Sympathetic modulation of the effect of nifedipine on myocardial contraction and Ca current in the rat.
The regulation of cardiac L-type Ca2- current (Ica) and contraction by dihydropyridine antagonists and beta-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 the beta-adrenergic receptors modify the sensitivity of the myocardium to dihydropyridine agonists? To answer this question, we examined in the present study how activation of the beta-adrenergic receptors modifies the effects of nifedipine on the mechanical and energetic parameters of the isolated perfused rat heart. Activation of the beta-adrenergic receptors was achieved by perfusing the hearts with isoprenaline, a non-selective beta-adrenergic receptor agonist, and could be reduced by atenolol, a beta-adrenergic receptor antagonist. To examine possible alterations during hypertension in the sensitivity of the hearts to the drug, tested, the study was performed in both normotensive Wistar-Kyoto (WKY) and spontaneously hypertensive animals (SHR). While 0.1 microM nifedipine 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 0.1 microM isoprenaline. Addition of 1 microM atenolol 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 1 microM nifedipine were significantly larger on basal Ica than after the current had been previously elevated by 0.1 microM isoprenaline. Addition of 1 microM atenolol 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 of beta 1-adrenergic receptors. This effect is partly explained by a reduced inhibitory effect of nifedipine on Ic during activation of cAMP-dependent phosphorylation.
Legssyer
A K
AK
Laboratoire de Cardiologie Cellulaire et Moléculaire, INSERM U-446, Université de Paris-Sud, Faculté de Pharmacie, Châtenay-Malabry, France.
Hove-Madsen
L
L
Hoerter
J
J
Fischmeister
R
R
D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000319:Adrenergic beta-Antagonists; D000818:Animals; D001262:Atenolol / Q000494:pharmacology; D002121:Calcium Channel Blockers / Q000494:pharmacology; D015220:Calcium Channels / Q000187:drug effects / Q000378:metabolism*; D002478:Cells, Cultured; D004095:Dihydropyridines / Q000037:antagonists & inhibitors; D006352:Heart Ventricles / Q000166:cytology; D006973:Hypertension / Q000188:drug therapy / Q000378:metabolism; D066298:In Vitro Techniques; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects* / Q000502:physiology; D015425:Myocardial Reperfusion; D009543:Nifedipine / Q000494:pharmacology*; D018408:Patch-Clamp Techniques; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D011943:Receptors, Adrenergic, beta / Q000187:drug effects / Q000378:metabolism*; D013565:Sympatholytics / Q000494:pharmacology; D013566:Sympathomimetics / Q000494:pharmacology*; D016276:Ventricular Function
D000318:Adrenergic beta-Agonists; D000319:Adrenergic beta-Antagonists; D002121:Calcium Channel Blockers; D015220:Calcium Channels; D004095:Dihydropyridines; D011943:Receptors, Adrenergic, beta; D013565:Sympatholytics; D013566:Sympathomimetics; D001262:Atenolol; C038806:1,4-dihydropyridine; D009543:Nifedipine; D007545:Isoproterenol