Mechanism of action of endothelin-1 in the canine pulmonary circulation.
Possible mechanisms of action by which endothelin (ET)-1 has an effect on pulmonary vascular resistance and compliance in the canine pulmonary circulation were investigated in the isolated blood-perfused dog lung by use of vascular occlusion techniques. In the present study, ET-1 (10(-8) M) increased pulmonary vascular resistance and pulmonary capillary pressure by postcapillary vasoconstriction. In addition, ET-1 decreased total vascular compliance and middle-compartment compliance. Pretreatment with the ETA receptor antagonist BQ-610 (10(-7) M) or the protein kinase C inhibitors staurosporine (10(-6) M) and calphostin C (10(-6) M) completely blocked the pressor effect of ET-1. Elimination of extracellular calcium mobilization through voltage-dependent calcium channels by verapamil (10(-5) M) or modulation of G protein signal transduction by pertussis toxin challenge (15 micrograms/kg) had no significant effect on the ET-1-induced pulmonary vascular response. The results of the present study indicate that ET-1 causes pulmonary vasoconstriction in the canine pulmonary circulation through ETA receptor mediation and protein kinase C activation, possibly leading to intracellular calcium release. In contrast, the ET-1-induced pulmonary vascular response does not appear to involve extracellular calcium entry through voltage-dependent calcium-channel activation or pertussis toxin-sensitive G protein-signaling mechanisms.
Barman
S A
SA
Department of Pharmacology and Toxicology, Medical College of Georgia, Augusta 30912, USA.
Pauly
J R
JR
D000818:Animals; D001345:Autoradiography; D001667:Binding, Competitive; D004285:Dogs; D016232:Endothelins / Q000494:pharmacology*; D005260:Female; D008168:Lung / Q000187:drug effects* / Q000502:physiology; D008297:Male; D009842:Oligopeptides / Q000494:pharmacology; D011652:Pulmonary Circulation / Q000187:drug effects* / Q000502:physiology; D011869:Radioligand Assay; D014700:Verapamil / Q000494:pharmacology
D016232:Endothelins; D009842:Oligopeptides; C087220:BQ 610; D014700:Verapamil