MECHANISM OF BILE-SALT VASOACTIVITY - DEPENDENCE ON CALCIUM CHANNELS IN VASCULAR SMOOTH-MUSCLE

1 The vasoactive mechanisms of bile salts have been investigated in rat isolated portal venous and superior mesenteric arterial rings and perfused mesentery. 2 The isolated perfused mesentery was precontracted with a selective alpha(1)-adrenoceptor agonist, cirazoline. Incremental doses of tauroursodeoxycholate (TUDC), taurochenodeoxycholate (TCDC) and taurodeoxycholate (TDC) caused a dose-dependent vasorelaxation. The order of potency of the vasodilator effect was TDC > TCDC > TUDC. 3 The effect of TDC (1.9 x 10(-8) - 1.9 x 10(-6) mol) was examined before and after propranolol (3 mu M), tetraethylammonium (5 mM), ouabain (10(-5) M), N-G-nitro-L-arginine methyl ester (10(-4) M) and capsaicin (50 mg kg(-1)) to block, respectively, beta-adrenoceptors, K+-channels, Na+, K+-ATPase, nitric oxide synthase, and primary sensory nerves. The vasodilator effect of TDC was not affected by any of these blocking agents or by denuding vascular endothelium with distilled water. 4 Infusion of TDC (1.9 x 10(-8) - 1.9 x 10(-6) mol) with K+-free or high K+ (60 mM) physiological salt solution (PSS) did not affect the vasodilator effect of TDC. 5 Contractions induced by KCl (0.01 - 1.0 M), arginine vasopressin (AVP, 10(-10) - 10(-7) M) or cirazoline (10(-7) x 10(-5) M) were all inhibited by TDC (300 mu M). 6 TDC (10(-6) to 10(-3) M) also inhibited the basal tension and the development of spontaneous contractions in the isolated portal vein. 7 TDC (300 mu M), however, did not affect noradrenaline-induced phasic contractions elicited in Ca-2+-free PSS by Ca?(2+ release from intracellular stores. 8 We conclude that TDC inhibits Ca2+ entry through both voltage-operated and receptor-operated calcium channels, whereas intracellular Ca2+ release is not affected.