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.

Figure 1

Data (mean±SEM) describing changes in SBP (Panel A), DBP (Panel B), MBP (Panel C) or HR (Panel D), presented as a change relative to within treatment group baseline. All data are presented for all animals receiving GLP-1 (7–36) infusion, GLP-1 (9–36) infusion or infusion rate matched saline-infused time controls. *p<0.05 vs. identically handled, time control.

Figure 2

Data (mean±SEM) describing changes in EDV (Panel A), ESV (Panel B), SV (Panel C) or CO (Panel D), presented as a change relative to within treatment group baseline. All data are presented for all animals receiving GLP-1 (7–36) infusion, GLP-1 (9–36) infusion or infusion rate matched saline-infused time controls. *p<0.05 vs. identically handled, time control.

Figure 3

Representative pressure-volume loops from saline infused time controls (Panel A), GLP-1 (7–36) (Panel C) and GLP-1 (9–36) (Panel D) treated animals at the highest infusion rate (10 pmol/kg/min) during normal perfusion (solid line; black) and subsequent to induction of regional myocardial ischemia (interrupted line; gray). Each representative loop is the result of averaging 3 consecutive loops from 3 separate animals during plateau of responses during the relevant, presented conditions. Panel B provides representative data from a single animal (3 averaged loops per condition) demonstrating effect of epinephrine on pressure volume relationships (interrupted gray line) during normal myocardial perfusion. Note the change in scale of Panel B; the dashed line represents the maximal Y scale value of other panels.

Figure 4

Summary plot for the relationships between end-diastolic volume (EDV) and cardiac output (CO) during regional myocardial ischemia and exposure to study treatments.

Figure 5

Effects of GLP-1 therapies on cardiac efficiency (cardiac output per unit oxygen consumption) at baseline and during ischemia. Data are presented as mean±SEM *p<0.05 GLP-1 (7–36) vs. saline and vs GLP-1 (9–36).