Glucagon and exenatide improve contractile recovery following ischaemia/reperfusion in the isolated perfused rat heart

Abstract

The inotropic effects of glucagon have been recognized for many years, but it has remained unclear whether glucagon signaling is beneficial to cardiac function.We evaluated the effects of glucagon alone and in combination with the glucagonlike peptide 1 (GLP-1) receptor agonist exenatide in the isolated perfused rat heart. The isolated perfused rat heart was used to investigate the initial inotropic and chronotropic effects of glucagon and exenatide during aerobic perfusion, and recovery of contractile function following ischaemia/reperfusion. Glucagon, but not exenatide, elicited an acute chronotropic and inotropic response during aerobic perfusion of the rat heart. Compared with control, glucagon improved recovery of left ventricular developed pressure (LVDP) by 33% (p < 0.05) and rate-pressure product (RPP) by 66% (p < 0.001) following ischaemia/reperfusion and amplified the mild recovery enhancement elicited by exenatide in a dosedependent manner. Glucagon shows inotropic properties in the isolated perfused rat heart and improves contractile recovery following ischaemia/reperfusion, both alone and when co-administered with a GLP-1 receptor agonist. Glucagon and exenatide, a GLP-1 receptor agonist, combine to stimulate greater recovery of postischaemic contractile function in the Langendorff heart. Glucagon was inotropic and chronotropic, yet this initial effect decreased over time and did not account for the increased contractility observed postischaemia/reperfusion.

Effect of GLP-1 Receptor Agonist on Ischemia Reperfusion Injury in Rats with Metabolic Syndrome

“…GLP-1-receptor-independent cardioprotection may be mediated through the NO/cGMP-dependent pathway given that we also measured the increase in NO 2 − values, as a marker of NO production, in coronary venous effluent ( Figure 4 C and Figure 5 C) [ 41 ]. A recent study showed that exenatide and glucagon have additive cardioprotective effects in the postconditioned isolated rat heart [ 42 ]. Co-administration of exenatide and glucagon elicited better recovery of the contractile function after ischemia in the isolated hearts.…”

Glucagon and Its Receptors in the Mammalian Heart

“…As already alluded to, glucagon can increase the force of heart contraction in many, but not all, tested species. Concentrations as low as 40 nM of glucagon could increase the force of contraction in isolated, perfused rat hearts [ 172 ]. However, these positive inotropic effects (an increase in left ventricular pressure has been reported) are accompanied by a positive chronotropic effect (an increase in the frequency of the heartbeat, [ 172 ]).…”

“…Concentrations as low as 40 nM of glucagon could increase the force of contraction in isolated, perfused rat hearts [ 172 ]. However, these positive inotropic effects (an increase in left ventricular pressure has been reported) are accompanied by a positive chronotropic effect (an increase in the frequency of the heartbeat, [ 172 ]). Now, changes in the beating rate alone can alter the force of contraction: the well known “treppe” or “staircase” phenomenon [ 173 ].…”