Calcium antagonists and cardiac noradrenaline release in ischemia

The effects of the calcium antagonists verapamil, gallopamil, nifedipine, felodipine and diltiazem on noradrenaline release during ischemia were studied in isolated perfused rat hearts. Endogenous levels of noradrenaline and its intraneuronal metabolite dihydroxyphenylethyleneglycol (DOPEG) were determined by high pressure liquid chromatography. Global isothermic ischemia of 20 min caused a release of endogenous noradrenaline amounting to 180 +/- 15 pmol/g. The calcium antagonists tested significantly suppressed ischemia-induced noradrenaline release (IC50 in mumols/l: verapamil 1, gallopamil 0.3, nifedipine 1, felodipine 3). Noradrenaline release during ischemia and the inhibitory effect of the calcium antagonists, were independent of extracellular calcium, indicating a nonexocytotic release mechanism. Interaction of the calcium antagonists with the major components of nonexocytotic release, intraneuronal storage and carrier-mediated transport, was tested in normoxic rat hearts. Vesicular storage was not stabilized by the calcium antagonists. In fact, verapamil, gallopamil, diltiazem and felodipine disturbed storage function, as indicated by an increased DOPEG release. Direct interaction with the noradrenaline carrier (uptake1) was demonstrated for verapamil, gallopamil, and diltiazem in a model of 3H-noradrenaline uptake. In conclusion, the calcium antagonists investigated inhibit noradrenaline release in ischemia by a mechanism which is different from blockade of neuronal calcium influx, and is rather due to an interaction with carrier-mediated transport of noradrenaline across the plasma membrane.