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 (I-Ba) by diltiazem was characterised in human mesenteric arterial myocytes. External (pH(o)) and internal (pH(i)) pH was varied to alter the proportion of drug in charged and neutral forms. Diltiazem (20 mu M) reduced I-Ba amplitude by approximately half at pH(o) 7.2 and 9.2 at holding potential - 60 mV. The I-Ba decay was increased by diltiazem at pH(o) = 9.2 (97% uncharged), but not at 7.2. The IC50 for inhibition of I-Ba by diltiazem at holding potential -60 mV was decreased from 51 to 20 mu M at pH(o) 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 pH(o) was raised from 6.2 to 9.2. Diltiazem also caused a hyperpolarizing shift in I-Ba availability at alkaline pH(o). The results suggest that raising pH promotes Ca2+ channel blockade by increasing the proportion of uncharged diltiazem. (C) 1998 Elsevier Science B.V. All rights reserved.