AM reverses pressor response to ET-1 independently of NO in rat coronary circulation

• Published in: American journal of physiology. Heart and circulatory physiology Vol. 281; no. 3; p. H1178
• Main Authors: Kinnunen, P, Piuhola, J, Ruskoaho, H, Szokodi, I
• Format: Journal Article
• Language: English
• Published: United States 01-09-2001
• Subjects: Adrenomedullin; Animals; Cardiac Pacing, Artificial; Coronary Circulation - drug effects; Coronary Circulation - physiology; Dose-Response Relationship, Drug; Endothelin-1 - antagonists & inhibitors; Endothelin-1 - pharmacology; Enzyme Inhibitors - pharmacology; In Vitro Techniques; Male; NG-Nitroarginine Methyl Ester - pharmacology; Nitric Oxide - metabolism; Nitric Oxide Synthase - antagonists & inhibitors; Peptides - pharmacology; Perfusion; Rats; Rats, Sprague-Dawley; Receptor, Endothelin A; Receptor, Endothelin B; Receptors, Endothelin - metabolism; Vascular Resistance - drug effects; Vasoconstrictor Agents - pharmacology; Vasodilator Agents - metabolism; Vasodilator Agents - pharmacology; Vasomotor System - drug effects; Vasomotor System - physiology
• ISSN: 0363-6135
• DOI: 10.1152/ajpheart.2001.281.3.H1178

Endothelin-1 (ET-1) elicits a vasoconstrictor response via ET(A) receptors, whereas simultaneous activation of ET(B) receptors triggers the release of nitric oxide (NO), which may limit the constrictor effect of ET-1. Recently, stimulation of ET(B) receptors has been shown to increase the secretion of adrenomedullin (AM), a newly identified vasorelaxing peptide. The present study was designed to see whether AM can oppose the vasoconstrictor response to ET-1. In the isolated perfused paced rat heart preparation, infusion of ET-1 at concentrations of 1 nmol/l for 30 min induced a significant coronary vasoconstriction, whereas it had no effect on perfusion pressure at a dose of 0.08 nmol/l. N(omega)-nitro-L-arginine methyl ester (L-NAME; 300 micromol/l), a potent inhibitor of NO synthase (NOS), did not change the perfusion pressure when added alone to the perfusion fluid but it unmasked the constrictor effect of ET-1 at both concentrations. In the presence of L-NAME, AM (0.03 to 1 nmol/l) markedly reversed the pressor response to ET-1 at both concentrations. Administration of AM (0.03 and 1 nmol/l) alone resulted in a dose-dependent decrease in perfusion pressure, which was not modified in the presence of L-NAME. In conclusion, the coronary vasoconstrictor response to ET-1 is markedly augmented in the presence of a NOS inhibitor. This constrictor response is substantially reversed by AM. Our results indicate that AM may serve as a paracrine modulator of ET-1-induced vasoconstriction independently of the NO pathway.