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The Effect of Flutamide on Systemic and Renal Hemodynamics in Zucker Diabetic Rats: Paradoxic Renal Vasodilator Response to Endothelin-1 and TXA2 Receptor Activation in Female Sex

Background: There is increasing evidence that endogenous sex hormones regulate vascular reactivity, and testosterone may contribute to the worse prognosis for renal disease in men. Male Zucker diabetic rats exhibit improved renal hemodynamic responses after castration. It is, however, unclear whether endogenous testosterone affects renal and systemic microcirculatory responses in the female sex, especially in type 2 diabetes. Aim: To test the hypothesis that endogenous testosterone in the female Zucker diabetic rat exerts a pathophysiologically relevant modulation of endothelial and renal microvascular function. Methods: Female Zucker diabetic rats (FZDR) aged 5−6 weeks and from the same litter were divided into 2 groups (n = 6−8 each). The experimental group received the androgen receptor blocker flutamide, dissolved in alcohol and added to their drinking water (500 mL) at 20 mg/rat/week. The control FZDR received only the alcohol vehicle added to the same volume of drinking water. Both FZDR groups were treated for 3 months before undergoing the hemodynamic studies. A sex comparison control group of male Zucker diabetic rats (MZDR), also aged 5−6 weeks, was studied, following same protocol. Mean arterial pressure (MAP) and renal cortical blood flow (RCF) response to phenylephrine, acetylcholine, TXA2−mimetic U46619, endothelin-1 (ET-1), angiotensin II, and l-NG-nitro arginine methyl ester were studied. Furthermore, the role of protein kinase C in the responses was assessed using phorbol-12,13 dibutyrate 10−4 M. The impact of flutamide on body weights and blood glucose of the rats were also determined. Results: Flutamide-treated FZDR had a significant reduction in body weight/adiposity to 432 ± 44 g, compared to controls at 553 ± 37 g (P = 0.045), and random blood glucose concentration of 185 ± 44 g/dL, compared to the control FZDR at 475 ± 34 g/dL (P = 0.002). Vehicle-treated FZDR (n = 6−8), exhibited little or no systemic or renal response to any of the agonists. By contrast, flutamide treatment of FZDR (n = 5−7) caused a normalization of the dose-dependent MAP and RCF pressor response to phenylephrine [P < 0.005, analysis of variance (ANOVA)] and the vasodilator response to acetylcholine (P <. 0.01, ANOVA). Flutamide-treated FZDR showed enhanced pressor response to U46619 (P = 0.024, ANOVA), ET-1, and angiotensin II (P < 0.03, ANOVA). Surprisingly, the augmented systemic pressor action of U46619 and ET-1 was accompanied by a renal vasodilator action, with paradoxic RCF increases to U46619 (P < 0.003, ANOVA) and to ET-1 (P < 0.001, ANOVA) only in flutamide-treated FZDR. By contrast, flutamide-treated MZDR exhibited no significant change in body weight and an attenuation of the vasoconstrictor responses and enhanced nitric oxide-mediated dilatation compared with male controls. However, no specific effect on ET-1 or TXA2 receptor-mediated renal perfusion was discernible. Both l-NG-nitro arginine methyl ester and the protein kinase C agonist phorbol-12,13 dibutyrate [10−4 M] significantly increased MAP and reduced RCF (P < 0.03) in the experimental FZDR compared with their controls. Conclusion: Flutamide administration to FZDR resulted in the reversal of abnormal systemic and renal α-1-mediated vasoconstriction and enhanced nitric oxide-mediated vasodilation. Flutamide caused a paradoxic but specific increase in renal perfusion during ET-1 and TXA2 receptor activation, which could be renoprotective in females. The salutary effects of flutamide on vascular reactivity in the FZDR may be mediated by a protein kinase C-dependent mechanism. These results are compatible with the notion that endogenous testosterone may regulate systemic and renal microcirculation in the female sex and in the type 2 diabetic state.