Reduced vasorelaxation to estradiol and G-1 in aged female and adult male rats is associated with GPR30 downregulation.

Previously, we reported that chronic activation of the estrogen receptor GPR30 by its selective agonist G-1 decreases blood pressure in ovariectomized hypertensive mRen2.Lewis (mRen2) rats but not intact male littermates. Furthermore, G-1 relaxes female mesenteric resistance arteries via both endothelium-dependent and -independent mechanisms. Because of the lack of a blood pressure-lowering effect by G-1 in males and the potential influence of aging on estrogen receptor expression, we hypothesized that GPR30-dependent vasodilation and receptor expression are altered in males and aged females. Thus, we assessed the response to 17ß-estradiol or G-1 in mesenteric arteries obtained from 15-wk-old normotensive Lewis and hypertensive mRen2 females and males as well as 52-wk-old Lewis females. Vasodilation to 17ß-estradiol (E2) and G-1 was significantly attenuated in 15-wk-old Lewis and mRen2 males compared with age-matched females. Pretreatment of male vessels with the nitric oxide synthase inhibitor L-NAME had no significant effect on the estradiol or G-1 response. In aged females, E2 and G-1 vasorelaxation was also significantly blunted; however, L-NAME essentially abolished the response. Associated with the reduced vascular responses, GPR30 expression in mesenteric arteries was approximately 50% lower in males and aged females compared with young females. We conclude that alterations in GPR30 expression and signaling may contribute to vascular dysfunction in aging females and a greater blood pressure in hypertensive males.

Renal GLUT1 reduction depends on angiotensin-converting enzyme inhibition in diabetic hypertensive rats.

AIMS: Angiotensin-converting enzyme (ACE) inhibitors are used in diabetic kidney disease to reduce systemic/intra-glomerular pressure. The objective of this study was to investigate whether reducing blood pressure (BP) could modulate renal glucose transporter expression, and urinary markers of diabetic nephropathy in diabetic hypertensive rats treated with ramipril or amlodipine. MAIN METHODS: Diabetes was induced in spontaneously-hypertensive rats (~210 g) by streptozotocin (50mg/kg). Thirty days later, animals received ramipril 15 µg/kg/day (R, n=10), or amlodipine 10mg/kg/day (A, n=8,) or water (C, n=10) by gavage. After 30-day treatment, body weight, glycaemia, urinary albumin and TGF-ß1 (enzyme-linked immunosorbent assay) and BP (tail-cuff pressure method) were evaluated. Kidneys were removed for evaluation of renal cortex glucose transporters (Western blotting) and renal tissue ACE activity (fluorometric assay). KEY FINDINGS: After treatments, body weight (p=0.77) and glycaemia (p=0.22) were similar among the groups. Systolic BP was similarly reduced (p<0.001) in A and R vs. C (172.4 ± 3.2; 1867 ± 3.7 and 202.2 ± 4.3 mmHg; respectively). ACE activity (C: 0.903 ± 0.086; A: 0.654 ± 0.025, and R: 0.389 ± 0.057 mU/mg), albuminuria (C: 264.8 ± 15.4; A: 140.8 ± 13.5 and R: 102.8 ± 6.7 mg/24h), and renal cortex GLUT1 content (C: 46.81 ± 4.54; A: 40.30 ± 5.39 and R: 26.89 ± 0.79 AU) decreased only in R (p<0.001, p<0.05 and p<0.001; respectively). SIGNIFICANCE: We concluded that the blockade of the renin-angiotensin system with ramipril reduced early markers of diabetic nephropathy, a phenomenon that cannot be specifically related to decreased BP levels.