MINIGLUCAGON [GLUCAGON-(19-29)] IS A COMPONENT OF THE POSITIVE INOTROPIC EFFECT OF GLUCAGON

Glucagon is well known for its cardiotonic effect, but its mechanism of action remains undetermined. In the present study, we showed that glucagon, under minimal degradation conditions, had no effect on the amplitude of contractility of beating chick embryo ventricular cells. This raised the question of the contribution of the active metabolite of glucagon, glucagon-(19-29), referred to as miniglucagon, to the positive inotropic effect of glucagon. Incubation of glucagon with heart cells led to its rapid conversion into miniglucagon, as measured by radioimmunoassay. Accumulation of the metabolite was maximal after 8 min and remained stable until 15 min, reaching 6% of the initial glucagon concentration. Bacitracin inhibited this processing of glucagon into miniglucagon. Miniglucagon, from 0.1 pM to 1 nM, exerted a potent negative inotropic action. The most striking observation was a 45% increase in the amplitude of cell contractility elicited by the combination of 30 nM glucagon with 1 nM miniglucagon. A similar effect was obtained when glucagon was replaced by a low concentration (75-mu-M) of 8-bromoadenosine 3',5'-cyclic monophosphate. We conclude that glucagon processing into miniglucagon may be essential for the positive inotropic effect of glucagon on heart contraction.