Abstract 14259: Contractile Effects of Glucagon in Atrial Preparations From Transgenic Mice and Men

Abstract

Glucagon, a peptide composed of 29 amino acids, produced mainly in the pancreas can also stimulate cardiac function. Glucagon might contribute to hyperglycemia in diabetes mellitus type 2 and is thus of clinical relevance. There is controversy in the literature whether glucagon affects force and beating rate in the human atrium and which receptor is involved. Hence, we studied the effect of glucagon on atrial preparations of wild type mouse hearts (WT), from transgenic mice with cardiac overexpression of the human glucagon receptor (GR-TG) and for comparison in human right atrial preparations. We noted that glucagon exerted concentration- and time-dependent positive chronotropic effects in atrial preparations from WT and GR-TG starting at 0.1 nM glucagon and amounting to 25 % of pre-drug value at 3 nM glucagon (n=8, p<0.05). These effects were antagonized by the glucagon receptor antagonist SC203973 (1 μM), the inhibitor of cAMP dependent protein kinase H89 (1 μM), by the M-cholinoceptor agonist 1 μM carbachol, by the A1-adenosine receptor antagonist R-phenylisopropyladenosine (1 μM) and the inhibitors of hyperpolarization-activated cyclic nucleotide gated channels namely ivabradine (1 μM) or cesium chloride (2 mM) (n=5-6, p<0.05). In left atrial preparations from GR-TG but not WT, glucagon exerted starting at 1 nM a positive inotropic effect. Interestingly, in human atrial preparations glucagon at 1 μM in the additional presence of the phosphodiesterase III inhibitor cilostamide (1 μM) increased force of contraction by 34 % (n=5, p<0.05). We conclude that glucagon can exert contractile effects in mammalian hearts via GR, but they exhibit considerable regional and species differences. The physiological and therapeutic relevance of glucagon in the human heart needs to be fully elucidated.