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 microM), tetraethylammonium (5 mM), ouabain (10(-5) M), NG-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 microM). 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 microM), however, did not affect noradrenaline-induced phasic contractions elicited in Ca(2+)-free PSS by Ca2+ 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.
Liver Unit, University of Calgary Faculty of Medicine, AB Canada.
J M
JM
Pak
A S
AS
Adeagbo
C R
CR
Triggle
E A
EA
Shaffer
S S
SS
Lee
D000818:Animals; D001647:Bile Acids and Salts / Q000494:pharmacology*; D015220:Calcium Channels / Q000502:physiology*; D004730:Endothelium, Vascular / Q000502:physiology; D008297:Male; D008638:Mesenteric Arteries / Q000187:drug effects / Q000502:physiology; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000502:physiology; D009638:Norepinephrine / Q000494:pharmacology; D010477:Perfusion; D015221:Potassium Channels / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011943:Receptors, Adrenergic, beta / Q000502:physiology; D000254:Sodium-Potassium-Exchanging ATPase / Q000502:physiology; D014664:Vasodilation / Q000187:drug effects
D001647:Bile Acids and Salts; D015220:Calcium Channels; D015221:Potassium Channels; D011943:Receptors, Adrenergic, beta; D000254:Sodium-Potassium-Exchanging ATPase; D009638:Norepinephrine