Endothelin plays a role in the maintenance of blood pressure in normotensive guinea pigs.
The objective of the present study was to evaluate if endothelin plays a role in the maintenance of arterial blood pressure in normotensive guinea pigs. For this purpose, the effects of a new mixed (ETA + ETB) endothelin receptor antagonist, Ro 47-0203 (bosentan), were evaluated in vitro on aortic rings and in anesthetized and conscious guinea pigs. In vitro, bosentan was a potent (pA2 = 7.5) and competitive endothelin receptor antagonist as shown by the parallel rightward shift of the concentration-response curve for endothelin-1 on guinea pig aortic rings in presence of increasing concentrations of bosentan. In vivo, bosentan significantly decreased arterial blood pressure of both anesthetized and conscious guinea pigs. This effect was similar to the effect of BQ-123, a selective ETA receptor antagonist. No additional effect was observed when bosentan was given on top of BQ-123. Neither inhibition of the renin angiotensin system with remikiren, cyclooxygenase inhibition with indomethacin, bradykinin antagonism with Hoe 140, ganglionic blockade with chlorisondamine, parasympathetic inhibition with atropine nor nitric oxide synthase blockade with L-NAME altered the effect of bosentan. In conclusion, the present results show that endothelin contributes to the maintenance of arterial blood pressure in normal normotensive guinea pigs most likely through stimulation of ETA receptors.
Véniant
M
M
Pharma Division, F. Hoffmann-La Roche Ltd., Basel, Switzerland.
Clozel
J P
JP
Hess
P
P
Clozel
M
M
D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D000077300:Bosentan; D004305:Dose-Response Relationship, Drug; D065128:Endothelin Receptor Antagonists; D016232:Endothelins / Q000502:physiology*; D006168:Guinea Pigs; D066298:In Vitro Techniques; D019331:NG-Nitroarginine Methyl Ester; D010456:Peptides, Cyclic / Q000494:pharmacology; D013449:Sulfonamides
D065128:Endothelin Receptor Antagonists; D016232:Endothelins; D010456:Peptides, Cyclic; D013449:Sulfonamides; D001120:Arginine; D000077300:Bosentan; C072247:cyclo(Trp-Asp-Pro-Val-Leu); D019331:NG-Nitroarginine Methyl Ester