Hypogonadal hypertension in male Sprague-Dawley rats is renin-angiotensin system-dependent: role of endogenous androgens.
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BACKGROUND: Acutely, testosterone (TES) and other androgens are efficacious vasodilators, both in vitro and in vivo; however, their long-term effects on arterial blood pressure (BP) remain unclear. It was hypothesized that endogenous androgens exert long-term anti-hypertensive effects on systemic BP through a combination of genomic and nongenomic effects to enhance vasodilation of the systemic vasculature. METHODS: The long-term effects of endogenous TES and exogenous TES replacement therapy (TRT) on BP were studied in intact (InT) and castrated (CsX) male Sprague-Dawley (SD) and testicular-feminized male (Tfm, androgen receptor defective) rats (12weeks old). Systolic BP (tail-cuff plethysmography) was determined weekly for 15weeks in InT-control and CsX rats. Some CsX-SD rats received androgen replacement therapy at 10-15weeks with TES-enanthate (TRT; 1.75mg/kg, 2x/week) or DHT-enanthate (DRT; 1.00mg/kg. 2x/week) and a separate group of CsX-SD rats received losartan-potassium in drinking water (LST, 250mg/L) for the entire 15week period. Expression of renin, angiotensinogen (Agt), angiotensin converting enzyme (ACE), and angiotensin II type I receptor (AT1R) mRNA in kidney and aorta were determined by real-time PCR (rt-PCR) and plasma renin levels were determined by radioimmunoassay. RESULTS: There was a progressive rise in BP over 10weeks in CsX (109 3.3 vs. 143 3.5mmHg), while BP remained stable in InT-control (109 3.0 vs. 113 0.3). BP gradually declined to normal in CsX-TRT rats (113 1.3), while BP remained elevated in CsX (140 1.2) and normal in InT-control (113 0.3). LST prevented the development of hypertension in CsX at 10weeks (100 1.5 in CsX + LST vs. 143 3.5 in CsX). During the next 5weeks with TES-RT, BP declined in CsX-TRT (113 1.3) and remained lower in CsX + LST (99 0.4). DHT-RT reduced BP in CxS to a similar extent. In Tfm, CsX resulted in a similar rise in BP (109 0.7 vs. 139 0.4mmHg), but TRT reduced BP more rapidly and to a greater extent (106 2.8). rt-PCR of the kidney revealed that CsX increased expression of mRNA for renin (92%), ACE (58%), and AT1R (80%) compared to InT, while TES RT normalized expression of renin, AT1R, and ACE mRNA to levels of InT rats. Plasma renin levels exhibited changes similar to those observed for renin mRNA expression. CONCLUSIONS: This is the first study to examine the long-term effects of endogenous and exogenous androgens on BP in male SD and Tfm rats. These data reveal that endogenous androgens (TES) exert anti-hypertensive effects that appear to involve non-genomic and possibly genomic mechanism(s), resulting in reductions in RAS expression in the kidney and enhanced systemic vasodilation.
