Beta-adrenergic and muscarinic agonists modulate inactivation of L-type Ca2+ channel currents in guinea-pig ventricular myocytes.
The objective of this study was to examine the effects of isoproterenol (isoprenaline) and carbachol upon voltage-dependent inactivation of L-type Ca(2+) current (I(Ca,L)). I(Ca,L) was recorded in guinea-pig isolated ventricular myocytes in the presence and absence of extracellular Ca(2+) to separate total inactivation and voltage-dependent inactivation. In the presence of Ca(2+), isoproterenol and carbachol had 'competitive' effects upon the relationships between membrane voltage and I(Ca,L) amplitude and inactivation. Neither agonist had a marked effect upon the decay of inward I(Ca,L) carried by Ca(2+). In the absence of Ca(2+), isoproterenol severely reduced and slowed I(Ca,L) inactivation; this effect was reversed by carbachol. Under control conditions decay was dominated by fast inactivation. Isoproterenol reduced fast-inactivating and increased time-independent currents in a dose-dependent manner. These effects were counteracted by carbachol. There was a reciprocal relationship between the amplitude of fast-inactivating and time-independent currents with agonist stimulation. It is concluded that agonist modulation of rapid voltage-dependent inactivation of L-type Ca(2+) channels involves an 'on-off' switch.
Findlay
Ian
I
CNRS UMR 6542, Faculté des Sciences, Université de Tours, Parc de Grandmont, France. findlay@univ-tours.fr
D000318:Adrenergic beta-Agonists / Q000494:pharmacology*; D000818:Animals; D002118:Calcium / Q000378:metabolism; D020746:Calcium Channels, L-Type / Q000187:drug effects*; D002217:Carbachol / Q000494:pharmacology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D004594:Electrophysiology; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects*; D066298:In Vitro Techniques; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D008564:Membrane Potentials / Q000502:physiology; D018721:Muscarinic Agonists / Q000494:pharmacology*; D009206:Myocardium / Q000166:cytology / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D010766:Phosphorylation
D000318:Adrenergic beta-Agonists; D020746:Calcium Channels, L-Type; D018721:Muscarinic Agonists; D002217:Carbachol; D017868:Cyclic AMP-Dependent Protein Kinases; D007545:Isoproterenol; D002118:Calcium