Effect of Ca++ channel blockers on energy level and stimulated insulin secretion in isolated rat islets of Langerhans.

To investigate the effect of calcium channel blockade on intracellular energy levels and stimulated insulin secretion in isolated rat pancreatic islets, five different blockers of calcium channels were used. Insulin secretion stimulated with 16 mM glucose, 40 mM KCl or 20 mM alpha-ketoisocaproic acid was inhibited dose dependently by nifedipine, diltiazem, flunarizine and verapamil, albeit with different potencies. Nifedipine and flunarizine were more potent than diltiazem and verapamil. omega-Conotoxin GVIA (100 nM) had no significant effect on insulin release with all stimuli tested, although it caused approximately 20% inhibition of the late phase of secretion stimulated with high glucose. The doses of L-type channel antagonists and of flunarizine chosen for the measurements of cellular energy levels gave 60 to 80% inhibition of total stimulated insulin release. The [ATP]/[ADP] ratio, with 5 mM glucose in the perifusion medium, was greater when these channel blockers were present than in controls, whereas it was smaller with omega-conotoxin. The rises in the nucleotide ratio elicited by 16 mM glucose were not affected by any of the antagonists tested. Thus, influx of Ca++ and a consequent rise in its intracellular level are unlikely to be the primary causal event in stimulation of energy synthesis which occurs upon addition of high concentrations of metabolic secretagogues.