooth, Vascular - drug effects; Muscle, Smooth, Vascular - metabolism; Muscle, Smooth, Vascular - physiology; Natriuretic Peptides - pharmacology; Natriuretic Peptides - physiology; Nitric Oxide - metabolism; Nitric Oxide - pharmacology; Nitric Oxide - physiology; Nitric Oxide Donors - pharmacology; Oxadiazoles - pharmacology; Oxazines - pharmacology; Patch-Clamp Techniques; Peptides - pharmacology; Swine; Vasodilation - drug effects; Vasodilation - physiology
• ISSN: 0022-3565; 1521-0103
• DOI: 10.1124/jpet.110.166652

The present experiments investigated whether endothelium-derived mediators modulate the effect of natriuretic peptides in porcine coronary arteries. Rings with and without endothelium were suspended in organ chambers for isometric tension recording. Concentration-relaxation curves to C-type natriuretic peptide (CNP) and atrial natriuretic peptide (ANP) were obtained during contractions to endothelin-1. Removal of the endothelium potentiated relaxations to both CNP and ANP. N(omega)-nitro-L-arginine methyl ester potentiated relaxations to natriuretic peptides only in arteries with endothelium. Sodium nitroprusside (SNP) inhibited the response to the natriuretic peptides only in the absence of the endothelium. In rings with endothelium, 1H-[1,2,4]oxadiazolo [4,3-a]quinoxalin-1-one (ODQ) and 4H-8-bromo-1,2,4-oxadiazolo[3,4-d]benz[b][1,4]oxazin-1-one (NS2028) potentiated CNP-mediated relaxations. Iberiotoxin (IBTX) reduced the response only in rings without endothelium. Glybenclamide inhibited the relaxations in both the presence and absence of endothelium. CNP-induced relaxations were reduced by 8-bromoguanosine 3',5'-cGMP (8-bromo-cGMP) to the same extent in rings with and without endothelium. There was no significant difference between the increased cGMP content caused by CNP in porcine coronary arteries with or without endothelium. In patch-clamp studies in porcine coronary arterial smooth muscle cells, the natriuretic peptide-mediated enhancement of the IBTX-sensitive big conductance calcium-activated potassium channel (BK(Ca)) amplitude was reversed by SNP and 8-bromo-cGMP. These findings demonstrate that, in the porcine coronary artery, the opening of BK(Ca) and ATP-dependent potassium channels of the vascular smooth muscle contributes to CNP-mediated relaxations. Endothelium-derived and exogenous NO inhibit the direct relaxing effect of natriuretic peptides by desensitizing the response of the BK(Ca)s of the vascular smooth muscle to the generation of cGMP.