Differences between negative inotropic and vasodilator effects of calcium antagonists acting on extra- and intracellular calcium movements in rat and guinea-pig cardiac preparations

Summary In order to get more insight into the utilization of calcium in the mammalian heart and the influence of calcium antagonists on this process we have evaluated the negative inotropic and vasodilator effect of nifedipine, diltiazem, verapamil, bepridil and lidoflazine as well as of the intracellularly acting calcium antagonists ryanodine and TMB-8 in the presence of 0.9 and 1.8 mmol/l calcium in rat Langendorff hearts. The effect of ryanodine was also studied in guinea-pig Langendorff hearts. In addition, in rat and guinea-pig papillary muscles the effect of these drugs on the force of contraction was examined.With the exception of ryanodine and TMB-8 all calcium antagonists induced a pronounced coronary vasodilator effect. The rank order of potency for this effect was: nifedipine > verapamil = diltiazem = bepridil = lidoflazine in the presence of 0.9 mmol/l calcium. At a calcium concentration of 1.8 mmol/l nifedipine and verapamil proved more potent, whereas diltiazem was less active. All calcium antagonists completely suppressed the development of the left ventricular pressure. At a calcium concentration of 0.9 mmol/l the potency order for this effect was: ryanodine > nifedipine = verapamil > diltiazem = bepridil = lidoflazine > TMB-8. In the presence of 1.8 mmol/l calcium the concentration-response curves for reduction of the left ventricular pressure by nifedipine, verapamil and diltiazem slightly shifted to the right. In contrast to all calcium antagonists investigated, in guinea-pig Langendorff hearts ryanodine only partially decreased the left ventricular pressure.In rat papillary muscles ryanodine nearly completely reduced the force of contraction, whereas nifedipine only partially inhibited the force of contraction. Lidoflazine only slightly affected the force of contraction. In guinea-pig papillary muscles all drugs partially decreased the force of contraction. Lidoflazine, however, was more effective than in rat papillary muscles. In rat and guinea-pig papillary muscles the force of contraction was fully suppressed by a combination of nifedipine and ryanodine.The results of the present study suggest that in the rat heart extracellular calcium plays a major role in the maintenance of the coronary vascular tone. The development of contractile force relies on the release of activator calcium from the sarcoplasmic reticulum but also requires the influx of calcium through dihydropyridine-sensitive channels. In the guinea-pig heart activator calcium may also be released from a source complementary to the sarcoplasmic reticulum. Lidoflazine displays certain selectivity towards this particular calcium pool.Preliminary results have been presented at the Spring Meeting of the German Pharmacological and Toxicological Society, 14–17 March, 1989, Mainz (Hugtenburg et al. 1989a)