Abstract-The ovariectomized (OVX) Dahl salt-sensitive (DS) rat fed a low-salt diet is a model of postmenopausal hypertension. In addition to estrogen loss, aging can also contribute to postmenopausal hypertension. We hypothesized that: (1) female DS rats on a low-salt diet become hypertensive with age; (2) ovariectomy accelerates age-dependent hypertension in the DS rat caused by estrogen depletion; and (3) this hypertension correlates with increased type 1 angiotensin receptor (AT 1 R) number (Bmax). Blood pressure was monitored by telemetry from 3 to 12 months and AT 1 R Bmax was determined by Scatchard analysis in glomeruli and adrenal cortex. Three groups of DS rats were studied: intact, OVX, and 17␤-estradiol-replaced OVX (OVXϩE). In intact rats, aging to 12 months resulted in hypertension (159Ϯ6 mm Hg) and an 82% decrease in estrogen. Blood pressure in OVX was significantly higher than OVXϩE through 12 months of age (173Ϯ4 versus 150Ϯ8 mm Hg). At 4 months, OVX increased AT 1 R Bmax compared with intact and OVXϩE in both glomeruli and adrenal cortex. Aging also increased AT 1 R Bmax in these tissues in intact rats. In summary, female DS rats fed a low-salt diet have hypertension develop with age, that is accelerated by OVX and attenuated by estrogen replacement. Concurrently, AT 1 Rs are upregulated by age and OVX, which is prevented by estrogen replacement. This study suggests that an increased activity of the renin angiotensin system contributes to the development of hypertension, and estrogen protects against this process. Key Words: aging Ⅲ Dahl rats Ⅲ hypertension, sodium-dependent Ⅲ estrogen Ⅲ renin-angiotensin system T he prevalence of hypertension in premenopausal women is lower compared with men of the same age. 1 After menopause, the incidence of hypertension in women doubles and becomes similar to men, suggesting that the loss of female gonadal steroids caused by menopause are a risk factor for postmenopausal hypertension. 2 In addition, there is evidence that salt-sensitivity also contributes to postmenopausal hypertension. 3 The mechanisms of postmenopausal hypertension are not well-understood and few animal models exist to study this phenomenon. We have shown that adult (4 months) female normotensive Dahl salt-sensitive (DS) rats maintained on a low-salt (LS) diet become hypertensive after ovariectomy (OVX). 4 Thus, the ovariectomized DS rat serves as an experimental model of postmenopausal hypertension. Furthermore, this is the first animal model in which OVX results in spontaneous hypertension. These studies suggest that salt-sensitive premenopausal women may be protected against the development of hypertension because of the presence of female gonadal steroids and that after menopause, the protective effects of these hormones are lost, thus contributing to the development of hypertension. Although these observations implicate a role for estrogen (E), the effects of aging on the regulation of blood pressure could also contribute to the development of salt-sensitive hypertension in postmenopa...

1. Females are protected against the development of hypertension. The purpose of the current review is to present the evidence for gender differences in the regulation of the sympatho-adrenal nervous system and to determine if these differences support the hypothesis that, in females, the regulation of the sympathetic nervous system (SNS) is altered such that sympatho-adrenal activation is attenuated or sympatho-adrenal inhibition is augmented. 2. The central control of sympatho-adrenal function is different in females and responses vary during the oestral and menstrual cycles. Pathways regulating the SNS appear to be less sensitive to excitatory stimuli and more sensitive to inhibitory stimuli in females compared with males. 3. Gender differences in arterial baroreflex sensitivity suggest that females may have a greater baroreflex sensitivity, such that alterations in blood pressure are more efficiently controlled than in males. Cardiopulmonary reflex inhibition of sympathetic nerve activity is greater in females, possibly resulting in a greater renal excretory function. 4. An attenuated sensitivity to adrenergic nerve stimulation, but not to noradrenaline (NA), suggests that gender differences in noradrenergic neurotransmission may protect females against sympathetic hyperactivity. Gender differences in the regulation of NA release via presynaptic alpha 2-adrenoceptors, the vasoconstrictor response to the cotransmitter neuropeptide Y and the clearance of catecholamines are consistent with this hypothesis. 5. Similarly, attenuated stress-induced increases in plasma catecholamines in women suggest that females are less sensitive and/or less responsive to adrenal medullary activation. This is supported by findings of gender differences in adrenal medullary catecholamine content, release and degradation. 6. We conclude that there is strong evidence that supports the hypothesis that, in females, the regulation of the SNS is altered such that sympatho-adrenal activation is attenuated or sympatho-adrenal inhibition is augmented.

Abstract. This study examined the effects of estrogen deficiency by ovariectomy (OVX) and 17␤-estradiol (E 2 ) replacement (OVXϩE 2 ) on glomerulosclerosis and tubulointerstitial fibrosis and the mechanisms contributing to these changes, including expression of collagen type IV and laminin, transforming growth factor-␤ (TGF-␤), and activity of matrix metalloproteinases (MMP) in the kidneys of young (4 mo [4M]) and aged (12 mo [12M]) Dahl salt-sensitive (DSS) rats maintained on a low-salt (0.1% NaCl) diet. While normal renal morphology was observed in the 4M rats in all treatment groups, moderate to severe glomerulosclerosis (glomerulosclerotic index [GSI]: 4M, 0.22 Ϯ 0.09 versus 12M, 1.43 Ϯ 0.17; P Ͻ 0.001) and cortical tubulointerstitial fibrosis (CTIFI: 4M, 0 versus 12M, 57.1 Ϯ 4.9; P Ͻ 0.01) was observed in the 12M rats. The severity of glomerulosclerosis and cortical tubulointerstitial fibrosis in the 12M group was augmented with OVX (GSI, 3.27 Ϯ 0.34; CTIFI, 74.4 Ϯ 9.2; P Ͻ 0.01 versus Intact at 12M) and attenuated with E 2 replacement ([GSI], 1.09 Ϯ 0.09; CTIFI, 49.2 Ϯ 6.8). In the 12M animals, OVX was also associated with increased deposition and expression of laminin (Intact, 228.1 Ϯ 6.7; OVX, 277.4 Ϯ 9.6 AU; P Ͻ 0.01), increased expression of TGF-␤ (Intact, 85.0 Ϯ 23.0; OVX, 178.0 Ϯ 20.5 AU; P Ͻ 0.001), and decreased activity of cortical MMP-9 (Intact, 3.8 Ϯ 0.8; OVX, 2.4 Ϯ 0.6 AUC; P Ͻ 0.01). E 2 replacement opposed these effects (laminin, 229.9 Ϯ 6.2 AU; TGF-␤, 101.3 Ϯ 25.2 AU; MMP-9, 5.2 Ϯ 0.2 AUC). The severity of the disease in the 12M rats correlated with a modest decrease in creatinine clearance (Intact, 0.26 Ϯ 0.01; OVX, 0.22 Ϯ 0.01; OVXϩE 2 , 0.28 Ϯ 0.01 mg/min per 100 g) and increase in BUN (Intact, 20.3 Ϯ 2.1; OVX, 32.6 Ϯ 5.1; OVXϩE 2 , 24.3 Ϯ 2.4 mg/dl). The authors conclude that E 2 is renoprotective in the aging DSS rat by attenuating glomerulosclerosis and tubulointerstitial fibrosis.The rate of progression of cardiovascular and renal disease and hypertension increases with age and is lower in premenopausal women compared with age-matched men (1-3). Interestingly, a re-evaluation of the Modification of Diet in Renal Disease (MDRD) study showed that the differences in the rate of decline of renal function between men and women is reduced after age 52 yr (their dividing point) (4), suggesting that menopause may affect the progression of renal disease in women; however, no studies to date have clearly demonstrated this point, suggesting that our understanding of the contribution of ovarian hormones to the development of age-related disease processes remains unclear. The Women's Health Initiative (WHI) reported that hormone replacement therapy with the estrogen-progesterone combination Prempro (conjugated equine estrogen and progestin) causes a slight increase in the risk of cardiovascular disease in a large population of postmenopausal women (5,6). However, numerous studies indicate that estrogen alone has cardiovascular protective effects. Estrogen improves serum lipid levels, increases end...

Lower body negative pressure (LBNP), a model of hemorrhage (Hem), shifts blood to the legs and elicits central hypovolemia. This study compared responses to LBNP and actual Hem in sedated baboons. Arterial pressure, pulse pressure (PP), central venous pressure (CVP), heart rate, stroke volume (SV), and +dP/dt were measured. Hem steps were 6.25%, 12.5%, 18.75%, and 25% of total estimated blood volume. Shed blood was returned, and 4 wk after Hem, the same animals were subjected to four LBNP levels which elicited equivalent changes in PP and CVP observed during Hem. Blood gases, hematocrit (Hct), hemoglobin (Hb), plasma renin activity (PRA), vasopressin (AVP), epinephrine (EPI), and norepinephrine (NE) were measured at baseline and maximum Hem or LBNP. LBNP levels matched with 6.25%, 12.5%, 18.75%, and 25% hemorrhage were -22 ± 6, -41 ± 7, -54 ± 10, and -71 ± 7 mmHg, respectively (mean ± SD). Hemodynamic responses to Hem and LBNP were similar. SV decreased linearly such that 25% Hem and matching LBNP caused a 50% reduction in SV. Hem caused a decrease in Hct, Hb, and central venous oxygen saturation (ScvO2). In contrast, LBNP increased Hct and Hb, while ScvO2 remained unchanged. Hem caused greater elevations in AVP and NE than LBNP, while PRA, EPI, and other hematologic indexes did not differ between studies. These results indicate that while LBNP does not elicit the same effect on blood cell loss as Hem, LBNP mimics the integrative cardiovascular response to Hem, and validates the use of LBNP as an experimental model of central hypovolemia associated with Hem.

Current monitoring technologies are unable to detect early, compensatory changes that are associated with significant blood loss. We previously introduced a novel algorithm to calculate the Compensatory Reserve Index (CRI) based on the analysis of arterial waveform features obtained from photoplethysmogram recordings. In the present study, we hypothesized that the CRI would provide greater sensitivity and specificity to detect blood loss compared with traditional vital signs and other hemodynamic measures. Continuous noninvasive vital sign waveform data, including CRI, photoplethysmogram, heart rate, blood pressures, SpO2, cardiac output, and stroke volume, were analyzed from 20 subjects before, during, and after an average controlled voluntary hemorrhage of ∼1.2 L of blood. Compensatory Reserve Index decreased by 33% in a linear fashion across progressive blood volume loss, with no clinically significant alterations in vital signs. The receiver operating characteristic area under the curve for the CRI was 0.90, with a sensitivity of 0.80 and specificity of 0.76. In comparison, blood pressures, heart rate, SpO2, cardiac output, and stroke volume had significantly lower receiver operating characteristic area under the curve values and specificities for detecting the same volume of blood loss. Consistent with our hypothesis, CRI detected blood loss and restoration with significantly greater specificity than did other traditional physiologic measures. Single measurement of CRI may enable more accurate triage, whereas CRI monitoring may allow for earlier detection of casualty deterioration.

Machine modeling can accurately identify reduced central blood volume and predict impending hemodynamic decompensation (shock onset) in individuals. Such a capability can provide decision support for earlier intervention.

Abstract-Female sex hormones protect against the development of Dahl hypertension mediated by increases in dietary sodium. The role of female sex hormones in the reversal of Dahl hypertension mediated by decreases in dietary sodium is unknown. The goal of this study was to identify sex differences in the reversal of Dahl hypertension and the associated changes in water and electrolyte homeostasis. Male (M, nϭ8), female (F, nϭ8), and ovariectomized female (OVX, nϭ9) Dahl salt-sensitive rats were instrumented with an abdominal radiotelemetry device for 24-hour monitoring of blood pressure (BP) and heart rate. Daily measurements of food intake, water intake, and urine output were recorded as diet was changed from a low-sodium diet (0.15% NaCl) to a diet containing 8% NaCl. The diet was then changed back to 0.15% NaCl. The responses to changes in the salt diet were compared with responses observed in rats (M, nϭ4; F, nϭ4; OVX, nϭ4) that were maintained on 0.15% NaCl during the experiment. Sex differences in BP were observed when M, F, and OVX rats were fed 8% NaCl diet for 2 weeks (152Ϯ4, 141Ϯ3, and 154Ϯ5 mm Hg, respectively). BP was significantly greater (PϽ0.05) in M and OVX rats than in F rats. Fluid balance (water intake minus urine volume) and sodium balance (sodium intake minus sodium excretion) were similar in all groups on the 8% NaCl diet. BP in time-control M, F, and OVX rats was 121Ϯ3, 130Ϯ4, and 162Ϯ11 mm Hg, respectively. Compared with time-control groups, differences in BP while rats were eating the 8% NaCl diet were observed in M and F rats but not OVX rats.Reinstatement of an NaCl-deficient diet reversed the hypertension in M and F but not OVX rats (124Ϯ4, 124Ϯ2, and 145Ϯ5 mm Hg, respectively). The changes in dietary sodium caused similar changes in renal handling of sodium and water in all groups of rats; therefore, the effect on blood pressure was independent of renal excretory function. The inability to reverse the hypertension by decreasing sodium intake in OVX rats and the development of spontaneous hypertension in OVX females maintained on a low-sodium diet indicates that removal of the female sex hormones predisposes the animal to the development of hypertension that is sodium independent. We conclude that female sex hormones protect Dahl S rats against the development of sodium-dependent and -independent hypertension. Key Words: hypertension, sodium-dependent Ⅲ salt sensitivity Ⅲ hormones T he relationship between salt intake and blood pressure has been extensively studied in humans and provides clear evidence that a subpopulation of humans are sensitive to alterations in salt intake. Salt sensitivity is usually identified by a reduction in blood pressure (5% to 10%) in response to a decrease in sodium intake or a rise in blood pressure (5% to 10%) in response to an increase in sodium intake. 1 Although the prevalence of hypertension in premenopausal women is lower than in men of the same age, the incidence of hypertension in women doubles after menopause, 2 which suggests that female sex hor...

The objectives of this study were to determine the hemodynamic and microcirculatory changes that occur during reduced renal mass hypertension in rats. In conscious animals with 75% reduction of total renal mass, mean arterial pressure was initially (4-8 hours) elevated by 15-20 mm Hg during intravenous infusion with isonatremic (145.4 mM) NaCl. Cardiac index was elevated by 15-20%, and total peripheral resistance index was normal or reduced. Cardiac index subsequently returned toward normal, but mean arterial pressure remained elevated (20-40 mm Hg), presumably because of an elevated total peripheral resistance. Cremasteric arterioles were actively constricted (35-50%) in rats with short-term (36 hours), but not chronic (5-6 weeks) reduced renal mass hypertension. Total microvessel density was approximately 15% lower in maximally dilated cremaster muscles of chronically hypertensive rats versus sham-operated controls, which suggests that arterioles are lost during sustained reduced renal mass hypertension. Arteriolar constriction in response to increased superfusate Po? (0% to 5% O*) was 2 -4 times greater in rats with both short-term and chronic reduced renal mass hypertension than in normotensive controls, which suggests that oxygen-dependent autoregulatory mechanisms are altered. The hemodynamic and microcirculatory alterations observed in these experiments suggest that classic short-term autoregulatory mechanisms and an enhanced response of arterioles to increased oxygen availability contribute to the elevated total peripheral resistance in short-term reduced renal mass hypertension, whereas structural changes and altered vascular oxygen responses contribute to an elevated microvascular resistance in chronic reduced renal mass hypertension. {Hypertension 1989;13:128-138)