Acidosis masks beta-adrenergic control of cardiac L-type calcium current

The beta-adrenergic control of the L-type Ca2+ current (ICa) was examined as a function of extracellular pH (pHo) in guinea-pig ventricular myocytes using the whole-cell voltage-clamp technique. ICa was elicited in Cs(+)-loaded myocytes by depolarizing pulses from a holding potential of -40 mV. The maximum ICa density in response to 0.01 or 1 microM isoproterenol was significantly less in myocytes pretreated with acidic external solution (pHo 6.6 or 5.8) compared with cells studied at control pHo 7.4. This acidosis-induced decrease in beta-responsiveness was also accompanied by a similar reduction in basal current density. Myocytes studied under alkaline conditions (pHo 8.2) also had reduced beta-responsiveness although basal ICa density tended to be greater than control. In addition to the diminished effects of isoproterenol, acidic myocytes had smaller responses to extracellular forskolin and internally applied adenosine 3',5'-cyclic monophosphate, compared with control. The blunted responses to these latter stimuli were similar in magnitude to that observed with 1 microM isoproterenol. These findings suggest that protons interfere with the beta-adrenergic control of ICa primarily by a direct inhibition of the Ca2+ channel which independently masks the effects of the adenylyl cyclase cascade.