Abstract 637: Angiotensin Receptor Blockade Ameliorates the Hypertension Associated with Acute Glucagon-like Peptide-1 Receptor Activation

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Abstract

Insulin resistance (IR) is associated with elevated renin-angiotensin system (RAS), impaired urinary Na+ excretion (UNaV), and high blood pressure. RAS blockade lowers blood pressure, decreases IR and fasting plasma glucose (FPG). Glucagon-like peptide 1 (GLP-1), has been reported to have natriuretic effects as well as blood glucose lowering effects, however, these findings are still controversial. To assess the contributions of GLP-1 receptor and angiotensin receptor type 1(AT1) activation on renal Na+ handling, systolic blood pressure (SBP) and FPG, metabolic measurements were taken at days 0, 2, 7, and every week thereafter for six weeks, SBP was measured daily using radio telemetry in five groups of rats: 1) untreated, lean LETO (n=7), 2) untreated, obese OLETF (n=5), 3) OLETF + angiotensin receptor blocker (ARB; 10 mg olmesartan /kg/d; n=4), 4) OLETF + GLP-1 mimetic (Ex; 10 ug exenatide/kg/d; n=7), and 5) OLETF + ARB + Exenatide (combo; n=6). FPG increased (101 ± 4 vs 131 ± 3 mg/dL) in OLETF compared to LETO, and ARB treatment decreased it (120 ± 2 mg/dL); however, the changes in Ex and combo groups were not significant. OLETF rats exhibited elevated SBP at the onset of the study compared to LETO (119 ± 1 vs. 130 ± 1 mmHg). UNaV decreased (1.07 ± 0.07 vs 0.43 ± 0.14 & 0.31 ± 0.11 mmol/day) in Ex and combo groups on day 2 compared to OLETF, and the decrease in UNaV in Ex was associated with increased (132 ± 1 vs 142 ± 1 mmHg) SBP. However, reduced UNaV in combo group was associated with reduced (114 ± 3 mmHg) SBP suggesting that activation of AT1 has a greater contribution to the insulin resistance-associated increase in SBP than the impaired UNaV. After this initial increase in SBP in Ex, it decreased to a nadir (124 ± 2 mmHg) at day 11 of treatment before increasing to 130 for the duration of the study. After six weeks of treatment UNaV increased (1.02 ± 0.05 vs 1.35 ± 0.09 mmol/day) only in combo group compared to OLETF. The results suggest that chronic GLP-1 receptor activation acutely increases SBP by decreasing UNaV, but co-treatment with an ARB abolishes this effect. These results also suggest that despite the lack of improved FBG, chronic GLP-1 receptor activation may protect against the development of high blood pressure associated with insulin resistance independent of increased UNaV.

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