STUDIES ON THE MECHANISM OF ACTION OF GLUCAGON IN STRIPS OF RABBIT RENAL ARTERY

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Abstract
1 The vasodilator effects of glucagon and adenosine cyclic 3′,5′-monophosphate (cyclic AMP) were evaluated in strips of rabbit renal artery contracted with noradrenaline (NA) in the absence and presence of phosphodiesterase inhibitors or calcium (Ca2+) antagonists. 2 The vascular relaxant effect of glucagon was markedly potentiated by various concentrations of four different phosphodiesterase inhibitors (papaverine, theophylline, 3-isobutyl-1-methylxanthine (IBMX) and indomethacin), while that of cyclic AMP was potentiated by only two of them (papaverine and indomethacin) and inhibited by the others (theophylline and IBMX). 3 Amongst the four phosphodiesterase inhibitors, IBMX (10 μg/ml) was found to produce the largest potentiation (e.g. the sensitivity increased by a factor of 10) of glucagon-induced vascular relaxations (ED50 of glucagon in the presence of IBMX = 9.2 ± 1.0 ng/ml). 4 Ca2+ antagonists such as verapamil and SKF 525A produced a dose-dependent inhibition of the vasodilator action of glucagon. Verapamil (2.5 μg/ml) also antagonized cyclic AMP-induced vascular relaxations. 5 The vasodilator effect of verapamil was inhibited dose-dependently by raising the concentration of extracellular Ca2+ from 0.05 to 0.2 g/l (or 1.25 to 5.0 mm) while those elicited by glucagon or cyclic AMP were not influenced, thus suggesting that the latter two drugs do not interfere with Ca2+ influx. 6 Disodium edetate (Na2EDTA, 210 to 840 μg/l) produced a dose-dependent vasodilator effect which was attributed to the facilitation of Ca2+ extrusion from the smooth muscle cells and/or Ca2+ binding to the cell membrane. The relaxation produced by Na2EDTA was significantly blocked by verapamil (10 μg/ml) or SKF 525A (10 μg/ml). 7 The results were taken as an indication that glucagon produces at least a fraction of its vasodilator effect by promoting Ca2+ extrusion from the vascular smooth muscle cells and/or Ca2+ binding to or sequestration into intracellular sites, presumably via a cyclic AMP-dependent mechanism.