Glucagon-like peptide-1 (7–36) but not (9–36) augments cardiac output during myocardial ischemia via a Frank–Starling mechanism

Abstract

This study examined the cardiovascular effects of GLP-1 (7–36) or (9–36) on myocardial oxygen consumption, function and systemic hemodynamics in vivo during normal perfusion and during acute, regional myocardial ischemia. Lean Ossabaw swine received systemic infusions of saline vehicle or GLP-1 (7–36 or 9–36) at 1.5, 3.0, and 10.0 pmol/kg/min in sequence for 30 min at each dose, followed by ligation of the left circumflex artery during continued infusion at 10.0 pmol/kg/min. Systemic GLP-1 (9–36) had no effect on coronary flow, blood pressure, heart rate or indices of cardiac function before or during regional myocardial ischemia. Systemic GLP-1 (7–36) exerted no cardiometabolic or hemodynamic effects prior to ischemia. During ischemia, GLP-1 (7–36) increased cardiac output by approximately 2 L/min relative to vehicle-controls (p=0.003). This response was not diminished by treatment with the non-depolarizing ganglionic blocker hexamethonium. Left ventricular pressure-volume loops measured during steady state conditions with graded occlusion of the inferior vena cava to assess load-independent contractility revealed that GLP-1 (7–36) produced marked increases in end diastolic volume (74 ± 1 to 92 ± 5 mL; p=0.03) and volume axis intercept (8 ± 2 to 26 ± 8; p=0.05), without any change in the slope of the end systolic pressure volume relationship vs. vehicle during regional ischemia. GLP-1 (9–36) produced no changes in any of these parameters compared to vehicle. These findings indicate that short-term systemic treatment with GLP-1 (7–36) but not GLP-1 (9–36) significantly augments cardiac output during regional myocardial ischemia, via increases in ventricular preload without changes in cardiac inotropy.

Obesity alters molecular and functional cardiac responses to ischemia/reperfusion and glucagon-like peptide-1 receptor agonism

“…Nevertheless, we noted statistically significant group- and treatment-related differences in key physiologic end points which were consistent with recent data from our laboratory [21, 22, 44] and directly associated with marked differences in the cardiac proteome and miR transcriptome between lean and obese swine both at baseline and in response to ischemic injury. These observations therefore are not compromised on statistical power overall.…”

“…In contrast, large clinical trials of GLP-1 based therapies in humans with obesity and type 2 diabetes have failed to show the expected cardiovascular benefits to date [64, 70]. Recent work from our laboratory suggests that cardiometabolic effects of GLP-1 are impaired in the setting of obesity, raising the possibility of “cardiovascular GLP-1 resistance” in the population being treated with these agents [20, 22, 44]. The troponin measures (Table 2) support that exendin-4 may diminish infarct size in lean and obese swine, with reductions in the median values in both groups although overall variability in this injury marker produced non-significant p values for this comparison (p=0.09).…”

The Cardiovascular Biology of Glucagon-like Peptide-1

“…Neither peptide affected coronary artery blood flow or myocardial contractility. Native GLP-1, but not GLP-1(9-36), increased cardiac output during ischemia, which correlated with increases in end-diastolic volume (preload), and which occurred independently of coadministration of hexamethonium to block nicotinic acetylcholine receptors and ganglionic neurotransmission (Goodwill et al, 2014).…”

“…Furthermore, the acute actions of GLP-1 (100 nM, 105 min) to attenuate glucolipotoxicity and reduce generation of reactive oxygen species (ROS) were extinguished in mouse Prkaa1 À/À CMs ex vivo (Balteau et al, 2014). The cardioprotective actions of native GLP-1 or GLP-1(9-36) were also examined in swine subjected to cardiac ischemia induced by coronary artery ligation (Goodwill et al, 2014). Acute administration of both peptides was commenced 30 min prior to ischemia and continued for an additional 30 min at a dose of 10 pmol/kg/min.…”

The Effect of Transplacental Administration of Glucagon-Like Peptide-1 on Fetal Lung Development in the Rabbit Model of Congenital Diaphragmatic Hernia

“…Clinically, GLP-1 is used for the treatment of type 2 diabetes mellitus and has an impact on obesity [20]. However, there are also promising preclinical results in the reduction of infarct volume in ischemic heart disease [21]. Adult rat and human type 2 pneumocytes show increased surfactant protein secretion in the presence of GLP-1 (7-36) amide [22,23].…”