Hypogonadal Hypertension In Male Sprague‐Dawley Rats Is Reversed By Testosterone and its Genomically Inactive Metabolite 5β‐Dihydrotestosterone

Abstract

Testosterone (TES) and its metabolites are efficacious vasodilators acutely, both in vitro and in vivo; however, their long‐term effects on blood pressure (BP) are unclear. We previously reported that castration (CsX) produced hypertension (HT) in normal male rats, and long‐term TES replacement therapy normalized BP and reduced renal renin‐angiotensin system (RAS) expression. Thus, in the present study, the effects of TES and 5β‐dihydrotestosterone (5β‐DHT), a metabolite with potent and efficacious vasodilator effects but lacking classic androgenic activity, were studied in CsX male Sprague‐Dawley rats. Rats were CsX at 12‐13 weeks age and then studied for 15 weeks. Weekly systolic BP (by tail cuff) revealed a progressive rise in BP over 10 weeks after CsX (110 ± 1.6 vs141 ± 1.2 mmHg). During the next 5 weeks, CsX rats received either TES (CsX + TES‐enanthate, 1.75 mg/kg, 2X/week) or 5β‐DHT‐propionate (CsX + 5β‐DHT, 2.00 mg/kg, 2X/week). BP gradually and progressively declined to normal by 5 weeks in CsX + TES rats (113 ± 1.3). In contrast, BP in CsX + 5β‐DHT rats was biphasic: a dramatic, more rapid decline to normal BP after only one week treatment (111 ± 0.7), and a continued more gradual decline to a hypotensive BP by 5 weeks (91 ± 1.1). Seminal vesicle (SV) weight after 5 weeks of androgen therapy (bioassay for androgenic activity) was 0.3250 ± 0.0180 g/100 g body weight in CsX + TES and 0.0122 ± 0.0006 in CsX + 5β‐DHT. In comparison, SV weights were 0.0160 ± 0.0010 in CsX without TES and 0.2860 ± 0.0110 in intact male rats. These data suggest that:1)endogenous and exogenous TES exert anti‐HT effects in male SD rats; 2) the TES metabolite 5β‐DHT exerts substantially greater, more rapid anti‐HT effects which appear to involve nongenomic, androgen receptor‐independent actions; and 3) while TES effects appear to involve diuretic/natriuretic effects on kidney via inhibition of renal RAS expression (our previous studies), the biphasic anti‐HT effects of 5β‐DHT in the present study appear to involve a rapid vasodilatory effect as well as a slower diuretic/natriuretic effect similar to that of TES. @font‐face {font‐family:“Cambria Math”; panose‐1:2 4 5 3 5 4 6 3 2 4; mso‐font‐charset:0; mso‐generic‐font‐family:roman; mso‐font‐pitch:variable; mso‐font‐signature:‐536870145 1107305727 0 0 415 0;}@font‐face {font‐family:Times; panose‐1:0 0 5 0 0 0 0 2 0 0; mso‐font‐charset:0; mso‐generic‐font‐family:auto; mso‐font‐pitch:variable; mso‐font‐signature:‐536870145 1342185562 0 0 415 0;}p.MsoNormal, li.MsoNormal, div.MsoNormal {mso‐style‐unhide:no; mso‐style‐qformat:yes; mso‐style‐parent:“”; margin:0in; mso‐pagination:widow‐orphan; text‐autospace:none; font‐size:12.0pt; font‐family:Times; mso‐fareast‐font‐family:“Times New Roman”; mso‐bidi‐font‐family:“Times New Roman”;}.MsoChpDefault {mso‐style‐type:export‐only; mso‐default‐props:yes; font‐size:11.0pt; mso‐ansi‐font‐size:11.0pt; mso‐bidi‐font‐size:11.0pt; font‐family:“Calibri”,sans‐serif; mso‐ascii‐font‐family:Calibri; mso‐ascii‐theme‐font:minor‐latin; mso‐fareast‐font‐family:Calibri; mso‐fareast‐theme‐font:minor‐latin; mso‐hansi‐font‐family:Calibri; mso‐hansi‐theme‐font:minor‐latin; mso‐bidi‐font‐family:“Times New Roman”; mso‐bidi‐theme‐font:minor‐bidi;}.MsoPapDefault {mso‐style‐type:export‐only; margin‐bottom:10.0pt; line‐height:115%;}div.WordSection1 {page:WordSection1;}