Effects of sustained beta-adrenergic stimulation on ionic currents of cultured adult guinea pig cardiomyocytes.
Short-term stimulation of beta-receptors is known to affect cardiac ion channels; however, the impact of longer-term stimulation on intrinsic channel function is poorly understood. To evaluate this, cultured guinea pig ventricular myocytes were exposed to isoproterenol (10 nM), vehicle, or isoproterenol plus propranolol (1 microM) for 48 h. Sustained exposure to isoproterenol decreased the density of the inward rectifier (I(K1)), slow delayed rectifier (I(Ks)), and L-type Ca2+ (I(Ca L)) currents, effects that were fully prevented by propranolol. Changes in K+ currents were prevented by the beta1-selective antagonist CGP-20712A, unaffected by the beta2-antagonist ICI-118,551, and mimicked by the membrane-permeable cAMP analog 8-bromo-cAMP. Isoproterenol did not alter the current-voltage relationship of the K+ currents but increased the density of T-type Ca2+ current (I(Ca T)) and thereby increased the proportion of the total Ca2+ current at more negative potentials. We conclude that sustained exposure to isoproterenol reduces I(K1), I(Ks), and I(Ca L) density and increases the density of I(Ca T). The direct ionic current remodeling effects of sustained beta-adrenoceptor stimulation resemble changes reported with heart failure and may be important in arrhythmogenic ionic remodeling.
Zhang
Li-Ming
LM
Research Center and Department of Medicine, Montreal Heart Institute, Montreal, Quebec H1T 1C8, Canada.
Wang
Zhiguo
Z
Nattel
Stanley
S
D000200:Action Potentials / Q000187:drug effects; D000316:Adrenergic alpha-Agonists / Q000494:pharmacology*; D000818:Animals; D020746:Calcium Channels, L-Type / Q000187:drug effects / Q000502:physiology*; D002478:Cells, Cultured; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects / Q000502:physiology*; D007545:Isoproterenol / Q000494:pharmacology*; D007700:Kinetics; D009206:Myocardium / Q000166:cytology*; D015221:Potassium Channels / Q000187:drug effects / Q000502:physiology*; D011433:Propranolol / Q000494:pharmacology*; D013997:Time Factors
D000316:Adrenergic alpha-Agonists; D020746:Calcium Channels, L-Type; D015221:Potassium Channels; D011433:Propranolol; D007545:Isoproterenol