Effects of calcium entry blockers on calcium‐dependent contractions of rat portal vein

The effects of six calcium entry blockers belonging to the dihydropyridine (isradipine or PN 200‐110, nifedipine, nicardipine), verapamil (D888 or desmethoxyverapamil, D600 or gallopamil) and diltiazem classes were investigated on isometric spontaneous contractions and contractions induced by high‐K+solutions, noradrenaline, acetylcholine and caffeine.The rank order of potency was PN 200‐110>nicardipine = nifedipine = D888>D600>diltiazem from experiments on spontaneous contractions and high‐K+induced contractions. With depolarized preparations, the concentration‐response curves for nicardipine, PN 200‐110, nifedipine and D600 were significantly shifted to the left indicating that the calcium entry blockers show voltage‐dependent inhibitory properties. This effect was not significant with D888 and diltiazem.All the calcium entry blockers strongly reduced the noradrenaline (NA)‐ and acetylcholine (ACh)‐induced contractions at concentrations which produced complete inhibition of spontaneous contractions. They had a slight effect on caffeine‐induced contractions.In Ca2+‐free, EGTA‐containing solutions, both ACh, NA and caffeine produced transient contractions, the amplitude of which could be taken as a measurement of the amount of internal calcium present in a drug‐sensitive calcium store. The filling of the calcium store was maximal after 10–12 min of calcium loading in 2.1 mmCa2+, while the depletion was complete after 4–6 min of perfusion in Ca2+‐free solution.At concentrations which abolished spontaneous contractions, PN 200‐110, nifedipine, D888 and D600 had no appreciable effect on contractions evoked in Ca2+‐free solutions by ACh, NA and caffeine. When added in Ca2+‐containing solutions diltiazem and, to a lesser extent, nicardipine strongly reduced the contractions evoked in Ca2+‐free solutions, suggesting that they inhibited the filling of the internal calcium store.These results indicate that the six calcium entry blockers are potent inhibitors of calcium influx through voltage‐dependent calcium channels. Two of them (diltiazem and nicardipine) may exert an additional effect to depress contractions dependent on intracellular calcium release.