Abstract 4369369: Sex Differences in GLP-1 Receptor Mediated Effects on Exercising Blood Pressure Responses in Peripheral Artery Diseas

Abstract

Background: Glucagon-like peptide-1 receptor agonists (GLP-1RA) are currently prescribed for diabetes and obesity and may also have beneficial effects for atherosclerotic conditions such as peripheral artery disease (PAD). We recently reported that the GLP-1RA liraglutide (lira) attenuated the exaggerated BP response to exercise in both male and female normoglycemic, non-obese rats with chronically ligated femoral arteries (PAD model). Whether the effect of lira was mediated entirely through GLP-1R stimulation or also involved a non-receptor dependent mechanism is unknown. Purpose: We investigated whether the attenuating effect of lira on the blood pressure response to treadmill exercise we previously reported in “ligated” rats was produced via a GLP-1 receptor dependent mechanism. Methods: Male (n=4) and female (n=4) rats had both femoral arteries ligated ~72 hrs prior to experiments. On experiment day, a carotid artery and jugular vein were cannulated for BP measurement and drug administration, respectively. Treadmill exercise was performed (4 min; 15 m/min, 1° incline) while BP was measured continuously. The GLP-1R antagonist exendin-3 (Ex-3, 400mg/kg) was infused followed 10 min later by lira (20mg /kg). 20 min after lira infusion, a second treadmill exercise bout was performed. The BP response to exercise before (control) and after (Ex-3+lira) drug infusions was compared between conditions and across sexes. Data are mean±SEM. Results: The mean arterial pressure (MAP) response to exercise was significantly reduced following Ex-3+lira compared to control in female rats (Peak ΔMAP control: 22±3; Ex-3+Lira: 17±2mmHg; P=0.013*). However, this effect of lira was significantly reduced when compared to our previous experiments in which lira was infused alone. There was no effect of Ex-3+lira on the MAP response to exercise in male rats ( n =4, Peak ΔMAP control: 24±2; Ex-3+Lira: 25±1mmHg; P=0.499). Conclusions: The attenuating effect of lira on the BP response to exercise was abolished by prior GLP-1 receptor blockade in ligated male rats but not female rats. Thus, the attenuating effect of lira on the BP response to exercise in male rats is entirely GLP-1 receptor dependent whereas in female rats the effect is mediated by both GLP-1R dependent and independent mechanisms.