Showing papers by "Suzanne Oparil published in 1996"

Estrogen reduces myointimal proliferation after balloon injury of rat carotid artery.

Abstract: Background Vascular disease progresses more slowly in females with functional ovaries than in males. The mechanisms of this vasoprotective effect of female sex are incompletely understood. This study tested (1) whether there is a sex difference in the development of myointimal proliferation after balloon injury of the rat carotid artery in vivo, (2) whether this response is estrogen or androgen dependent, and (3) whether there is a sexual dimorphism in expression of the c- myc proto-oncogene in intact and/or damaged rat carotid arteries. Methods and Results Ten-week-old male and female Sprague-Dawley rats were either gonadectomized or studied intact. Gonadectomized rats of both sexes were implanted with estradiol, testosterone, or nothing (control) 3 days before vascular injury. Two weeks later, the rats were killed by overdose of pentobarbital, and the injured right and uninjured control left carotid arteries were fixed and subjected to morphometric analysis for evaluation of the degree of myointimal thickening. Separate groups of intact male and female rats were killed at 1 and 2 hours after vascular injury, and total RNA from injured and uninjured vessels was subjected to Northern blot analysis for assessment of steady state c- myc mRNA levels. Neointimal area and the ratio of neointimal to medial area were significantly less in intact female rats than in intact male rats ( P <.05). Gonadectomy of female rats was associated with a greater increase in neointima formation after balloon injury than that observed in intact females ( P <.05), but testosterone replacement did not further enhance this response. Estradiol treatment significantly inhibited myointimal proliferation after vascular injury in gonadectomized rats of both sexes ( P <.05). Neither gonadectomy nor gonadectomy plus testosterone replacement altered the myointimal proliferative response to balloon injury in male rats. Steady state c- myc mRNA levels were detectable in undamaged carotid arteries in intact rats of both sexes and were significantly greater in males than in females; c- myc mRNA levels were increased in both sexes after carotid injury, but the response was significantly larger in magnitude and more rapid in males than in females. Conclusions These data indicate that the sex difference in myointimal proliferation after vascular injury is estrogen dependent. C- myc gene expression is greater in the undamaged carotid artery of the male than in that of the female, and the responsiveness of this gene to balloon injury of the artery is more rapid and more robust in the male than in the female rat. These findings have direct implications for the prevention and treatment of vascular disease in humans.

Medroxyprogesterone attenuates estrogen-mediated inhibition of neointima formation after balloon injury of the rat carotid artery.

Abstract: Background Estrogen blunts the neointimal proliferative response to balloon injury of the carotid artery in intact female rats and gonadectomized rats of both sexes. This study tested whether, in gonadectomized rats of both sexes, (1) progestin (medroxyprogesterone acetate, MPA) alters neointima formation in injured carotid arteries, (2) addition of MPA alters the antiproliferative effects of estrogen, and (3) an interaction between MPA and estrogen can be accounted for by MPA-induced alterations in serum 17β-estradiol levels. Methods and Results Male and female Sprague-Dawley rats were subjected to gonadectomy, then were randomly divided into four subgroups and treated with either (1) 17β-estradiol, (2) MPA, (3) 17β-estradiol+MPA, or (4) vehicle, and balloon injury of the right common carotid artery was carried out. Two weeks later, rats were killed by overdose of pentobarbital, and the carotid arteries were subjected to morphometric analysis for evaluation of myointimal thickening. Estradiol inhibited m...

Salt Intake and Plasma Atrial Natriuretic Peptide and Nitric Oxide in Hypertension

Abstract: In response to a high salt intake, salt-sensitive hypertensive individuals retain more sodium and manifest a rise in blood pressure greater than that in salt-resistant individuals. In this study, we tested whether salt sensitivity might be related at least in part to reduced secretion of atrial natriuretic peptide (ANP) or to abnormal nitric oxide production. We measured plasma ANP and NO2+NO3 in 7 normotensive individuals and 13 salt-sensitive and 14 salt-resistant blacks with essential hypertension under conditions of low (10 mEq/d) and high (250 mEq/d) salt intake. To evaluate possible racial differences in ANP secretion, we also measured plasma ANP in 6 salt-sensitive and 8 salt-resistant hypertensive whites during low and high salt intakes. Under low salt conditions, plasma ANP levels were not different in normotensive control subjects and salt-sensitive and salt-resistant hypertensive blacks. During high salt intake, plasma ANP levels did not change in control subjects and salt-resistant patients but decreased in salt-sensitive patients. ANP levels after high salt diet were lower (P < .01) in salt-sensitive than salt-resistant blacks. In hypertensive whites, high salt intake caused no significant change in plasma ANP. Under low salt conditions, plasma NO2+NO3 levels were higher (P < .05) in salt-sensitive (189 +/- 7.9 mumol/L) and salt-resistant (195 +/- 13.5 mumol/L) black patients than in control subjects (108 +/- 9.7 mumol/L). During high salt intake, plasma NO2+NO3 decreased significantly (P < .01) in both salt-sensitive (150 +/- 7.0 mumol/L) and salt-resistant (142 +/- 9.0 mumol/L) patients. These studies show that under conditions of high salt intake, salt-sensitive hypertensive blacks manifest a paradoxical decrease in ANP secretion. This abnormality may play a role in the reduced ability of these individuals to excrete a sodium load and in the sodium-induced rise in blood pressure. This study does not support the hypothesis that salt sensitivity depends on a deficit of nitric oxide production, but it suggests that high salt intake may alter the endothelium-dependent adaptation of peripheral resistance vessels.

Sex Hormones and the Vasculature

Abstract: Epidemiological studies have defined a sexually dimorphic pattern in the development of atherosclerotic vascular disease in humans (1). The incidence of cardiovascular disease is lower in premenopausal women than in age-matched men, but rises steadily after menopause (2). Postmenopausal women on estrogen replacement therapy have less severe coronary artery disease and a lower risk for cardiovascular mortality than women without hormone treatment (3). Thus, estrogens inhibit the development of atherosclerotic cardiovascular disease in women (4). The mechanism of this vasoprotective effect is complex and involves alterations in lipid metabolism, endothelial function, vascular smooth muscle cell (VSMC) proliferation and associated extracellular matrix formation, and vascular reactivity. Evidence that other sex hormones, including androgens and progestogens, can also alter these processes is emerging. This chapter reviews effects of sex hormones on the vasculature with emphasis on the processes that influence the progression of atherosclerosis and thus alter cardiovascular risk. Effects of postmenopausal hormone replacement on cardiovascular risk are reviewed.

Acute Saline Infusion Decreases Norepinephrine Release in the Anterior Hypothalamic Area

Abstract: Ingestion of a high NaCl diet elevates arterial pressure in spontaneously hypertensive rats, at least in part, by reducing the release of norepinephrine in the anterior hypothalamic area. The mechanism by which dietary NaCl excess alters anterior hypothalamic area norepinephrine release is unknown. Plasma Na + is slightly elevated after ingestion of a meal; therefore, in the present study we tested the hypothesis that a small increase in plasma Na + could reduce the release of norepinephrine in the anterior hypothalamic area and elevate arterial pressure. Male spontaneously hypertensive rats were randomized to be fed a diet containing either 1% (basal) or 8% (high) NaCl at age 7 weeks and were maintained on the diets for 2 weeks. Age-matched normotensive Wistar-Kyoto rats received a basal NaCl diet only. All rats were instrumented with a push/pull cannula, and 5 days later, the baseline release of 3-methoxy-4-hydroxyphenyl glycol (the major metabolite of norepinephrine in brain) was measured in awake, freely moving rats. Rats were then challenged with an intravenous infusion (75 μL/min) of hypertonic (2.7%) saline for 20 minutes. In spontaneously hypertensive rats fed a basal NaCl diet, the hypertonic saline infusion elevated mean arterial pressure by 12% and reduced the concentration of the norepinephrine metabolite in the anterior hypothalamic area by 19%; these alterations persisted after termination of the hypertonic saline infusion. Spontaneously hypertensive rats maintained on the high NaCl diet showed greatly reduced arterial pressure and norepinephrine metabolite responses. In normotensive control rats compared with the hypertensive rats fed the basal NaCl diet, the hypertonic saline had considerably less effects on arterial pressure and norepinephrine metabolite levels in the anterior hypothalamic area, and the responses were significantly shorter. Thus, a small elevation in plasma Na + can reduce the release of norepinephrine in the anterior hypothalamic area. This response is greatly exaggerated in spontaneously hypertensive rats fed a basal (but not a high) NaCl diet, suggesting that a postprandial rise in NaCl could initiate the fall in norepinephrine and thereby contribute to the rise in arterial pressure in spontaneously hypertensive rats ingesting a high NaCl diet.

Atrial Natriuretic Peptide Blunts Arterial Baroreflex in Spontaneously Hypertensive Rats

Abstract: We and other laboratories have reported that arterial baroreflex–mediated control of heart rate is blunted in spontaneously hypertensive rats (SHR) compared with normotensive controls. Recently, we reported that atrial natriuretic peptide (ANP) microinjected into the caudal nucleus tractus solitarii of SHR further blunts this defect. The present study tested the hypothesis that ANP modulates arterial baroreflex–mediated control of sympathetic nervous system activity. Nine-week-old, male SHR (n=29) and normotensive Wistar-Kyoto control rats (n=24) were instrumented for microinjection into the caudal nucleus tractus solitarii and for direct measurement of arterial blood pressure, heart rate, and lumbar sympathetic nervous system activity. After urethane- and α-chloralose–induced anesthesia, arterial baroreflex–mediated control of heart rate and lumbar sympathetic nerve activity was assessed during phenylephrine- (5 to 40 μg·kg−1·min−1) induced increases and sodium nitroprusside– (15 to 300 μg·kg−1·min−1) induced decreases in mean blood pressure before and after microinjection of ANP (50 ng) or monoclonal antibody to ANP (0.55 μg) into the caudal nucleus tractus solitarii. ANP reduced and the antibody enhanced the sensitivity of baroreflex-mediated control of both heart rate and lumbar sympathetic nerve activity in SHR but not in Wistar-Kyoto controls ( P <.05). Arterial baroreflex sensitivity was unchanged with control microinjections of vehicle or mouse IgG in SHR. These data suggest that endogenous ANP in the caudal nucleus tractus solitarii may contribute to the development and/or maintenance of hypertension in SHR by blunting baroreflex-mediated control of sympathetic nervous system activity.

Tissue Angiotensin Converting Enzyme

Abstract: Biochemical, immunohistochemical, and molecular biologic evidence indicates that all components of the renin-angiotensin system (renin, angiotensinogen, angiotensin converting enzyme (ACE), angiotensin peptides and angiotensin receptors) are found in a variety of tissues, including heart, kidney, brain and vasculature. The renin-angiotensin system plays an important role in the maintenance of blood pressure and volume homeostasis and of cardiovascular structure in normotensive subjects without obvious cardiovascular disease and in various disease states, including systemic hypertension and congestive heart failure (Oparil and Haber, 1974; Gibbons and Dzau, 1994). Renin (EN 3.4.23.15), a highly selective serine protease, cleaves its substrate, angiotensinogen, to produce the biologically inactive decapeptide, angiotensin I (ANG I) (Figure 1). The peptidyl dipeptide hydrolase angiotensin- converting enzyme (ACE; EN 3.4.15.1) removes the carboxyl terminal His-Leu from ANG I to produce the octapeptide angiotensin II (ANG II). In addition, ACE inactivates bradykinin, a vasodilator peptide/mediator of inflammation, as well as substance P, enkephalins and endorphins. ANG I and ANG II are both rapidly hydrolyzed to inactive products by a number of proteolytic enzymes, the angiotensinases (Regoli et al., 1975).

Cardiovascular Risk Reduction in Women

Abstract: Recent attention to the high prevalence of fatal and nonfatal cardiovascular disease in women has underscored the importance of lifestyle modification and cardiovascular risk factor reduction in this population. Recommendations for risk factor reduction in women are generally the same as in men, with one major and several minor exceptions. Postmenopausal hormone replacement therapy has a powerful effect on cardiovascular risk reduction but may be inappropriate for some women because of apparent enhanced breast cancer risk. The utility of aspirin therapy in the primary prevention of cardiovascular disease in women remains to be established. In contrast, aspirin is effective in the secondary prevention of cardiovascular disease in both sexes. Further, the benefits of, and prescription for, lipid-lowering therapy may prove to be different in women than in men, and the benefits of antihypertensive treatment may be less. For the other risk factors, including smoking, diabetes mellitus, obesity, sedent...