Effects of PDE inhibitors and carbachol on the L-type Ca current in guinea pig ventricular myocytes.
The phosphodiesterase inhibitors 3-isobutyl-1-methylxanthine (IBMX; 100 microM) and papaverine (100 microM) increased peak L-type Ca current (ICa) more than fivefold in a way similar to isoproterenol, forskolin, or intracellular adenosine 3',5'-cyclic monophosphate in guinea pig ventricular myocytes studied with the whole cell voltage-clamp technique at 22-24 degrees C. IBMX and papaverine could also induce a chloride current. Both drugs caused an apparent increase of ICa inactivation as revealed by 1) a negative shift of the ICa inactivation curve between -40 and 0 mV and 2) a suppression of the relief from inactivation at potentials positive to 0 mV. In the presence of IBMX or papaverine, the amplitudes of both the rapidly and slowly inactivating components of ICa were increased; the effect on the fast component was more pronounced. The drugs did not accelerate the inactivation time course of either component. Carbachol (CCh; 100 microM) reversed the increase in ICa produced by IBMX or papaverine. However, ICa could not be restored to its original magnitude on washout of CCh in the presence of phosphodiesterase inhibitors. In pertussis toxin-treated cells or in the presence of Ly-83583 (1-100 microM), IBMX retained its effect but CCh was unable to reduce ICa. Dialysis with guanosine 3',5'-cyclic monophosphate (cGMP; 0.1-100 microM) or 8-bromoguanosine 3',5'-cyclic monophosphate (30 microM) suppressed the increase of ICa by IBMX; the inhibition by cGMP was additive with that produced by CCh. We suggest that the major part of IBMX and papaverine effect is mediated by phosphodiesterase inhibition and involves an increase in intracellular adenosine 3',5'-cyclic monophosphate levels. CCh reversal of phosphodiesterase inhibitor action probably involves an elevation of cGMP levels and activation of cGMP-dependent protein kinase.
Mubagwa
K
K
Department of Pharmacology, University of Connecticut Health Center, Farmington 06030.
Shirayama
T
T
Moreau
M
M
Pappano
A J
AJ
D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology; D000818:Animals; D015220:Calcium Channels / Q000187:drug effects* / Q000502:physiology; D002217:Carbachol / Q000494:pharmacology*; D018118:Chloride Channels / Q000502:physiology; D000242:Cyclic AMP / Q000378:metabolism; D006152:Cyclic GMP / Q000502:physiology; D004553:Electric Conductivity; D006168:Guinea Pigs; D006352:Heart Ventricles; D009206:Myocardium / Q000166:cytology / Q000378:metabolism*; D010208:Papaverine / Q000494:pharmacology; D010277:Parasympathomimetics / Q000494:pharmacology; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*
D015220:Calcium Channels; D018118:Chloride Channels; D010277:Parasympathomimetics; D010726:Phosphodiesterase Inhibitors; D002217:Carbachol; D010208:Papaverine; D000242:Cyclic AMP; D006152:Cyclic GMP; D015056:1-Methyl-3-isobutylxanthine