Testosterone Dependence of Salt-Induced Hypertension in Sabra Rats and Role of Renal α<sub>2</sub>-Adrenoceptor Subtypes

Mostafa, Khalid; Ilhami, Norelyaquine; Giudicelli, Yves; Dausse, Jean‐Pierre

doi:10.1124/jpet.300.1.43

Cited by 18 publications

(13 citation statements)

References 36 publications

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“…A similar mechanism has been demonstrated in salt-induced hypertension of Sabra rats, a phenomenon depending on testosterone [21], and also in spontaneously hypertensive rats in which blood pressure decrease after gonadectomy and increases signifi cantly upon dihydrotestosterone replacement [29] . Basal heart rate did not change either after testosterone or nandrolone treatment; this fi nding could be related to baroreceptor adjustment of heart rate according to blood pressure rise in resting conditions.…”

Section: Discussionmentioning

confidence: 80%

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Testosterone and Nandrolone Sensitization of Brain Anteroventral Area of Third Ventricle to Hypertonic NaCl-Induced Sympathetic Response

et al. 2005

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Androgenic steroids increase atherogenesis, thrombogenicity and endothelial dysfunction when administered in high doses, however their effects on NaCl sensitivity of the brain anteroventral area of the third ventricle (ΔV3V) have not been explored. Sprague-Dawley male rats were anesthetized with sodium pentobarbital (40 mg/kg) and the femoral intra-arterial blood pressure and heart rate monitored through a strain-gauge blood pressure transducer and tachograph. ΔV3V microinjections of (2 µl) 1.5 mol/l NaCl solution were done according to brain coordinates: AP = 7.0 mm, L = 1.0 mm, D = 7.5 mm through a 0.2-mm diameter stainless steel needle. The injection site was verified with 1.0 µl neutral red solution. Basal systolic blood pressure increased 37.6 and 39.6 mm Hg after testosterone (1 mg/kg/day for 20 days) and nandrolone (1 mg/kg/day for 20 days) treatment respectively; diastolic blood pressure also increased upon testosterone and nandrolone treatment in 36.4 and 53.1 mm Hg, respectively; basal heart rate did not change. Vasopressor response to 1.5 mol/l NaCl ΔV3V microinjection was higher in testosterone-treated rats; systolic blood pressure increased 56.0 vs. 28.3 control mm Hg; diastolic blood pressure increased 54.0 vs. 25 control mm Hg. This hypertensive response was 29% longer lasting in testosterone compared to vehicle-treated rats. The same pattern of ΔV3V sensitization to hypertonic NaCl was observed in nandrolone-treated rats. Blood lipid profile changed to a proatherogenic fashion upon testosterone and nandrolone long-term treatment; the plasma-free testosterone concentration increased from 4.9 ± 0.9 to 36.0 ±7.1 pg/ml with the same testosterone treatment schedule. In conclusion, long-term androgenic steroid treatment sensitizes the brain ΔV3V region to hypertonic NaCl which in turn conducts into a sympathetic vasopressor and heart rate-stimulating action.

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Section: Discussionmentioning

confidence: 80%

“…The infl uence of testosterone on salt-induced hypertension depends on a lower reactivity of ␣ 2 -adrenergic receptors in a rodent model [21] , but central nervous system sodium sensitivity and its effect on the efferent sympathetic system of rats exposed to androgenic steroids has not been explored.…”

Section: Introductionmentioning

confidence: 99%

Testosterone and Nandrolone Sensitization of Brain Anteroventral Area of Third Ventricle to Hypertonic NaCl-Induced Sympathetic Response

et al. 2005

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“…The greater exacerbation in males might be related to the influence of male hormones because testosterone is required for the full expression of the salt-sensitive hypertension phenotype in some rat models. 38 Afsar 39 recently evaluated hypertensive male patients and reported a negative correlation between testosterone levels and urinary sodium excretion, 39 which could be a mechanism for increased hypertension. Yanes et al 16 reported that castration in male rats reduced intrarenal expression of AGT, mean arterial blood pressure, and proteinuria during salt-sensitive hypertension in the Dahl SS model.…”

Section: Discussionmentioning

confidence: 99%

Sexual Dimorphism in Urinary Angiotensinogen Excretion During Chronic Angiotensin II−Salt Hypertension

et al. 2012

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Background The intrarenal renin–angiotensin system contributes to hypertension by regulating sodium and water reabsorption throughout the nephron. Sex differences in the intrarenal components of the renin–angiotensin system have been involved in the greater incidence of high blood pressure and progression to kidney damage in males than females. Objective This study investigated whether there is a sex difference in the intrarenal gene expression and urinary excretion of angiotensinogen (AGT) during angiotensin II (Ang II)–dependent hypertension and high-salt (HS) diet. Methods Male and female Sprague-Dawley rats were divided into 5 groups for each sex: Normal-salt control, HS diet (8% NaCl), Ang II–infused (80 ng/min), Ang II–infused plus HS diet, and Ang II–infused plus HS diet and treatment with the Ang II receptor blocker, candesartan (25 mg/L in the drinking water). Rats were evaluated for systolic blood pressure (SBP), kidney AGT mRNA expression, urinary AGT excretion, and proteinuria at different time points during a 14-day protocol. Results Both male and female rats exhibited similar increases in urinary AGT, with increases in SBP during chronic Ang II infusion. HS diet greatly exacerbated the urinary AGT excretion in Ang II–infused rats; males had a 9-fold increase over Ang II alone and females had a 2.5-fold increase. Male rats displayed salt-sensitive SBP increases during Ang II infusion and HS diet, and female rats did not. In the kidney cortex, males displayed greater AGT gene expression than females during all treatments. During Ang II infusion, both sexes exhibited increases in AGT gene message compared with same-sex controls. In addition, HS diet combined with Ang II infusion exacerbated the proteinuria in both sexes. Concomitant Ang II receptor blocker treatment during Ang II infusion and HS diet decreased SBP and urinary AGT similarly in both sexes; however, the decrease in proteinuria was greater in the females. Conclusion During Ang II–dependent hypertension and HS diet, higher intrarenal renin-angiotensin system activation in males, as reflected by higher AGT gene expression and urinary excretion, indicates a mechanism for greater progression of high blood pressure and might explain the sex disparity in development of salt-sensitive hypertension.

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“…Up to now the mechanisms responsible for mediating sex diff erences in blood pressure depending on the salt content of the diet are still unknown. Possible mechanisms for increasing blood pressure in sodium-loaded animals might be an increased sodium reabsorption [ 16 ] , an increase in gene expression and density of α2-adrenoceptors in the kidney [ 13 ] , and an increased renal cortical angiotensinogen mRNA and protein expression suggesting a locally active intrarenal RAAS (renin-angiotensinaldosterone system). The latter may play a major role in mediating salt-sensitive hypertension [ 19 ] .…”

Section: Blood Pressurementioning

confidence: 99%

Sex-specific Effects of Spironolactone on Blood Pressure in Gonadectomized Male and Female Wistar Rats

et al. 2012

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A low-salt diet is known to decrease and salt excess to increase blood pressure in humans and rodents. Sex steroids seem to play a role in salt dependent hypertension. However, little is known about sex differences in mineralocorticoid receptor blockade between male and female rats. The objective of the work was at first to investigate the effects of a low-salt vs. a high-salt diet on blood pressure without the influence of gonadal steroids in male and female rats. Second, to determine the sex-specific effects of mineralocorticoid receptor blockade by spironolactone in high-salt and low-salt fed gonadectomized male and female animals. Normotensive male and female Wistar rats were gonadectomized and put on a low (NaCl<0.03%) or high (NaCl=4%) salt diet. On each diet animals received spironolactone or placebo. Blood pressure was measured by tail-cuff-method; 24-h urine samples were collected in metabolic cages and blood was collected for hormonal measurements. High-salt diet significantly increased systolic blood pressure in both sexes. This effect could be blocked effectively by spironolactone only in male rats. Spironolactone treatment significantly increased aldosterone levels in males and females independent of the sodium content of the diet. High sodium diet significantly increased relative kidney weight, which was not altered by spironolactone treatment. Independently of gonadal steroids a high-salt diet increased blood pressure in gonadectomized male and female rats. Spironolactone lowered blood pressure only in male not in female rats on a high-salt diet clearly indicating sex-specific effects of the mineralo-corticoid antagonist spironolactone.

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

Cited by 18 publications

References 36 publications

Testosterone and Nandrolone Sensitization of Brain Anteroventral Area of Third Ventricle to Hypertonic NaCl-Induced Sympathetic Response

Testosterone and Nandrolone Sensitization of Brain Anteroventral Area of Third Ventricle to Hypertonic NaCl-Induced Sympathetic Response

Sexual Dimorphism in Urinary Angiotensinogen Excretion During Chronic Angiotensin II−Salt Hypertension

Sex-specific Effects of Spironolactone on Blood Pressure in Gonadectomized Male and Female Wistar Rats

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

Cited by 18 publications

References 36 publications

Testosterone and Nandrolone Sensitization of Brain Anteroventral Area of Third Ventricle to Hypertonic NaCl-Induced Sympathetic Response

Testosterone and Nandrolone Sensitization of Brain Anteroventral Area of Third Ventricle to Hypertonic NaCl-Induced Sympathetic Response

Sexual Dimorphism in Urinary Angiotensinogen Excretion During Chronic Angiotensin II−Salt Hypertension

Sex-specific Effects of Spironolactone on Blood Pressure in Gonadectomized Male and Female Wistar Rats

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