Characterization of endothelin-1-induced vascular effects in the rat heart by using endothelin receptor antagonists.
The coronary vasoconstrictor effect of endothelin-1 was characterized in the isolated rat heart by using the endothelin ETA receptor antagonist D-Asp-L-Pro-D-Val-L-Leu-D-Trp (BQ-123) and the endothelin ETB receptor antagonist [Cys11-Cys15]endothelin-1-(11-21) (IRL 1038). In addition, the involvement of nitric oxide and cyclooxygenase products was investigated. Endothelin-1 (0.012-0.4 nmol) dose dependently reduced coronary flow, which reached a maximum reduction of 83% at 0.4 nmol. BQ-123 (1 microM) attenuated the responses to all doses of endothelin-1, whereas a lower concentration of BQ-123 (0.1 microM) only reduced the vasoconstriction due to the lower doses of endothelin-1 (0.012-0.12 nmol). In contrast, IRL 1038, which markedly antagonized the vasodilator response to the endothelin ETB receptor agonist Suc-[Glu9,Ala11,15]endothelin-1-(8-21) (IRL 1620), significantly enhanced the endothelin-1-evoked coronary vasoconstriction. Endothelin-1 (0.04 nmol) reduced coronary flow by 61% in the presence of IRL 1038 as compared to 30% in the absence of the endothelin ETB receptor antagonist. The endothelin-1-evoked reduction in coronary flow was also significantly enhanced by the nitric oxide synthesis inhibitor NG-nitro-L-arginine but was unaffected by the cyclooxygenase inhibitor diclofenac. IRL 1038 did not affect the response to endothelin-1 after blockade of nitric oxide synthesis. These results demonstrate that the coronary vasoconstriction induced by endothelin-1 in the isolated rat heart is a net effect of the stimulation of both endothelin ETA and endothelin ETB receptors.(ABSTRACT TRUNCATED AT 250 WORDS)
Wang
Q D
QD
Department of Cardiology, Karolinska Hospital, Stockholm, Sweden.
Li
X S
XS
Pernow
J
J
D000595:Amino Acid Sequence; D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives / Q000494:pharmacology; D003326:Coronary Circulation / Q000187:drug effects; D065128:Endothelin Receptor Antagonists; D016232:Endothelins / Q000494:pharmacology*; D006321:Heart / Q000187:drug effects*; D066298:In Vitro Techniques; D008297:Male; D008969:Molecular Sequence Data; D019335:Nitroarginine; D010446:Peptide Fragments / Q000494:pharmacology; D010456:Peptides, Cyclic / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D014662:Vasoconstrictor Agents / Q000494:pharmacology*; D017725:Ventricular Pressure / Q000187:drug effects
D065128:Endothelin Receptor Antagonists; D016232:Endothelins; D010446:Peptide Fragments; D010456:Peptides, Cyclic; D014662:Vasoconstrictor Agents; C074308:sovateltide; C077420:Cys(11)-Cys(15)-endothelin-1 (11-21); D019335:Nitroarginine; D001120:Arginine; C072247:cyclo(Trp-Asp-Pro-Val-Leu)