Obesity is associated with an inappropriately activated renin-angiotensin-aldosterone system, suppressed glucagon-like peptide-1 (GLP-1), increased renal Na reabsorption, and hypertension. To assess the link between GLP-1 and angiotensin receptor type 1 (AT) signaling on obesity-associated impairment of urinary Na excretion (UV) and elevated arterial pressure, we measured mean arterial pressure (MAP) and heart rate by radiotelemetry and metabolic parameters for 40 days. We tested the hypothesis that stimulation of GLP-1 signaling provides added benefit to blockade of AT by increasing UV and further reducing arterial pressure in the following groups: (1) untreated Long-Evans Tokushima Otsuka (LETO) rats (n = 7); (2) untreated Otsuka Long-Evans Tokushima Fatty (OLETF) rats (n = 9); (3) OLETF + ARB (ARB; 10 mg olmesartan/kg/day; n = 9); (4) OLETF + GLP-1 receptor agonist (EXE; 10 µg exenatide/kg/day; n = 7); and (5) OLETF + ARB + EXE (Combo; n = 6). On day 2, UV was 60% and 62% reduced in the EXE and Combo groups, respectively, compared with that in the OLETF rats. On day 40, UV was increased 69% in the Combo group compared with that in the OLETF group. On day 40, urinary angiotensinogen was 4.5-fold greater in the OLETF than in the LETO group and was 56%, 62%, and 58% lower in the ARB, EXE, and Combo groups, respectively, than in the OLETF group. From day 2 to the end of the study, MAP was lower in the ARB and Combo groups than in the OLETF rats. These results suggest that GLP-1 receptor activation may reduce intrarenal angiotensin II activity, and that simultaneous blockade of AT increases UV in obesity; however, these beneficial effects do not translate to a further reduction in MAP.

Metabolic syndrome is associated with increased activation of the renin‐angiotensin system, high blood pressure and decreased circulating levels of glucagon‐like peptide‐1 (GLP‐1). GLP‐1 mimetics have been shown to decrease systolic blood pressure (SBP) via unknown mechanisms. To assess the effects of angiotensin receptor type 1 (AT1) and GLP‐1 receptor (GLP‐1r) activation on SBP, urinary Na+ (UNaV), aldosterone (UAldoV), and corticosterone (UBV) excretion were recorded for six weeks in five groups of rats: 1) untreated, lean LETO (n=7), 2) untreated, obese OLETF (n=5), 3) OLETF + AT1 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 + Ex (combo; n=6). Ex UAldoV and UBV increased 207% and 123%, respectively, compared to OLETF on day 2 and were associated with a 62% UNaV decrease and 8% SBP increase. However, the 13% reduction in UAldoV in combo was associated with 94% increase in UBV, and 80% and 16% decrease in UNaV and SBP, respectively, compared to OLETF suggesting that activation of AT1 has a greater contribution to the insulin resistance‐associated increase in SBP than impaired UNaV. By day 7, Ex UAldoV was 48% lower than OLETF, but UBV, UNaV, and SBP were similar to OLETF. While GLP‐1r activation acutely increases SBP independently of aldosterone‐mediated sodium retention, ultimately the effect is rectified SBP and normalization of UNaV. Grant Funding Source: Amylin Pharmaceuticals (Bristol‐Myers Squibb)

Insulin resistance (IR) is associated with elevated renin-angiotensin system (RAS), impaired urinary Na + excretion (U Na V), 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). U Na V 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 U Na V in Ex was associated with increased (132 ± 1 vs 142 ± 1 mmHg) SBP. However, reduced U Na V 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 U Na V. 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 U Na V 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 U Na V, 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 U Na V.