No abstract

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 (12 weeks old). Systolic BP (tail-cuff plethysmography) was determined weekly for 15 weeks in InT-control and CsX rats. Some CsX-SD rats received androgen replacement therapy at 10-15 weeks with TES-enanthate (TRT; 1.75 mg/kg, 2x/week) or DHT-enanthate (DRT; 1.00 mg/kg. 2x/week) and a separate group of CsX-SD rats received losartanpotassium in drinking water (LST, 250 mg/L) for the entire 15 week period. Expression of renin, angiotensinogen (Agt), angiotensin converting enzyme (ACE), and angiotensin II type I receptor (AT 1 R) mRNA in kidney and aorta were determined by real-time PCR (rt-PCR) and plasma renin levels were determined by radioimmunoassay.

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) are unclear. We previously reported that castration (CsX) produced hypertension in male rats, and that TES replacement therapy (TRT) was antihypertensive and normalized BP via inhibition of renin‐angiotensin system function. Thus, long‐term effects of endogenous TES and exogenous TRT on BP were studied in male Sprague‐Dawley (SD) and Testicular‐feminized male (Tfm, androgen receptor defective) rats. 12–13 wk old male rats were castrated (CsX) and weekly measurements of systolic BP (tail cuff plethysmography) revealed a progressive rise in BP over 10 wks in CsX‐SD (109.5 ± 1.3 vs. 139.1 ± 0.4 mmHg) and in CsX‐Tfm (108 ± 0.9 vs. 138.4 ± 0.3 mmHg). During the next 5 weeks, TRT with 5α‐dihydro‐TES‐enanthate (1.00 mg/kg 2X/wk) gradually reduced BP to normal in CsX‐SD rats (111.4 ± 1). TRT of CsX‐Tfm rats over 5 weeks with TES‐enanthate (1.75 mg/kg 2X/wk) reduced BP to a similar extent. 24 hr urine output (UO) in intact SD was 48.3 ml/kg at baseline, 34.3 at 10 wks, 38.4 at 12 wks, and 34.8 at 15 wks. UO in CsX‐SD was 47.6, 30.3, 25.2, and 27.7; UO in CsX+TRT was 46.1, 29.2 36.2, and 29.5. Plasma TES in SD rats (radioimmunoassay, RIA) was 0.40 ng/ml in intact rats, <0.1 ng/ml in CsX, and 1.05 ng/ml in CsX+TRT. Plasma estrogen in SD (RIA) was 15.1 pg/ml in intact rats, 15.2 in CsX, and 15.4 in CsX+TRT. These data suggest that: 1) TES exerts antihypertensive effects in male SD and Tfm rats; 2) the antihypertensive effect of TES appear to involve a diuretic effect on the kidney, which is non‐genomically mediated and independent of TES aromatization to estrogen. (State of Texas).Support or Funding InformationState of TexasThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Testosterone (TES) and other androgens are efficacious vasodilators acutely, both in vitro and in vivo; however, their long‐term effects on arterial blood pressure (BP) are unclear. We previously reported that castration (CsX) produced hypertension in normal male rats, and that TES replacement therapy (TRT) was antihypertensive and normalized BP. Thus, long‐term effects of endogenous TES and exogenous TRT on BP and renin‐angiotensin system (RAS) function were studied in intact (InT) and castrated (CsX) male Sprague‐Dawley (SD) and Testicular‐feminized male (Tfm, androgen receptor defective) rats (12–13 wk old). Weekly measurements of systolic BP (tail cuff plethysmography) revealed a progressive rise in BP over 10 wks in CsX (108 ± 0.9 vs. 139 ± 1.2 mmHg), while BP remained stable in InT (109 ± 3.1 vs. 115 ± 0.5). During the next 5 weeks, half of CsX received TRT (CsX+TES‐enanthate‐replaced; 1.75 mg/kg, 2X/wk). BP gradually declined to normal in CsX+TES replaced rats (115 ± 1.2), while BP remained elevated in CsX (141 ± 1.2) and normal in InT (113 ± 0.3). In separate CsX‐SD rats, treatment with Losartan (LST; 250 mg/L drinking water) prevented development of hypertension at 10 wks (95 ± 0.8 CsX+LST vs. 139 ± 1.2 in CsX). During the next 5 weeks with TRT, BP declined in CsX+TES (113 ± 1.3) and remained lower in CsX+LST (99 ± 0.4). In Tfm, CsX resulted in a similar rise in BP (108 ± 0.6 vs. 139 ± 0.4 mmHg), and TRT reduced BP to a similar extent (106 ± 1.5). Real‐time PCR (rt‐PCR) of kidney from InT, CsX, and CsX+TES rats revealed that CsX increased expression of renin (45.5%), AT1 receptor (AT1R; 38%), and angiotensin converting enzyme (ACE; 239%) mRNA, while TRT normalized expression of renin, AT1R, and ACE mRNA to levels of InT rats. In contrast, CsX reduced expression of angiotensinogen (Angt) mRNA (59%) while TRT restored Angt mRNA to 78% of InT rats. 24 hr urine output (UO) in InT‐SD was 48.3 ml/kg at baseline, 34.3 at 10 wks, 38.4 at 12 wks, and 34.8 at 15 wks. UO in CsX‐SD was 47.6, 30.3, 25.2, and 27.7; UO in CsX+TRT was 46.1, 29.2 36.2, and 29.5. These data suggest that: 1) endogenous androgens (TES) exert antihypertensive effects in male SD and Tfm rats; 2) the antihypertensive effect of TES appear to involve a diuretic effect on the kidney, which is non‐genomically mediated; and 3) these antihypertensive effects may involve TES‐induced reductions in RAS expression in the kidney.Support or Funding InformationState of TexasThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Preeclampsia (PE) is a pregnancy‐induced disorder and a major cause of both fetal and maternal morbidity and mortality. During pregnancy, the placenta produces abundant androgens, and these rapid, non‐genomic vasodilators may serve to maintain uterine blood flow during normal pregnancy and may be impaired in PE. Of the known placental androgens, testosterone (TES) and its genomically inactive metabolite, 5β‐dihydrotestosterone (5β‐DHT), were previously reported to induce vasorelaxation in uterine arteries (UA). This study aimed to determine the nitric oxide (NO) signaling mechanisms involved in TES‐ and 5β‐DHT‐ induced relaxation in the rat UA using the DOCA‐salt model of PE. Endothelium‐intact UA rings (200 μm, dia.) from normal pregnant (NP) and DOCA‐treated pregnant (DSP) female (F) Sprague‐Dawley rats (250–300g) were prepared for measurements of isometric contractile force (DMT myograph). UA were pretreated with L‐NG ‐monomethyl arginine citrate (L‐NMMA, 100 μM), a non‐selective nitric oxide synthase (NOS) inhibitor or NW‐propyl‐L‐arginine (200 nM), a specific nNOS inhibitor. UA were then precontracted with U‐46619 (thromboxane A2 agonist, 1 μM) and a concentration‐dependent relaxation to TES and 5β‐DHT was obtained (0.1–1000 nM). Data are means ± SE (n = 6 rats). Androgen‐induced maximal UA relaxation was reduced by L‐NMMA in NP (TES: 33.84 ± 4.6 vs. 1.24 ± 4.0 and 5β‐DHT: 28.12 ± 6.1 vs. 2.0 ± 6.3) and in DSP (TES: 36.23 ± 4.6 vs. 4.44 ± 2.3 and 5β‐DHT: 30.71 ± 4.6 vs. 0.9 ± 2.4). Maximal relaxation was reduced by NW‐propyl‐L‐arginine in NP for both TES (24.53 ± 6.1) and 5β‐DHT (20.38 ± 3.8) and in DSP for 5β‐DHT (18.78 ± 6.7); however TES induced UA relaxation was unchanged with NW‐propyl‐L‐arginine in DSP (33.60 ± 10.4). These data suggest that: 1) androgen‐induced UA relaxation is both nNOS and eNOS dependent in NP; and 2) nNOS dependent TES‐induced relaxation of UA is decreased in DSP. (State of Texas)This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.