Systemic hypotensive effects of testosterone are androgen structure-specific and neuronal nitric oxide synthase-dependent

Am J Physiol Regul Integr Comp Physiol. 2015 Jul 15;309(2):R189-95. doi: 10.1152/ajpregu.00110.2015. Epub 2015 May 6.

Abstract

Testosterone (TES) and other androgens exert a direct vasorelaxing action on the vasculature in vitro that is structurally specific and independent of cytosolic androgen receptor (AR). The effects of intravenous androgen infusions on mean arterial blood pressure (BP) and heart rate (HR) were determined in conscious, unrestrained, chronically catheterized, ganglionically blocked (hexamethonium, HEX; 30 mg/kg ip) male Sprague-Dawley (SD) and testicular-feminized male (Tfm; AR-deficient) rats, 16-20 wk of age. BP and HR were recorded at baseline and with increasing doses of androgens (0.375-6.00 μmol·kg(-1)·min(-1) iv; 10 min/dose). Data are expressed as means ± SE (n = 5-8 rats/group). In SD rats, baseline BP and HR averaged 103 ± 4 mmHg and 353 ± 12 beats/min (bpm). TES produced a dose-dependent reduction in BP to a low of 87 ± 4 mmHg (Δ16%), while HR was unchanged (354 ± 14 bpm). Neither BP (109 ± 3 mmHg) nor HR (395 ± 13 bpm) were altered by vehicle (10% EtOH in 0.9% saline; 0.15 ml·kg(-1)·min(-1), iv). In Tfm, TES produced a similar reduction in BP (99 ± 3 to 86 ± 3 mmHg, Δ13%); HR was unchanged (369 ± 18 bpm). In SD, 5β-dihydrotestosterone (genomically inactive metabolite) produced a greater reduction in BP than TES (102 ± 2 to 79 ± 2 mmHg, Δ23%); HR was unchanged (361 ± 9). A 20-μg iv bolus of sodium nitroprusside in both SD and Tfm rats reduced BP 30-40 mmHg, while HR was unchanged, confirming blockade by HEX. Pretreatment of SD rats with neuronal nitric oxide synthase (nNOS) inhibitor (S-methyl-thiocitrulline, SMTC; 20 μg·kg(-1)·min(-1) × 30 min) abolished the hypotensive effects of TES infusion on BP (104 ± 2 vs. 101 ± 2 mmHg) and HR (326 ± 11 vs. 324 ± 8 bpm). These data suggest the systemic hypotensive effect of TES and other androgens involves a direct vasodilatory action on the peripheral vasculature which, like the effect observed in isolated arteries, is structurally specific and AR-independent, and involves activation of nNOS.

Keywords: 5β-DHT; blood pressure; neuronal NOS; testosterone; vasodilation.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Androgen-Insensitivity Syndrome / genetics
  • Androgen-Insensitivity Syndrome / metabolism
  • Androgen-Insensitivity Syndrome / physiopathology
  • Androgens / administration & dosage*
  • Androgens / chemistry
  • Animals
  • Arterial Pressure / drug effects*
  • Arteries / drug effects*
  • Arteries / enzymology
  • Arteries / physiopathology
  • Dihydrotestosterone / administration & dosage
  • Dose-Response Relationship, Drug
  • Enzyme Activation
  • Enzyme Inhibitors / pharmacology
  • Heart Rate / drug effects
  • Hypotension / chemically induced*
  • Hypotension / enzymology
  • Hypotension / physiopathology
  • Infusions, Intravenous
  • Male
  • Molecular Structure
  • Nitric Oxide Synthase Type I / antagonists & inhibitors
  • Nitric Oxide Synthase Type I / metabolism*
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Androgen / genetics
  • Receptors, Androgen / metabolism
  • Structure-Activity Relationship
  • Testosterone / administration & dosage*
  • Testosterone / analogs & derivatives
  • Testosterone / chemistry
  • Time Factors
  • Vasodilation / drug effects

Substances

  • Androgens
  • Enzyme Inhibitors
  • Receptors, Androgen
  • Dihydrotestosterone
  • Testosterone
  • Nitric Oxide Synthase Type I
  • Nos1 protein, rat