Cardiac dose response relationship for intravenously infused glucagon in normal intact dogs and men

Abstract

The mechanism of glucagon's cardiac effects is not well understood. As the cardiac dose response to glucagon in intact animals has not been elucidated, this was determined in normal men and dogs. In man, heart rate, blood pressure, systolic time intervals and echocardiographic indices of ventricular wall motion were determined. Plasma glucagon levels (PGL) were measured by radioimmunoassay. Men received 3 glucagon infusions of 10 −10 to 10 −8 moles/minute followed by a bolus of 0.5 mg. or 1.0 mg. Small but significant changes were observed in ejection fraction and left ventricular posterior wall displacement at the 10 −9 moles/minute infusion rate (mean PGL 1.9 ng./ml.), a PGL close to that of some pathophysiologic states such as burns, ketoacidosis, and acute myocardial infarction, while cardiac output, heart rate, and other indices of cardiac performance were significantly changed only at the 10 −8 moles/minute and bolus injections. Some indices, notably stroke volume, were unchanged. In dogs, left ventricular (LV) pressure, LV pressure derivative (LV dP dt ), and aortic flow were measured with implanted LV solid state pressure transducers and electromagnetic flow probes. Dogs received six infusions from 2.7 × 10 −11 to 2.7 × 10 −8 moles/minute followed by a bolus of 2 mg. In dogs, significant changes occurred in LV dP dt at 2.7 × 10 −9 moles/minute (mean PGL 31.5 ng./ml.) and in heart rate at 2.7 × 10 −8 moles/minute only. It appears that substantial hemodynamic effects do not appear in man or dogs until PGL 10 to 100 times those seen in pathophysiologic states are achieved. Thus, it seems unlikely that glucagon contributes substantially to the hyperdynamic circulatory conditions observed in these states. Significant hemodynamic response to glucagon was noted in normal men, however, at a PGL less than that achieved by usual pharmacologic doses of glucagon and this lower PGL was not associated with the gastrointestinal symptoms commonly observed clinically.