AM reverses pressor response to ET-1 independently of NO in rat coronary circulation.
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.
Kinnunen
P
P
Department of Pharmacology and Toxicology, Biocenter Oulu, University of Oulu, 90014 Oulu, Finland.
Piuhola
J
J
Ruskoaho
H
H
Szokodi
I
I
D053607:Adrenomedullin; D000818:Animals; D002304:Cardiac Pacing, Artificial; D003326:Coronary Circulation / Q000187:drug effects* / Q000502:physiology*; D004305:Dose-Response Relationship, Drug; D019332:Endothelin-1 / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D010455:Peptides / Q000494:pharmacology*; D010477:Perfusion; D051381:Rats; D017207:Rats, Sprague-Dawley; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D017466:Receptors, Endothelin / Q000378:metabolism; D014655:Vascular Resistance / Q000187:drug effects; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D014665:Vasodilator Agents / Q000378:metabolism / Q000494:pharmacology; D014666:Vasomotor System / Q000187:drug effects / Q000502:physiology
D019332:Endothelin-1; D004791:Enzyme Inhibitors; D010455:Peptides; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D017466:Receptors, Endothelin; D014662:Vasoconstrictor Agents; D014665:Vasodilator Agents; D053607:Adrenomedullin; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D019331:NG-Nitroarginine Methyl Ester