Characterization in rat aorta of the binding sites responsible for blockade of noradrenaline‐evoked calcium entry by nisoldipine

Morel, Nicole; Godfraind, Théophile

doi:10.1111/j.1476-5381.1991.tb12196.x

Cited by 52 publications

(17 citation statements)

References 37 publications

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“…Therefore, we tried to characterize the L-type Ca 21 channels using [3H]PN200-110 binding to aortic strip in the presence of PE. It has been reported that both membrane depolarization and the stimulation of a,-adrenoceptors increases the binding affinity of di hydropyridines without changing the number of dihy dropyridine receptors in vascular smooth muscles (7,16,20,27). Similar results were obtained in the present study ( (20).…”

Section: Discussionsupporting

confidence: 82%

Mechanisms of the Enhanced Contractile Response to Phenylephrine in Thoracic Aorta Isolated from Rats with Dietary Magnesium Deficiency

Sakaguchi

Nishio

1994

Japanese Journal of Pharmacology

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ABSTRACT-The mechanisms underlying the enhanced contractile response to phenylephrine (PE) and increased susceptibility to nifedipine of de-endothelialized thoracic aorta isolated from rats with dietary magnesium deficiency (Mg-deficient rats) were examined by functional and radioligand binding studies. Enhanced PE-induced contractions and increased susceptibility to nifedipine in Mg-deficient rats were not observed in the presence of 10 pM H7. PE significantly decreased the KD value without changing Bmax in the binding of [3H]PN200-110 to de-endothelialized aortic strips. The KD value obtained in the Mg-deficient rats was significantly smaller than that in the controls. Nifedipine displaced the binding of [3H]PN200-110 con centration-dependently, and the pK; value in Mg-deficient rats was significantly larger than that in the con trols. A combination of PE and H7 abolished this difference. These results indicate that the modulation of L-type Ca 21 channels via the stimulation of a,-adrenoceptors may be involved in the enhancement of vasoconstriction and increased susceptibility to nifedipine in aortas isolated from Mg-deficient rats. The H7-sensitive mechanisms may play an important role in these phenomena.

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Section: Discussionsupporting

confidence: 82%

Mechanisms of the Enhanced Contractile Response to Phenylephrine in Thoracic Aorta Isolated from Rats with Dietary Magnesium Deficiency

Sakaguchi

Nishio

1994

Japanese Journal of Pharmacology

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“…This finding is entirely confirmed by the present investigation which demonstrates that in noradrenaline-contracted, nitrendipine-pretreated aortic rings, the vasorelaxant effects of aprikalim are comparable to those measured in vessels contracted only with 25 mM KCl. Interestingly, in these two preparations the degree of membrane depolarisation is similar despite the different contractile agonists used (Morel and Godfraind 1991). Furthermore, an increase in [KCl] of the bathing solution produced a decline of aprikalim vasorelaxant potency and efficacy in both KCl-and noradrenaline-contracted, nitrendipine-pretreated aortic rings.…”

Section: Discussionmentioning

confidence: 77%

“…With 50 mM KCl this potential falls to -40 mV and a reversal potential is reached with 130 mM KCl which approximates the intracellular [K + ]. Furthermore, in some experiments noradrenaline was used to contract aortic rings and the concentration used (1 µM) drives the cell membrane potential to a value similar to that measured after 25 mM KCl (Morel and Godfraind 1991).…”

Section: Discussionmentioning

confidence: 99%

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

Magnon

Calderone

Floch

et al. 1998

Naunyn-Schmiedeberg's Arch Pharmacol

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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.

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“…To explain the possible differences between strains, the al-adrenoceptor reserve in rings with and without endothelium, and the al-adrenoceptor density were explored. Parameters governing agonism were quantified by means of the nested hyperbolic method (Parker & Waud, 1971;James et al, 1989) and the operational model of agonism (Black & Leff, 1983 [3H]-prazosin binding assay Binding studies were performed by incubation of rat tail artery rings (1.5-2 mg wet weight) under conditions similar to those previously described for the mesenteric artery (Morel & Godfraind, 1991 (Fleming et al, 1972;Leff et al, 1990). Two-way analysis of variance was applied to investigate whether each parameter was affected by the strain and/or the endothelium.…”

Section: Introductionmentioning

confidence: 99%

Endothelial modulation of α₁‐adrenoceptor contractile responses in the tail artery of spontaneously hypertensive rats

Tabernero¹,

Giraldo²,

Vivas³

et al. 1996

British J Pharmacology

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1 Vascular contraction induced by phenylephrine was studied in tail artery rings from spontaneously hypertensive (SHR) and Wistar Kyoto rats (WKY) with particular focus on the role of endothelium. The influence of receptor reserve and the density of cxl-adrenoceptors on the possible differences observed were also analysed.2 Phenylephrine (0.01-100 giM) induced concentration-dependent vasoconstrictions. The maximum response (a, P<0.001) was greater but the pECm (P<0.05) smaller in rings from SHR than from WKY rats irrespective of the presence or absence of endothelium. 3 Removal of endothelial cells resulted in a decrease of the maximum contraction with no modification in the pEC50 in arteries from both WKY and SHR.4 The density of cl-adrenoceptors (Bmn,x) and the dissociation constant (KD) were found to be the same for preparations from SHR and WKY rats in [3H]-prazosin binding experiments. 5 The apparent affinity (pKA) determined by the nested hyperbolic method and the operational model was similar in tail arteries from the two rat strains, irrespective of the presence or absence of endothelium. However, in endothelium-denuded rings, the pKA value was enhanced when compared with intact rings, in both SHR and WKY rats. 6 In rings from hypertensive rats, the operational parameter maximum possible effect (Em) was greater and the agonist efficacy (z) was smaller than in rings from normotensive rats. When the endothelium was removed log T and Em diminished in preparations from both rat strains. 7 In summary, the increased maximum responsiveness to phenylephrine in rings from SHR could be due to enhancement in Em. The log Tvalues indicate a deterioration in the transduction of the stimulus provided by the agonist in tail arteries from hypertensive animals. This study also suggests that the absence of endothelium modifies the a,-adrenoceptor-mediated vasocontriction probably by altering the transduction signalling mechanisms. The importance of analysing the degree of endothelium functionality when comparing results from different groups of rats is stated.

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Characterization in rat aorta of the binding sites responsible for blockade of noradrenaline‐evoked calcium entry by nisoldipine

Cited by 52 publications

References 37 publications

Mechanisms of the Enhanced Contractile Response to Phenylephrine in Thoracic Aorta Isolated from Rats with Dietary Magnesium Deficiency

Mechanisms of the Enhanced Contractile Response to Phenylephrine in Thoracic Aorta Isolated from Rats with Dietary Magnesium Deficiency

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

Endothelial modulation of α₁‐adrenoceptor contractile responses in the tail artery of spontaneously hypertensive rats

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Characterization in rat aorta of the binding sites responsible for blockade of noradrenaline‐evoked calcium entry by nisoldipine

Cited by 52 publications

References 37 publications

Mechanisms of the Enhanced Contractile Response to Phenylephrine in Thoracic Aorta Isolated from Rats with Dietary Magnesium Deficiency

Mechanisms of the Enhanced Contractile Response to Phenylephrine in Thoracic Aorta Isolated from Rats with Dietary Magnesium Deficiency

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

Endothelial modulation of α1‐adrenoceptor contractile responses in the tail artery of spontaneously hypertensive rats

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Endothelial modulation of α₁‐adrenoceptor contractile responses in the tail artery of spontaneously hypertensive rats