Julio C. Sartori-Valinotti

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.

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-PGF2&agr; (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.

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.

Oxidative Stress Contributes to Sex Differences in Blood Pressure in Adult Growth-Restricted Offspring

Numerous experimental studies suggest that oxidative stress contributes to the pathophysiology of hypertension and, importantly, that oxidative stress plays a more definitive role in mediating hypertension in males than in females. Intrauterine growth restriction induced by reduced uterine perfusion initiated at day 14 of gestation in the rat programs hypertension in adult male growth-restricted offspring; yet, female growth-restricted offspring are normotensive. The mechanisms mediating sex differences in blood pressure in adult growth-restricted offspring are not clear. Thus, this study tested the hypothesis that sex-specific differences in renal oxidative stress contribute to the regulation of blood pressure in adult growth-restricted offspring. A significant increase in blood pressure measured by telemetry in male growth-restricted offspring (P<0.05) was associated with a marked increase in renal markers of oxidative stress (P<0.05). Chronic treatment with the antioxidant Tempol had no effect on blood pressure in male control offspring, but it normalized blood pressure (P<0.05) and renal markers of oxidative stress (P<0.05) in male growth-restricted offspring relative to male control offspring. Renal markers of oxidative stress were not elevated in female growth-restricted offspring; however, renal activity of the antioxidant catalase was significantly elevated relative to female control offspring (P<0.05). Chronic treatment with Tempol did not significantly alter oxidative stress or blood pressure measured by telemetry in female offspring. Thus, these data suggest that sex differences in renal oxidative stress and antioxidant activity are present in adult growth-restricted offspring and that oxidative stress may play a more important role in modulating blood pressure in male but not female growth-restricted offspring.

Sex Steroids and Renal Disease: Lessons From Animal Studies

Epidemiological studies have shown that male sex is an independent risk factor for the development and progression of renal disease, and men progress to end stage renal disease (ESRD) faster than premenopausal women in such diseases as autoimmune glomerulonephritis, hypertensive glomerulosclerosis, and polycystic kidney disease.1–3 Although the age-related decline in renal function is also faster in men, women become more susceptible to renal diseases after menopause.4 Insight from in vitro studies and animal models suggest that sex steroids play pivotal roles in modifying the progression to ESRD. Because there is a paucity of data in humans showing the mechanisms by which sex steroids impact renal disease, most of the studies discussed this review will be in animals, mainly rats. Furthermore, determining the roles of sex steroids in various diseases has been done using gonedectomized animals; however, although gonadectomy removes more than sex steroids and most studies only replace the sex steroid of interest, these are still the best studies in which to evaluate mechanisms responsible for sex differences in renal disease. Studies in postmenopausal women will also be kept to a minimum in this review because it is likely that sex steroids change action with aging, as suggested by the Women’s Health Initiative study. Estrogen receptors (ER) are present in the kidney, although their localization in nephron segments has not been fully elucidated. Mesangial cells contain both ERα and ERβ,5 as do endothelium and vascular smooth muscle cells.5–7 Whether the newly described transmembrane estrogen receptor, GPR30,8 is present in kidneys has not been determined. Ovariectomy (ovx) of Dahl salt sensitive rats (DS) caused decreases in ERα but increases in ERβ expression in the renal cortex and medulla,9 whereas ovx in salt resistant (DR) rats caused decreases in cortical and increases in medullary ERα, and …

Sexual Dimorphism in the Blood Pressure Response to Angiotensin II in Mice After Angiotensin-converting Enzyme Blockade

BACKGROUND The incidence of hypertension and progression of renal disease are greater in men than in women. Data suggest that there is a dimorphic response to angiotensin II (Ang II) in rats, with male rats exhibiting a greater increase in mean arterial pressure (MAP) than females. However, during endogenous renin-angiotensin system (RAS) blockade with angiotensin-converting enzyme (ACE) inhibition, female rats have a greater MAP response to Ang II. We tested whether female mice exhibit a greater MAP response to chronic Ang II during ACE inhibition. METHODS Twenty-week-old male and female C57BL/6J mice (n > or = 6/group), treated with enalapril (40 mg/kg/day in drinking water), were assigned to groups receiving either Ang II (800 ng/kg/min) or saline for 2 weeks. Enalapril treatment began 4 days before and continued throughout the experiment. RESULTS MAP was higher in male mice than female mice treated with enalapril and Ang II (male: 144 +/- 3 vs. female: 121 +/- 6 mm Hg, P < 0.05) and was not different between mice treated with enalapril alone (male: 99 +/- 3 vs. female: 100 +/- 3 mm Hg). F2-isoprostanes were not increased by Ang II; however, female mice had significantly higher levels than males. Renal cortical expression of catalase and Cu/Zn-superoxide dismutase (SOD) was not different between experimental groups. Urinary protein was higher in male mice when compared to females, but was not changed after treatment with Ang II in either group. CONCLUSIONS These data suggest that there are species and sex-specific differences in the mechanism of the blood pressure response to Ang II, even during ACE inhibition.

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.

Response to Assessment of Urinary F2-Isoprostanes in Experimental and Clinical Studies: Mass Spectrometry Versus ELISA

We thank Tsikas et al ( Assessment of Urinary F 2 - Isoprostanes in Experimental and Clinical Studies: Mass Spectometry Versus ELISA )1 for their interest in our work. We agree with the authors that measurement of urinary F2-isoprostane by ELISA is not the gold standard method; however, we would like to emphasize that we did not base our conclusions solely on the results obtained from this method. We utilized an ELISA kit for urinary F2-isoprostane …

Postmenopausal Hypertension: Insights from Rat Models

The increase in blood pressure following menopause sets women up for increased risk of negative cardiovascular outcomes. The increase in blood pressure occurs 5-10 years following cessation of menses which suggests that mechanisms other than loss of female sex hormones may play roles in mediating the hypertension. Recent studies using rat models of aging have begun to shed light on some of possible mechanisms responsible for postmenopausal hypertension. This review outlines the most recent studies and addresses questions remaining to be addressed.