ACIDOSIS MASKS BETA-ADRENERGIC CONTROL OF CARDIAC L-TYPE CALCIUM CURRENT

The beta-adrenergic control of the L-type Ca2+ current (I-Ca) was exam ined as a function of extracellular pH (pH(o)) in guinea-pig ventricul ar myocytes using the whole-cell voltage-clamp technique. I-Ca was eli cited in Cs+-loaded myocytes by depolarizing pulses from a holding pot ential of -40 mV. The maximum I-Ca density in response to 0.01 or 1 mu M isoproterenol was significantly less in myocytes pretreated with ac idic external solution (pH(o) 6.6 or 5.8) compared with cells studied at control pH(o) 7.4. This acidosis-induced decrease in beta-responsiv eness was also accompanied by a similar reduction in basal current den sity. Myocytes studied under alkaline conditions (pH(o) 8.2) also had reduced beta-responsiveness although basal I-Ca density tended to be g reater than control. In addition to the diminished effects of isoprote renol, acidic myocytes had smaller responses to extracellular forskoli n and internally applied adenosine 3',5'-cyclic monophosphate, compare d with control. The blunted responses to these latter stimuli were sim ilar in magnitude to that observed with 1 mu M isoproterenol. These fi ndings suggest that protons interfere with the beta-adrenergic control of I-Ca primarily by a direct inhibition of the Ca2+ channel which in dependently masks the effects of the adenylyl cyclase cascade. (C) 199 5 Academic Press Limited