Role of Cl- channels in alpha-adrenoceptor-mediated vasoconstriction in the anesthetized rat

In vitro studies have provided evidence that Cl- ion currents are important for activation of vascular smooth muscle contraction. The stilbene, 4,4'-d iisothiocyanatostilbene-2,2'-disulfonic acid (DIDS), disrupts Cl- metabolis m by blocking Cl- channels and by inhibiting Cl- bicarbonate exchange. The aims of this study were to: (i) characterize the hemodynamic responses prod uced by DIDS in pentobarbital anesthetized rats, and (ii) examine vasoconst rictor responses to norepinephrine before and after administration of DIDS. DIDS (2.5-50 mu mol/kg, 92.5 mu mol/kg total dose, i.v.) produced dose-dep endent but transient reductions in mean arterial blood pressure and in hind quarter, renal and mesenteric vascular resistances. Prior to the administra tion of DIDS, norepinephrine (1.0-5.0 mu g/kg, i.v.) produced dose-dependen t increases in mean arterial pressure, renal resistance and mesenteric resi stance, but decreases in hindquarter resistance that were inversely related to dose. After administration of DIDS, the peak presser responses produced by norepinephrine were either slightly diminished (1.0, 2.5 mu g/kg) or un changed (5.0 mu g/kg). Peak norepinephrine-induced changes in hindquarter a nd renal vascular resistance were unaffected by DIDS, while increases in me senteric resistance were augmented. The total norepinephrine-induced increa ses in mean arterial pressure (mm Hg x s) were markedly reduced by DIDS. Th ese effects of DIDS on norepinephrine-induced responses were similar, but n ot identical to those of the voltage-sensitive Ca2+ channel blocker, nifedi pine (500 nmol/kg, i.v.). These findings suggest that DIDS may interfere wi th norepinephrine-induced depolarization of resistance arteries, thereby pr eventing activation of voltage-sensitive Ca2+ channels. (C) 2000 Elsevier S cience B.V. All rights reserved.