Androgen receptor and the testes influence hypertension in a hybrid rat model.

Abstract

The objective of this study was to determine if males with a deficient androgen receptor would develop hypertension when crossed with a hypertensive parent Female King-Holtzman rats (n=15), heterozygous for the testicular feminization (Tfm) gene, were crossed with male spontaneously hypertensive rats (SHR), and blood pressure was measured weekly from 5-14 weeks in the F, hybrid males. Approximately 50% of the F, hybrid males were Tfm males and androgen receptor-deficient, and 50% were normal. Blood pressure in the parent KingHoltzman males, Tfms, and female rats was also followed for the same time period. The F, normal male hybrids had a significantly higher (p<0.05) systolic blood pressure than the Tfm hybrid males after 12 weeks (195±8 versus 170±8 mm Hg, respectively). Blood pressure in the male and Tfm Holtzman rats was 120±5 mm Hg and 110±6 mm Hg, respectively. Castration lowered blood pressure by 38 mm Hg in the hybrid males and 27 mm Hg in the Tfm hybrids. Female F, hybrids also showed a pressure rise above that of female Holtzman controls (155±6 mm Hg versus 110±6 mm Hg, /><0.01) but lower than the F, males and Tfm hybrids. Ovariectomized females with testosterone implants did not show an elevation in blood pressure. Plasma electrolytes, norepinephrine, and cholesterol were not significantly different between normal and Tfm hybrid males. The results suggest that the presence of an androgen receptor and a testis-derived factor mediate the blood pressure rise in the hybrid males. A Y chromosome effect or sex-influenced locus may be involved since both the normal and Tfm males had significantly higher blood pressures than their female siblings. (Hypertension S ex differences in systolic and diastolic blood pressure by age have been reported in most studies of developed societies. The US Public Health Service National Health Survey, 1 The Tecumseh Study, 2 and similar epidemiological longitudinal studies in Norway, 3 Poland, 4 and Japan 5 have reported that men have higher blood pressure than women at younger ages (second through third decade) with a crossover in women to higher pressures in the fourth to sixth decade. The crossover phenomenon appears to be characteristic of nearly all developed societies and is seen most clearly with systolic pressure. Similar conclusions are reached whether the results are expressed as the mean pressure by age and sex or as prevalence of hypertension. There are only a few blood pressure studies in children, but available data suggest that there are no significant sex differences. 6 These studies and experimental studies suggest that the male sex hormones, specifically testosterone, play a role in the sexual differentiation of hypertension.

The hypertensive Y chromosome elevates blood pressure in F11 normotensive rats.

“…Discussion In our previous work we showed that the Y chromosome interacted with an autosomal component to increase BP 7 -8 and that the AR was necessary for the full expression of the SHR Y chromosome BP effect as well as a possible androgen effect that did not function through the AR. 8 The present research continues to support these findings and extends this work to show that the Y chromosome from a hypertensive father continues to elevate BP after 11 generations of backcrossing to normotensive mothers. The pressure difference between the pure WKY males and F n SHR/y males averaged 12 mm Hg, which can be thought of as the hypertensive Y effect against a normotensive autosomal background.…”

Testosterone Effects on Renal Norepinephrine Content and Release in Rats With Different Y Chromosomes

“…22 Testosterone most likely was the main steroid responsible for the blood pressure effect because castration reduced blood pressure, and testosterone replacement after castration restored blood pressure to control levels. 19,22,23 However, not as much is known about the interaction of NE and testosterone. Testosterone can influence NE metabolism, storage, and release.…”

“…The SHR has increased SNS activity 5,6,9,19 that can lead to increased circulating NE, 12,19 which has been implicated in the genesis of hypertension. The testosterone-induced increase in renal NE release (125% to 167%) was seen in both groups with an SHR Y chromosome (SHR and SHR/y animals), possibly due to increased NE stores and more release per stimulation.…”

“…The ends were sealed with Silastic medical-grade silicone adhesive (Type A, Dow Corning). 19 Before implantation, the implants were cured overnight in 5% bovine serum albumin, 10 mmol/L sodium phosphate buffer, 0.9% NaCl, and 0.0001% merthiolate and soaked in 70% ethanol for 2 hours. Two weeks after testosterone implantation, the animals were again sedated (50 mg/kg Brevital), and a retro-orbital blood sample was taken before kidney retrieval to determine serum testosterone levels.…”

Testosterone Dependence of Salt-Induced Hypertension in Sabra Rats and Role of Renal α2-Adrenoceptor Subtypes

“…This sexual difference in blood pressure is present in genetically hypertensive rats, including SHR (Ely and Turner, 1990;Chen and Meng, 1991;Ely et al, 1991;Chen et al, 1992), and the Dahl salt-sensitive (Dahl et al, 1975) as well as their normotensive control strains Wistar Kyoto (Ely et al, 1991) and the Dahl salt-resistant (Rapp and Dene, 1985), respectively. It has been shown that gonadectomy retards the development of hypertension in SHR rats (Iams and Wexler, 1977;Masubuchi et al, 1982;Chen and Meng, 1991).…”