Roles played by 20-HETE, angiotensin II and endothelin in mediating the hypertension in aging female spontaneously hypertensive rats.

Prevalence of hypertension (HT) increases in women after menopause, and there is evidence that HT is not as well controlled in postmenopausal women as men. The reasons for this are not clear but may be related to the lack of adequate blockade of the systems contributing to HT in women. This study aimed to determine the roles of three of the systems known to contribute to HT in animal studies: angiotensin II (ANG II; enalapril inhibitor), eicosanoids [1-aminobenzotriazole (1-ABT) inhibitor], and endothelin (ET(A) receptor antagonist), on blood pressure (BP) in three groups of female spontaneously hypertensive rats (SHR), aged 18 mos (postmenopausal rat, PMR). After baseline telemetry BP, three drug periods were performed for 5 days each: single blockade (ABT or enalapril), double blockade (ABT+enalapril or enalapril+ABT), and triple blockade (all 3 drugs). Controls received no treatment until the third period when they received ET(A) receptor antagonist alone. Single drug blockade reduced BP in PMR to similar levels. Double blockade reduced mean arterial pressure more in ABT+enalapril rats than in the other group (enalapril+ABT). Triple drug blockade reduced BP to similar levels in both groups, but the BP remained ∼110 mmHg. The data suggest that these three systems, ANG II, eicosanoids, and endothelin, contribute together and independently to BP control in old female SHR. However, other systems also contribute to the HT since the BP was not normalized, supporting the notion that HT in postmenopausal women may require complex multidrug therapy to be better controlled and that may require the development of additional drugs.

Testosterone supplementation in male obese Zucker rats reduces body weight and improves insulin sensitivity but increases blood pressure.

Androgen levels are lower in obese men as compared with normal weight individuals. However, there are no safety data regarding the chronic use of androgen supplements in middle-aged men. The present study was undertaken to determine the cardiovascular and metabolic effects of chronic (10 weeks) testosterone treatment in male obese Zucker rats, starting at 22 weeks of age, when testosterone levels were significantly decreased. Testosterone supplements increased plasma levels, 10-fold in both obese Zucker rats and lean Zucker rats. In obese Zucker rats, testosterone supplements reduced body weight, plasma insulin, and cholesterol levels and improved the oral glucose tolerance test. None of these parameters were affected in lean Zucker rats. Mean arterial pressure was significantly increased in obese Zucker rats but not lean Zucker rats. Testosterone supplements increased proteinuria and accelerated renal injury in lean Zucker rats only. Thus, treatment of obese men with chronic testosterone supplements should be done with careful monitoring of blood pressure.

Cardiovascular-renal and metabolic characterization of a rat model of polycystic ovary syndrome.

BACKGROUND: Polycystic ovary syndrome (PCOS) is the most common reproductive dysfunction in premenopausal women. PCOS is also associated with increased risk of cardiovascular disease when PCOS first occurs and later in life. Hypertension, a common finding in women with PCOS, is a leading risk factor for cardiovascular disease. The mechanisms responsible for hypertension in women with PCOS have not been elucidated. OBJECTIVE: This study characterized the cardiovascular-renal consequences of hyperandrogenemia in a female rat model. METHODS: Female Sprague-Dawley rats (aged 4-6 weeks) were implanted with dihydrotestosterone or placebo pellets lasting 90 days. After 10 to 12 weeks, blood pressure (by radiotelemetry), renal function (glomerular filtration rate, morphology, protein, and albumin excretion), metabolic parameters (plasma insulin, glucose, leptin, cholesterol, and oral glucose tolerance test), inflammation (plasma tumor necrosis factor-α), oxidative stress (mRNA expression of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase subunits, p22(phox), p47(phox), gp91(phox), and NOX4), nitrate/nitrite excretion and mRNA expression of components of the renin-angiotensin system (angiotensinogen, angiotensin-I-converting enzyme [ACE], and AT1 receptor) were determined. RESULTS: Plasma dihydrotestosterone increased 3-fold in hyperandrogenemic female (HAF) rats, whereas plasma estradiol levels did not differ compared with control females. HAF rats exhibited estrus cycle dysfunction. They also had increased food intake and body weight, increased visceral fat, glomerular filtration rate, renal injury, insulin resistance and metabolic dysfunction, oxidative stress, and increased expression of angiotensinogen and ACE and reduced AT1 receptor expression. CONCLUSIONS: The HAF rat is a unique model that exhibits many of the characteristics of PCOS in women and is a useful model to study the mechanisms responsible for PCOS-mediated hypertension.

Postmenopausal hypertension: role of 20-HETE.

Blood pressure (BP) increases after menopause. However, the mechanisms responsible have not been elucidated. In this study we tested the hypothesis that 20-hydroxyeicosatetraenoic acids (20-HETE), produced by cytochrome P-450 (CYP450) ω-hydroxylase, contributes to the hypertension in a model of postmenopausal hypertension, aged female spontaneously hypertensive rats (PMR). 1-Aminobenzotriazole, a nonselective inhibitor of arachidonic acid metabolism, for 7 days, reduced BP in PMR but had no effect in young females. Acute intravenous infusion of HET-0016, a specific inhibitor of 20-HETE, over 3 h, also reduced BP in PMR. CYP4A isoform mRNA expression showed no difference in renal CYP4A1 or CYP4A3 but increases in CYP4A2 and decreases in CYP4A8. CYP4A protein expression was decreased in kidney of PMR compared with young females. Endogenous 20-HETE was significantly higher in cerebral vessels of PMR than young females (YF) but was significantly lower in renal vessels of PMR. Omega-hydroxylase activity in cerebral vessels was also higher in PMR but was similar in kidney vessels in both groups. In renal microsomal preparations, endogenous 20-HETE was not different in PMR and young females, but ω-hydroxylase activity was significantly lower in PMR than YF. The data with blockers suggest that 20-HETE contributes to postmenopausal hypertension in SHR. The data also suggest that cerebral production of 20-HETE may be increased and renal tubular production may be decreased in PMR, thus both contributing to their elevated BP.

Postmenopausal hypertension.

Cardiovascular disease is the leading cause of morbidity and mortality in postmenopausal women. Hypertension is a major risk factor for cardiovascular disease. The mechanisms responsible for postmenopausal hypertension have not been completely elucidated. However, various mechanisms have been implicated to play a role. For example, there is evidence that changes in estrogen/androgen ratios favoring increases in androgens, activation of the renin-angiotensin and endothelin systems, activation of the sympathetic nervous system, metabolic syndrome and obesity, inflammation, increased vasoconstrictor eicosanoids, and anxiety and depression may be important in the pathogenesis of postmenopausal hypertension. There is also evidence that hypertension is less well controlled in aging women than in aging men, but the reasons for this gender difference is not clear. Postmenopausal hypertension is likely multifactorial. Future studies will be necessary to determine the contribution of these systems listed above in mediating postmenopausal hypertension and to design treatment strategies that encompass these mechanisms to improve the quality of life of postmenopausal women as they age.

A single pill to treat postmenopausal hypertension? Not yet.

Postmenopausal women make up one of the fastest growing populations in the United States. Women typically have a higher incidence of cardiovascular disease following menopause. One of the major risk factors for cardiovascular disease is hypertension, and after menopause, blood pressure (BP) increases progressively in women. Also after menopause, the progression of renal disease increases in women compared with aged matched men. However, the mechanism(s) responsible for the post-menopausal increase in BP and renal injury are yet to be elucidated. Moreover the best therapeutic options to treat postmenopausal hypertension in women are not clear. Hypertension in postmenopausal women are usually associated with other cardiovascular risk factors, such as dyslipidemias, visceral obesity and endothelial dysfunction. Recently it became apparent that in a large number of hypertensive postmenopausal women, their BP is not well controlled with conventional antihypertensive medications. A clear understanding of the complex pathogenesis of postmenopausal hypertension is needed in order to offer the best therapeutic options for these women.

Postmenopausal hypertension: role of the Renin-Angiotensin system.

After menopause, blood pressure increases in women. However, the underlying mechanisms responsible for postmenopausal hypertension are not completely understood. This study was conducted to determine the role that the renin-angiotensin system (RAS) plays in post-menopausal hypertension. Post-estrous cycling (postmenopausal) spontaneously hypertensive rats or young female controls were treated with losartan, an angiotensin (Ang) II type 1 receptor blocker, for 25 days. Mean arterial pressure was recorded continuously by radiotelemetry. Losartan significantly decreased blood pressure in postmenopausal rats and young female controls but failed to normalize blood pressure in postmenopausal rats to levels found in young controls. Plasma renin activity and plasma angiotensinogen were significantly elevated, and intrarenal Ang II type 1 receptor and renin mRNA expression were significantly downregulated in postmenopausal rats. Therefore, RAS only partially contributes to hypertension in postcycling spontaneously hypertensive rats, whereas hypertension in young females is mediated mainly by the RAS. The data suggest that other mechanisms besides activation of the RAS are likely involved in postmenopausal hypertension.

Rosiglitazone reduces blood pressure in female Dahl salt-sensitive rats.

Postmenopausal women (PMW) are at greater risk for salt-sensitive hypertension and insulin resistance than premenopausal women. Peroxisome-proliferator-activated receptor-gamma (PPARgamma) agonists reduce blood pressure (BP) and insulin resistance in humans. As in PMW, ovariectomy (OVX) increases salt sensitivity of BP and body weight in Dahl salt-sensitive (DS) rats. This study addressed whether rosiglitazone (ROSI), a PPARgamma agonist, attenuates salt-sensitive hypertension in intact (INT) and OVX DS rats, and if so, whether insulin resistance, nitric oxide (NO), oxidative stress, and/or renal inflammation were contributing mediators. Telemetric BP was similar in OVX and INT on low salt diet (0.3% NaCl), but was higher in OVX than INT on high salt (8% NaCl). ROSI reduced BP in OVX and INT on both low and high salt diet, but only attenuated salt sensitivity of BP in OVX. Nitrate/nitrite excretion (NO(x); index of NO) was similar in INT and OVX on low salt diet, and ROSI increased NO(x) in both groups. High salt diet increased NO(x) in all groups but ROSI only increased NO(x) in OVX rats. OVX females exhibited insulin resistance, increases in body weight, plasma leptin, cholesterol, numbers of renal cortical macrophages, and renal MCP-1 and osteopontin mRNA expression compared to INT. ROSI reduced cholesterol and macrophage infiltration in OVX, but not INT. In summary, PPARgamma activation reduces BP in INT and OVX females, but attenuates the salt sensitivity of BP in OVX only, likely due to increases in NO and in part to reductions in renal resident macrophages and inflammation.

Dihydrotestosterone stimulates aldosterone secretion by H295R human adrenocortical cells.

Men exhibit a higher incidence of cardiovascular diseases than do women. The cardiovascular actions of sex steroids have been suggested as primary factors in mediating this sex difference. The mechanisms by which sex steroids, androgens and estrogens, mediate cardiovascular actions remain unclear. Excess aldosterone secretion has been associated with cardiovascular diseases. The hypothesis tested in this study was that at physiological concentrations, androgens stimulate and estradiol inhibits aldosterone secretion by human adrenal cells. In contrast to our hypothesis, physiological concentrations of sex steroids did not modify aldosterone secretion by H295R human adrenocortical cells. However, supraphysiological concentrations (300-1000 nM) of dihydrotestosterone (DHT) significantly stimulated basal and Angiotensin II-mediated aldosterone secretion. The stimulatory effect of DHT on aldosterone secretion was not blocked by the classical androgen receptor blocker flutamide. The stimulatory effect of DHT on aldosterone secretion was also independent of the intra-adrenal renin-angiotensin system since it was neither modified by treatment with the Angiotensin II receptor type 1 blocker losartan or the angiotensin converting enzyme inhibitor captopril. Inhibitors of the calmodulin/calmodulin-dependent protein kinase (CaMK) and protein kinase C intracellular signaling pathways abolished the DHT stimulatory effect on aldosterone secretion by H295R cells. In conclusion, physiological concentrations of sex steroids did not modify aldosterone secretion by human adrenal cells. However, supraphysiological concentrations of DHT-stimulated aldosterone secretion by human adrenal cells by the calmodulin/CaMK and protein kinase C intracellular signaling pathways but independently of the classical androgen receptor. Supraphysiological doses of androgen may promote cardiovascular diseases via stimulation of aldosterone secretion.

Testosterone-dependent hypertension and upregulation of intrarenal angiotensinogen in Dahl salt-sensitive rats.

Blood pressure (BP) is more salt sensitive in men than in premenopausal women. In Dahl salt-sensitive rats (DS), high-salt (HS) diet increases BP more in males than females. In contrast to the systemic renin-angiotensin system, which is suppressed in response to HS in male DS, intrarenal angiotensinogen expression is increased, and intrarenal levels of ANG II are not suppressed. In this study, the hypothesis was tested that there is a sexual dimorphism in HS-induced upregulation of intrarenal angiotensinogen mediated by testosterone that also causes increases in BP and renal injury. On a low-salt (LS) diet, male DS had higher levels of intrarenal angiotensinogen mRNA than females. HS diet for 4 wk increased renal cortical angiotensinogen mRNA and protein only in male DS, which was prevented by castration. Ovariectomy of female DS had no effect on intrarenal angiotensinogen expression on either diet. Radiotelemetric BP was similar between males and castrated rats on LS diet. HS diet for 4 wk caused a progressive increase in BP, protein and albumin excretion, and glomerular sclerosis in male DS rats, which were attenuated by castration. Testosterone replacement in castrated DS rats increased BP, renal injury, and upregulation of renal angiotensinogen associated with HS diet. Testosterone contributes to the development of hypertension and renal injury in male DS rats on HS diet possibly through upregulation of the intrarenal renin-angiotensin system.

Sex differences in control of blood pressure: role of oxidative stress in hypertension in females.

In general, blood pressure is higher in normotensive men than in age-matched women, and the prevalence of hypertension in men is also higher until after menopause, when the prevalence of hypertension increases for women. It is likely then that the mechanisms by which blood pressure increases in men and women with aging may be different. Although clinical trials to reduce blood pressure with antioxidants have typically not been successful in human cohorts, studies in male rats suggest that oxidative stress plays an important role in mediating hypertension. The exact mechanisms by which oxidative stress increases blood pressure have not been completely elucidated. There may be several reasons for the discrepancies between clinical and animal studies. In this review, the data obtained in selected clinical and animal studies are discussed, and the hypothesis is put forward that oxidative stress may not be as important in mediating hypertension in females as has been shown previously in male rats. Furthermore, it is likely that differences in genetics, age, length of time with hypertension, endothelial dysfunction, and sex are all factored in to modulate the responses to antioxidants in humans. As such, future clinical trials should be designed and powered to evaluate the effects of oxidative stress on blood pressure separately in men and women.

Sex differences in the pressor response to angiotensin II when the endogenous renin-angiotensin system is blocked.

The present study determined whether there are sex differences in the pressor response to angiotensin II (Ang II) when the endogenous renin-angiotensin system (RAS) is blocked by enalapril (ACEI), and whether this pressor response is changed in the presence of high salt (HS). Telemetry BP was measured in rats treated with ACEI (250 mg/L drinking water) (n=6 to 7/grp), or with ACEI and Ang II (150 ng/kg/min, sc; n=5 to 6/grp), for 3 wk. For the last 2 wk of the study, rats received HS (4% NaCl). MAP was lower in females during baseline (100.8+/-1.1 versus 105.2+/-1.3; P<0.05), and with ACEI the last 3 days on normal salt diet (78.8+/-1.2 versus 88.5+/-0.9; P<0.05), but increased to higher levels than in males on day 6 of Ang II (129.0+/-2.2 versus 117.3+/-2.9; P<0.05). One week of Ang II increased albuminuria in males, but not females, and urinary 8-iso-PGF2alpha (F2-isoP) was not increased in either males or females. MAP was salt-sensitive in both sexes receiving ACEI, but was only salt-sensitive in males with Ang II (129.3+/-3.7 versus 145.1+/-5.7; P<0.05). Albuminuria continued to increase with HS and Ang II in males, but not in females. F2-isoP excretion increased with MAP during the last week of HS and Ang II in males but was independent of MAP in females. With ACEI, MAP in females on normal salt is more responsive to Ang II but is independent of oxidative stress or renal injury. MAP in males is salt-sensitive with Ang II, which may be mediated by oxidative stress and renal injury.

Regulators of G-protein signaling 4 in adrenal gland: localization, regulation, and role in aldosterone secretion.

Regulators of G-protein signaling (RGS proteins) interact with Galpha subunits of heterotrimeric G-proteins, accelerating the rate of GTP hydrolysis and finalizing the intracellular signaling triggered by the G-protein-coupled receptor (GPCR)-ligand interaction. Angiotensin II (Ang II) interacts with its GPCR in adrenal zona glomerulosa cells and triggers a cascade of intracellular signals that regulates steroidogenesis and proliferation. On screening for adrenal zona glomerulosa-specific genes, we found that RGS4 was exclusively localized in the zona glomerulosa of the rat adrenal cortex. We studied RGS4 expression and regulation in the rat adrenal gland, including the signaling pathways involved, as well as the role of RGS4 in steroidogenesis in human adrenocortical H295R cells. We reported that RGS4 mRNA expression in the rat adrenal gland was restricted to the adrenal zonal glomerulosa and upregulated by low-salt diet and Ang II infusion in rat adrenal glands in vivo. In H295R cells, Ang II caused a rapid and transient increase in RGS4 mRNA levels mediated by the calcium/calmodulin/calmodulin-dependent protein kinase and protein kinase C pathways. RGS4 overexpression by retroviral infection in H295R cells decreased Ang II-stimulated aldosterone secretion. In reporter assays, RGS4 decreased Ang II-mediated aldosterone synthase upregulation. In summary, RGS4 is an adrenal gland zona glomerulosa-specific gene that is upregulated by aldosterone secretagogues, in vivo and in vitro, and functions as a negative feedback of Ang II-triggered intracellular signaling. Alterations in RGS4 expression levels or functions may be involved in deregulations of Ang II signaling and abnormal aldosterone secretion.

Sex differences in oxidative stress and the impact on blood pressure control and cardiovascular disease.

1. In the present review, we addressed studies in humans and rats to determine the role that oxidative stress may play in mediating cardiovascular outcomes. 2. Biochemical evaluation of oxidative stress in both humans and spontaneously hypertensive rats gives equivocal results as to the relative levels in males versus females. Clinical trials with anti-oxidants in humans have not shown consistent results in protecting against detrimental cardiovascular outcomes. In spontaneously hypertensive rats (SHR), blockade studies using tempol or apocynin reduce renal oxidative stress and blood pressure in male SHR, but not in female rats. In addition, increasing oxidative stress with molsidomine increases blood pressure in male, but not female, SHR. Treatment with vitamins E and C reduces blood pressure in young male, but not aged, animals. Furthermore tempol is unable to reduce blood pressure in young male SHR in the absence of a functional nitric oxide system. 3. Neither human nor animal studies are consistent in terms of whether oxidative stress levels are higher in males or females. Furthermore, anti-oxidant therapy in humans often does not ameliorate, or even attenuate, the negative cardiovascular consequences of increased oxidative stress. Our studies in SHR shed light on why these outcomes occur.

Induction of 5-aminolevulinate synthase by activators of steroid biosynthesis.

Different cytochromes P450 are involved in steroid biosynthesis. These cytochromes have heme as the prosthetic group. We previously reported that ACTH, an activator of glucocorticoid biosynthesis in adrenal, requires heme biosynthesis for a maximal response. In the present study, we investigated the effect of ACTH, and the effect of two activators of the adrenal mineralocorticoid synthesis, endothelin-1 and low sodium diet on 5-aminolevulinate-synthase (ALA-s) mRNA. ALA-s is the rate-limiting enzyme in heme biosynthesis. It was found that infusion of rats with ACTH for 1 h caused an increase of adrenal ALA-s mRNA and activity accompanied by an increase in plasma corticosterone. CYP21, a cytochrome involved in the synthesis of both corticosterone and aldosterone, was not modified at the RNA level in adrenal glands by 1 h of ACTH infusion. Consistently, infusion of endothelin-1 for 1 h increased ALA-s mRNA and aldosterone content in adrenal gland without modifying CYP21 mRNA levels. To study if ALA-s is also regulated by the main physiological stimuli that increase adrenal mineralocorticoid secretion, we fed rats with low salt diet for 2 or 15 days. Low salt diet treatment increased adrenal gland ALA-s mRNA levels. On the other hand, the rapid stimulation of ALA-s mRNA by ACTH which acts through cyclic AMP was confirmed in H295R human adrenocortical cells, the only human adrenal cell line that has a steroid secretion pattern and regulation similar to primary cultures of adrenal cells. Our findings suggest that the acute activation of adrenal steroidogenic cytochromes by trophic hormones involves an increase in heme biosynthesis which will favor the production of active cytochromes.

Adrenal transcription regulatory genes modulated by angiotensin II and their role in steroidogenesis.

Transcription regulatory genes are crucial modulators of cell physiology and metabolism whose intracellular levels are tightly controlled to respond to extracellular stimuli. We studied transcription regulatory genes modulated by angiotensin II, one of the most important regulators of adrenal cortical cell function, and their role in adrenal steroidogenesis in H295R human adrenocortical cells. Angiotensin II-modulated transcription regulatory genes were identified with high-density oligonucleotide microarrays and the results validated by real-time RT-PCR. Cotransfection reporter assays were performed in H295R cells to analyze the role of these transcription regulatory genes in the control of the expression of 11beta-hydroxylase and aldosterone synthase, the last and unique enzymes of the glucocorticoid and mineralocorticoid biosynthetic pathways, respectively. We selected a subset of the most regulated genes for reporter plasmid studies to determine the effect on these enzymes. BHLHB2, BTG2, and SALL1 decreased expression of both enzymes, whereas CITED2, EGR2, ELL2, FOS, FOSB, HDAC5, MAFF, MITF, NFIL3, NR4A1, NR4A2, NR4A3, PER1, and VDR increased expression for both enzymes. By the ratio of aldosterone synthase to 11beta-hydroxylase expression, NFIL3, NR4A1, NR4A2, and NR4A3 show the greatest selectivity toward upregulating expression of the mineralocorticoid biosynthetic pathway preferentially. In summary, this study reports for the first time a set of transcription regulatory genes that are modulated by angiotensin II and their role in adrenal gland steroidogenesis. Abnormal regulation of the mineralocorticoid or glucocorticoid biosynthesis pathways is involved in several pathophysiological conditions; hence the modulated transcription regulatory genes described may correlate with adrenal steroidogenesis pathologies.

Disabled-2 is expressed in adrenal zona glomerulosa and is involved in aldosterone secretion.

The differentiation of the adrenal cortex into functionally specific zones is probably due to differential temporal gene expression during fetal growth, development, and adulthood. In our search for adrenal zona glomerulosa-specific genes, we found that Disabled-2 (Dab2) is expressed in the zona glomerulosa of the rat adrenal gland using a combination of laser capture microdissection, mRNA amplification, cDNA microarray hybridization, and real-time RT-PCR. Dab2 is an alternative spliced mitogen-regulated phosphoprotein with features of an adaptor protein and functions in signal transduction, endocytosis, and tissue morphogenesis during embryonic development. We performed further studies to analyze adrenal Dab2 localization, regulation, and role in aldosterone secretion. We found that Dab2 is expressed in the zona glomerulosa and zona intermedia of the rat adrenal cortex. Low-salt diet treatment increased Dab2-long isoform expression at the mRNA and protein level in the rat adrenal gland, whereas high-salt diet treatment did not cause any significant modification. Angiotensin II infusion caused a transient increase in both Dab2 isoform mRNAs in the rat adrenal gland. Dab2 overexpression in H295R human adrenocortical cells caused an increase in aldosterone synthase expression and up-regulated aldosterone secretion under angiotensin II-stimulated conditions. In conclusion, Dab2 is an adrenal gland zona glomerulosa- and intermedia-expressed gene that is regulated by aldosterone secretagogues such as low-salt diet or angiotensin II and is involved in aldosterone synthase expression and aldosterone secretion. Dab2 may therefore be a modulator of aldosterone secretion and be involved in mineralocorticoid secretion abnormalities.

Testosterone contributes to marked elevations in mean arterial pressure in adult male intrauterine growth restricted offspring.

Our laboratory uses a model of intrauterine growth restriction (IUGR) induced by placental insufficiency in the rat to examine the developmental origins of adult disease. In this model only male IUGR offspring remain hypertensive in adulthood, revealing sex-specific differences. The purpose of this study was to determine whether testosterone with participation of the renin-angiotensin system (RAS) contributes to hypertension in adult male IUGR offspring. At 16 wk of age a significant increase in testosterone (346 +/- 34 vs. 189 +/- 12 ng/dl, P < 0.05) was associated with a significant increase in mean arterial pressure (MAP) measured by telemetry in IUGR offspring (147 +/- 1 vs. 125 +/- 1 mmHg, P < 0.05, IUGR vs. control, respectively). Gonadectomy (CTX) at 10 wk of age significantly reduced MAP by 16 wk of age in IUGR offspring (124 +/- 2 mmHg, P < 0.05 vs. intact IUGR) but had no effect in control (125 +/- 2 mmHg). A significant decrease in MAP in intact IUGR (111 +/- 3 mmHg, P < 0.05 vs. untreated intact IUGR) and castrated IUGR (110 +/- 4 mmHg, P < 0.05 vs. untreated CTX IUGR) after treatment with enalapril for 2 wk suggests a role for RAS involvement. However, the decrease in blood pressure in response to enalapril was greater in intact IUGR (Delta36 +/- 1 mmHg, P < 0.05) compared with CTX IUGR (Delta15 +/- 2 mmHg), indicating an enhanced response to RAS blockade in the presence of testosterone. Thus these results suggest that testosterone plays a role in modulating hypertension in adult male IUGR offspring with participation of the RAS.