EFFECTS OF CALCIUM-ANTAGONISTS ON INSULIN-MEDIATED GLUCOSE-METABOLISMIN SKELETAL-MUSCLE

The effect of three calcium antagonists (verapamil, diltiazem, and nif edipine) on insulin effects was investigated in isolated rat soleus mu scles. Soleus muscles were incubated in the presence of insulin (100 m u U/ml), a concentration that stimulates the rates of lactate formatio n and glycogen synthesis half-maximally and with and without a calcium antagonist. A decrease (48%; P < 0.001) was noted in the insulin-medi ated rate of glycogen synthesis by verapamil at 100 mu M; no effect wa s observed at lower concentrations of verapamil. Diltiazem decreased t he insulin-mediated rates of glycogen synthesis by 36 (P < 0.001), 64 (P < 0.001), and 73% (P < 0.001) at 1, 10, and 100 mu M, respectively. Nifedipine decreased the insulin-mediated rates of glycogen synthesis by 37% at O.1 mu M (P < 0.001), 36% at 1 mu M (P < 0.001), 21% at 10 mu M (P < 0.05), and 72% at 100 mu M (P < 0.001). Verapamil at 100 mu M decreased lactate formation by 48% (P < 0.001). However, diltiazem i ncreased the rate of lactate formation by 22 (P < 0.01), 43 (P < 0.001 ), and 61% (P < 0.001) at 1, 10, and 100 mu M, respectively In contras t, nifedipine increased the insulin-mediated rate of lactate formation by 45% only at 100 mu M (P < 0.01). The increased rate of lactate for mation was probably caused by an increased rate of glycogenolysis, bec ause high concentrations of all the calcium antagonists significantly decreased muscle glycogen content. The insulin-stimulated rate of 3-O- methyl-D-glucose transport or cAMP content was not affected by diltiaz em at 1 or 10 mu M. The results suggest that the calcium antagonists w ork by a mechanism, possibly by activating a calcium channel or an ext racellular receptor, to influence markedly insulin-mediated intracellu lar glucose metabolism in skeletal muscle.