Protein kinase C mediates angiotensin II-induced contractions and the release of endothelin and prostacyclin in rat aortic rings.

Angiotensin II (Ang II) stimulation of vascular smooth muscle results in a myriad of intracellular signals that interact to produce the final physiologic response of the cell. We used rat aortic rings to investigate the role of protein kinase C (PKC) in Ang II-induced contractions and in the concomitant release of endothelin (ET) and prostacyclin (PGI2). Ang II (10(-9) M) produced a rapid contraction which was sustained for 10 min. When aortic rings were pretreated with graded concentrations of each of the four different inhibitors of PKC, that is, (i) 1-(5-isoquinolinesulfonylmethyl) piperazine (H7); (ii) 1-(5-isoquinolinesulfonyl) piperazine(CL); (iii) staurosporine; or (iv) calphostin C, inhibition of Ang II-induced contractions began at 10(-9) M, and was nearly complete at 10(-6) M. Ang II-induced contractions were associated with a 10-fold increase in the release of both ET and PGI2. Pretreatment with 10(-6) M of any one of the same four PKC inhibitors blocked Ang II-induced release of both ET and PGI2. Pretreatment with a blocker of the endothelin-A receptor, BQ123 (10(-6) M), inhibited, by approximately 50%, Ang II-induced contractions, and the release of both ET and PGI2. In aortic rings denuded of endothelium, Ang II-induced contractions, and the release of both ET and PGI2 were significantly reduced, compared to intact rings. We conclude that PKC mediates Ang II-induced contractions in rat aortic rings and that the secondary release of both ET and PGI2 during Ang II-induced contractions is mediated, at least in part, by PKC. In addition, approximately half of Ang II-induced contractile force and of PGI2 release is dependent upon the ET released from endothelial cells.