pH-dependent block of the L-type Ca2+ channel current by diltiazem in human mesenteric arterial myocytes

Inhibition of the L-type Ca2+ channel current (IBa) by diltiazem was characterised in human mesenteric arterial myocytes. External (pHo) and internal (pHi) pH was varied to alter the proportion of drug in charged and neutral forms. Diltiazem (20 microM) reduced IBa amplitude by approximately half at pHo 7.2 and 9.2 at holding potential -60 mV. The IBa decay was increased by diltiazem at pHo = 9.2 (97% uncharged), but not at 7.2. The IC50 for inhibition of IBa by diltiazem at holding potential -60 mV was decreased from 51 to 20 microM at pHo 7.2 and 9.2, respectively. At holding potential of -90 mV, but not -60 mV, tonic block increased and use-dependent block decreased as pHo was raised from 6.2 to 9.2. Diltiazem also caused a hyperpolarizing shift in IBa availability at alkaline pHo. The results suggest that raising pH promotes Ca2+ channel blockade by increasing the proportion of uncharged diltiazem.