Influence of depolarization on vasorelaxant potency and efficacy of Ca2+ entry blockers, K+ channel openers, nitrate derivatives, salbutamol and papaverine in rat aortic rings

Abstract

We examined the effects of various KCl concentrations on the actions of some vasodilators belonging to different pharmacological classes in rat aortic rings. In some experiments, tissues were precontracted with noradrenaline after blocking voltage-dependent channels to assess the effects of depolarisation unaccompanied by the entry of extracellular Ca2+ into the cytosol. Concentration/response curves for the vasorelaxant effect of calcium entry blockers (e.g. diltiazem), K+ channel openers (e.g. aprikalim), nitrate derivatives (e.g. nitroglycerin), a beta2-adrenergic agonist (salbutamol) and papaverine were obtained by using endothelium-denuded rat aortic rings precontracted with KC1 (20-60 mM) to determine the potencies and efficacies of the drugs. The efficacies and potencies of calcium entry inhibitors were virtually independent of the [KCl]. A reduction in the potency (up to 18-fold) of papaverine occurred without changes in efficacy when the [KCl] was raised from 20 to 60 mM. The decline in potency was even greater for nitrate-like compounds. The potency of K+ channel openers in aortic rings precontracted with 30 mM KCI decreased by three- to sixfold compared with those precontracted with 20 mM KCl. With the exception of pinacidil, the efficacy of these agents already started to decline in preparations precontracted with 25 mM KCI and was virtually zero in preparations precontracted with 60 mM KCI. In contrast to other K+ channel openers, the vasorelaxant action of pinacidil was relatively resistant to glibenclamide. Salbutamol produced only a slight relaxation even in preparations precontracted with 20 mM KCl. In nitrendipine-pretreated, noradrenaline-precontracted aortic rings, the vasorelaxant effects of aprikalim, but not those of linsidomine or papaverine, declined when the [KCl] of the bathing medium was increased. In conclusion, the vasorelaxant potency and efficacy of calcium entry blockers is independent of the [KCI] used to precontract rat aortic rings, and thus, of the degree of membrane depolarisation. In contrast, increasing the [KCl] strongly reduces the potency and the efficacy of K+ channel openers not only in this preparation but also in noradrenaline-precontracted rings in which the entry of extracellular Ca2+ was prevented with nitrendipine. This indicates that, with the exception of pinacidil, the vasorelaxant activity of K+ channel openers depends on the degree of membrane depolarisation. Finally, the vasorelaxant potency and efficacy of nitrate-like compounds and papaverine are independent of depolarisation per se but they are markedly affected by the influx of Ca2+ accompanying elevated [KCI]. Thus, the degree of vessel depolarisation should be taken into consideration when attempting to compare potencies and efficacies among vasorelaxant agents.

Relaxation in Different-Sized Rat BloodVessels Mediated by Endothelium-Derived Hyperpolarizing Factor: Importance of Processes Mediating Precontractions

“…obs. ], as documented by other investigators [30]. Interestingly, the hyperpolarizing effects of pinacidil were greater in the aorta than in mesenteric arteries, and the resting membrane potentials were more positive in the aorta than in the mesenteric arteries.…”

(+/−)‐Naringenin as large conductance Ca2+‐activated K+ (BKCa) channel opener in vascular smooth muscle cells

“…60 m M ) KCl concentrations, owing to – inter alia – the decrease of the chemical K + gradient accounting for the outward flow of K + , (+/−)‐naringenin and naringin were also tested on 60 m M KCl precontracted vessels. Indeed, their vasorelaxant activity was markedly depressed at high concentrations of K + (60 m M KCl), a finding compatible with the pharmacodynamic pattern typical of the K + channel openers (Magnon et al ., 1998). In a recent study on intact aorta rings, the vasorelaxant effect of (+/−)‐naringenin was shown to be mediated, at least in part, by endothelium released nitric oxide (Ajay et al ., 2003).…”

Facial Nerve Palsy After Intracisternal Papaverine Application During Aneurysm Surgery

“…Therefore, the degree of depolarization of the vessel is an important consideration. 13) Isoquinolines have been shown to act on mureceptors. 2) Activated mu-receptors can delay neurotransmission and produce an analgesic effect.…”