Endothelin production in cultured vascular smooth muscle cells—Modulation by the atrial, brain, and C-type natriuretic peptide system

Abstract

We examined the regulatory mechanisms of endothelin-1 (ET-1) production in cultured rat vascular smooth muscle cells (VSMC) with a special focus on the roles of protein kinase C (PKC)- and cyclic guanosine-3′,5′-monophosphate (GMP)-mediated signaling systems. Effects of atrial, brain, and C-type natriuretic peptides (ANP, BNP, and CNP) on angiotensin II (Ang II)-, and arginine vasopressin (AVP)-induced production of ET-1 were examined in cultured rat aortic VSMC. Ang II and AVP stimulated ET-1 production in a concentration-dependent manner through angiotensin subtype 1 (AT 1) and vasopressin subtype 1 (V 1) receptors, respectively. The stimulatory effects of Ang II and AVP were markedly abolished in PKC-depleted cells. Rat ANP (1–28), rat BNP-45, and rat CNP-22 potently inhibited Ang II- and AVP-stimulated ET-1 production in a concentration-dependent manner, respectively. The inhibitory effect by CNP on ET-1 production was paralleled by an increase in the cellular level of cyclic GMP. 8-Bromo cyclic GMP reduced the stimulated ET-1 production by Ang II and AVP. These results indicate that Ang II and AVP stimulate ET-1 production in cultured rat VSMC through AT 1 and V 1 receptors by a mechanism probably involving activation of PKC, and that ANP, BNP, and CNP inhibit this stimulated production through a cyclic GMP—dependent process.