The effect of oximes on the dihydropyridine-sensitive Ca current of isolated guinea-pig ventricular myocytes.
Exposure of isolated guinea-pig ventricular myocytes to the uncharged oximes 2,3 butanedionemonoxine (BDM) and norPAM (but not by the charged PAM) results in a dose-dependent reduction of the duration of the action potential. The nifedipine-sensitive Ca current is fully inhibited by BDM (IC(50)5.8 +/- 0.4 mM) and nor PAM but is little affected by PAM. This inhibition is unaltered by the presence of BAY K 8644 but is antagonized by isoprenaline. The effect of isoprenaline is more pronounced when the solution in the patch pipette contains the non-hydrolysable analogue of adenosine 5'-triphosphate, ATP gamma S (the IC50 is increased to 44.0 +/- 5.2 mM). A hastening of the inactivation of the L-type Ca current persists when either 10 mM 1,2-bis(2-aminophenoxy)-ethane-N,N,N',N-tetraacetic acid (BAPTA) or 3 mM ATP gamma S is present in the pipette solution or when BAY K 8644 or isoprenaline are present in the bathing fluid. These results suggest that the inhibition of the Ca current is due to the phosphatase-like activity of the oximes but differs in some respects from previous work where a reduced level of phosphorylation is achieved by the introduction of protein kinase inhibitors or protein phosphatases into the sarcoplasm in guinea-pig myocytes. These differences could be explained if Ca channel availability is regulated by at least two sites of cAMP-dependent phosphorylation with oximes able to rapidly dephosphorylate both sites, while one of these sites is not readily dephosphorylated by the endogenous phosphatases.
Department of Physiology, School of Veterinary Science, Bristol, UK.
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Chapman
D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D015220:Calcium Channels / Q000187:drug effects / Q000502:physiology*; D002801:Cholinesterase Reactivators / Q000494:pharmacology*; D003931:Diacetyl / Q000031:analogs & derivatives* / Q000494:pharmacology; D006168:Guinea Pigs; D006352:Heart Ventricles / Q000166:cytology; D007545:Isoproterenol / Q000494:pharmacology*; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D010091:Oximes / Q000494:pharmacology*; D016276:Ventricular Function
D015220:Calcium Channels; D002801:Cholinesterase Reactivators; D010091:Oximes; C004717:diacetylmonoxime; C060977:pyridine-2-aldoxime; D003931:Diacetyl; D007545:Isoproterenol