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Sympathetic Modulation of the Effect of Nifedipine on Myocardial Contraction and Ca Current in the Rat

Abstract : The regulation of cardiacl-type Ca2+current (ICa) and contraction by dihydropyridine antagonists andβ-adrenergic receptor agonists has been the subject of numerous studies over the last decade. However, little is known on the crosstalk between these two regulatory pathways. For instance, a fundamental question that remains unanswered is: does activation of theβ-adrenergic receptors modify the sensitivity of the myocardium to dihydropyridine agonists? To answer this question, we examined in the present study how activation of theβ-adrenergic receptors modifies the effects of nifedipine on the mechanical and energetic parameters of the isolated perfused rat heart. Activation of theβ-adrenergic receptors was achieved by perfusing the hearts with isoprenaline, a non-selectiveβ-adrenergic receptor agonist, and could be reduced by atenolol, aβ1-adrenergic receptor antagonist. To examine possible alterations during hypertension in the sensitivity of the hearts to the drugs tested, the study was performed in both normotensive Wistar–Kyoto (WKY) and spontaneously hypertensive animals (SHR). While 0.1μMnifedipine reduced left ventricular pressure (LVP) by 36% and 34% in WKY and SHR rats, respectively, under basal conditions, its effects became negligible in both groups of rats after stimulation of the hearts with 0.1μMisoprenaline. Addition of 1μMatenolol in the presence of isoprenaline restored the inhibitory effect of nifedipine to control values in both WKY and SHR rats. Additional experiments were performed in isolated ventricular myocytes from WKY rats using the whole-cell patch-clamp technique. The inhibitory effects of 0.1 to 1μMnifedipine were significantly larger on basal ICathan after the current had been previously elevated by 0.1μMisoprenaline. Addition of 1μMatenolol in the presence of isoprenaline partially restored the inhibitory effect of nifedipine on ICa. Our results demonstrate a reduced sensitivity of the heart muscle to nifedipine during activation ofβ1-adrenergic receptors. This effect is partly explained by a reduced inhibitory effect of nifedipine on ICaduring activation of cAMP-dependent phosphorylation
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https://hal-universite-paris-saclay.archives-ouvertes.fr/hal-03617473
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Submitted on : Wednesday, March 23, 2022 - 6:53:29 PM
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Abdelkhaleq Legssyer, Leif Hove-Madsen, Jacqueline Hoerter, Rodolphe Fischmeister. Sympathetic Modulation of the Effect of Nifedipine on Myocardial Contraction and Ca Current in the Rat. Journal of Molecular and Cellular Cardiology, Elsevier, 1997, 29 (2), pp.579-591. ⟨10.1006/jmcc.1996.0301⟩. ⟨hal-03617473v2⟩

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