Pharmacological modulation of calcium and potassium channels in isolated vascular smooth muscle cells.

Calcium antagonists relax vascular smooth muscle cells (VSM) by decreasing Ca-influx and intracellular Ca-load. In isolated VSM, Ca-influx was measured as Ca-current by the voltage clamp technique applied to a patch of membrane (single-channel current) or to the whole cell (whole-cell current ICa). Gallopamil exerted Ca-antagonism mostly by reducing channel availability, i.e. the probability that the Ca-channel opens upon depolarization. Whole-cell-Ca-currents revealed prominent frequency dependence, i.e. reduction of ICa increased with the number of depolarizations. In addition, the gallopamil effect was voltage-dependent such that depolarized myocytes were more sensitive than hyperpolarized cells. The dihydropyridine nitrendipine abbreviated the life time which the Ca-channel stood in the open state and it hindered the channel to re-open again. Reduction of availability was found only after a prolonged application. In whole cell ICa, nitrendipine accelerated the inactivation time course. The Ca-antagonistic effect was voltage-dependent but not frequency-dependent. Potassium agonists are supposed to activate K-channels thereby hyperpolarizing the membrane, hyperpolarization shuts off the Ca-channels and thereby reduces Ca-influx. The K-agonists cromakalim, (+) niguldipine and diazoxide activated the Ca-dependent maxi K-channel (inside-out patches studied at [Ca2+]c of 50 nmol/l or 500 nmol/l. They increased the open probability mainly by decreasing the long closures between the channel openings. The K-agonists can repolarize the cell once it excited and suppress further excitability.