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.
Identification of an Integration Center for Cross-talk between Protein Kinase C and G Protein Modulation of N-type Calcium Channels