Enhanced sensitivity to acute angiotensin II is testosterone dependent in adult male growth-restricted offspring

Abstract

cental insufficiency results in intrauterine growth restriction (IUGR) and hypertension in adult male growth-restricted rats. Although renal ANG II and plasma renin activity do not differ between growthrestricted and control rats, blockade of the renin-angiotensin system (RAS) abolishes hypertension in growth-restricted rats, suggesting that the RAS contributes to IUGR-induced hypertension. Moreover, castration abolishes hypertension in growth-restricted rats, indicating an important role for testosterone. Therefore, we hypothesized that enhanced responsiveness to ANG II contributes to hypertension in this model of IUGR and that androgens may play a pivotal role in this enhanced response. Physiological parameters were determined at 16 wk of age in male rats pretreated with enalapril (40 mg·kg Ϫ1 ·day Ϫ1 ) for 1 wk. Baseline blood pressures were similar between growthrestricted (112 Ϯ 3 mmHg) and control (110 Ϯ 2 mmHg) rats; however, an enhanced pressor response to acute ANG II (100 ng·kg Ϫ1 ·min Ϫ1 for 30 min) was observed in growth-restricted (160 Ϯ 2 mmHg) vs. control (136 Ϯ 2 mmHg; P Ͻ 0.05) rats. Castration abolished the enhanced pressor response to acute ANG II in growthrestricted (130 Ϯ 2 mmHg) rats with no significant effect on blood pressure in controls (130 Ϯ 2 mmHg). Blood pressure was increased to a similar extent above baseline in response to acute phenylephrine (100 g/min) in control (184 Ϯ 5 mmHg) and growth-restricted (184 Ϯ 8 mmHg) rats, suggesting the enhanced pressor response in growthrestricted rats is ANG II specific. Thus, these results suggest that growth-restricted rats exhibit an enhanced responsiveness to ANG II that is testosterone dependent and indicate that the RAS may serve as an underlying mechanism in mediating hypertension programmed in response to IUGR. sex steroids; blood pressure; developmental programming ADVERSE INFLUENCES DURING early life can lead to an increased risk for cardiovascular and renal disease (4, 21). Using a model of reduced uterine perfusion in the pregnant rat, our laboratory has begun to elucidate the mechanisms linking intrauterine growth restriction (IUGR) and blood pressure (1). We previously reported that male growth-restricted offspring from reduced uterine perfusion dams exhibit a marked increase in arterial pressure in adulthood that is associated with a marked increase in intrarenal renin and angiotensinogen mRNA expression, and a marked increase in renal angiotensin I-converting enzyme (ACE) activity (9). However, despite these increases in intrarenal renin and angiotensinogen mRNA expression and intrarenal ACE activity, expression of intrarenal ANG II and its receptor, AT 1 R, are similar in hypertensive male growth-restricted rats compared with normotensive age-matched male control rats (9). Moreover, plasma renin activity, plasma renin substrate, and serum ACE activity are not altered in adult male growth-restricted rats relative to control (9, 22) suggesting that inappropriate activation of the systemic renin angiotensin system (RAS) is not obse...

Enhanced Mesenteric Arterial Responsiveness to Angiotensin II Is Androgen Receptor-Dependent in Prenatally Protein-Restricted Adult Female Rat Offspring1

“…This finding suggests that the enhanced responsiveness to Ang II in female protein-restricted rats is testosterone dependent and, importantly, indicates that involvement of the RAS in prenatal protein restriction-induced hypertension may necessitate modulation by testosterone. Similar responses of testosterone-dependent enhancement in responsiveness to Ang II is observed in adult growth-restricted male rats born to pregnant rats with reduced uterine perfusion [28].…”

Testosterone Induces Vascular Smooth Muscle Cell Migration by NADPH Oxidase and c-Src–Dependent Pathways

“…[1][2][3][4][5] This steroid hormone contributes not only to the development of arterial hypertension but also to hypertensionassociated vascular and renal abnormalities. 6 In humans, it is still controversial whether testosterone contributes to or protects from cardiovascular disease. Although many reports indicate that low testosterone levels are associated with high risk of cardiovascular disease and that testosterone replacement improves cardiovascular and metabolic functions, [7][8][9] other studies indicate that older men with higher testosterone levels are more likely to have cardiovascular disease.…”

Renin is activated in monochorionic diamniotic twins with birthweight discordance who do not have twin-to-twin transfusion syndrome

“…In addition, some reports of animal studies have shown that intrauterine growth-restricted offspring exhibited an enhanced sensitivity to angiotensin in spite of normal expressions of intrarenal angiotensin. 26,27 RAA activation in the pathogenesis of TTTS may be applied not only to TTTS patients, but also to MD twins with BW discordance and with selective intrauterine growth restriction.…”