![]() The inotropic effects of glucagon seem to be more marked at the ventricular than at the atrial level. Additionally, isolated auricles of the dog, cat or guinea pig, but not of the rabbit, responded to glucagon by an increase in contractility. For instance, glucagon markedly increased left ventricular pressure, dP/dt, and ventricular cAMP levels of the paced rat heart but had no effect on any of these variables in the paced guinea pig heart. ![]() Further investigations showed both species and regional differences within the myocardium for the inotropic effects of glucagon. However, glucagon did not produce any significant changes in heart rate, ECG, or blood pressure after being given intravenously or intracardially to anaesthetized dogs. Glucagon also caused inotropic effects in isolated preparations of different animal species. When heart failure was induced in these preparations by means of pentobarbital, glucagon caused a recovery to control levels. The earliest report on the inotropic effect of glucagon was presented by Farah and Tuttle and showed an increase in heart rate and contractility in dogs after adding glucagon to heart–lung preparations. Experimental and clinical features of glucagon effects on cardiac contractility are discussed next. Based upon this hypothesis, glucagon has been given for treating low cardiac output disorders, but the inotropic effect of glucagon in the human heart and its beneficial effects when given to these patients have not been proved. The positive inotropic effect of glucagon in the hearts of different animal species was first described in 1960 by Fara and Tuttle, and it is also considered to occur in humans. This process, so-called “Ca 2+ induced Ca 2+ release”, is intensified by glucagon-induced cAMP enhancement, leading to an increase in cardiac contractility. An incoming action potential leads to the opening of voltage-dependent L-type Ca 2+ channels and activation of a relatively small Ca 2+ influx current this triggers a quantitatively larger intracellular Ca 2+ release from sarcoplasmic reticulum Ca 2+ stores through ryanodine receptors, the final event responsible for cardiac contraction. Ĭardiac contractility is also regulated by the cAMP-dependent protein kinase A that phosphorylates different substrates, including the L-type Ca 2+ channel or ryanodine receptors, which are essential for controlling muscle contraction during each heartbeat. This is a vital factor in the generation of sinoatrial node rate by activating an inward Na +–Ca 2+ exchange current that accelerates firing of the pacemaker. ![]() Likewise, cAMP also regulates the spontaneous, rhythmic sarcoplasmic reticulum Ca 2+ release, via ryanodine receptors. Elevation in cAMP facilitates its binding to and activation of cyclic nucleotide gated channels, leading to an inward current carried by Na + and K + ions (funny current), which is considered the most important determinant of cardiac automaticity. Indeed, the chronotropic effect of glucagon is a consequence of the increase in cAMP levels in the sinoatrial node, which is the primary pacemaker of the heart, and the determinant of cardiac automaticity and generation of the heart beat. Thus, the combination of enhanced cAMP production and the reduction in cAMP hydrolysis leads to an increase in myocardial cAMP levels that is responsible for the cardiac actions of glucagon. Glucagon also seems to inhibit the activity of cyclic nucleotide phosphodiesterase enzymes, which breakdown cAMP into its product 5′AMP. The mechanism responsible for these effects is the stimulation of glucagon receptors associated with Gs protein, stimulation which causes adenylyl cyclase activation and the consequent increase in 3′,5′-cyclic adenosine monophosphate (cAMP) production in the myocardium. In addition to its metabolic effects, glucagon is considered to be a cardiostimulant agent that increases heart rate and contractility. Glucagon is a polypeptide hormone produced and secreted by the alpha cells of the pancreatic islets of Langerhans it increases glucose production and counteracts the effect of insulin in maintaining normoglycaemia in the fasting state. ![]()
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