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

The β-adrenergic control of the L-type Ca^2* current (I_ca) was examined as a function of extracellular pH (pH_o) in guinea-pig ventricular myocytes using the wholecell voltage-clamp technique. I_Ca was elicited in Cs⁺-loaded myocytes by depolarizing pulses from a holding potential of -40 mV. The maximum I_Ca density in response to 0.01 or 1 μM isoproterenol was significantly less in myocytes pretreated with acidic external solution (pH 6.6 or 5.8) compared with cells studied at control pH_o 7.4. This acidosis-induced decrease in β-responsiveness was also accompanied by a similar reduction in basal current density. Myocytes studied tinder alkaline conditions (pH_o 8.2) also had reduced β-responsiveness although basal I_Ca 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 mononophosphate. compared with control. The blunted responses to these latter stimuli were similar in magnitude to that observed with 1 μM isoproterenol. These findings suggest that protons interfere with the β-adrenergic control of I_Ca primarily by a direct inhibition of the Ca²⁺ channel which independently masks the effects of the adenylyl cyclase cascade.