Search PubMed⌕ Search

Biomedical subjects

S Oparil

Publications and source records attributed to S Oparil.

At least 91 records · Page 5Linked to original sources
PubMed1998

Antihypertensive treatment in postmenopausal women: results from a prospective, randomized, double-blind, controlled study comparing an ACE inhibitor (moexipril) with a diuretic (hydrochlorothiazide).

The present study was designed to compare the safety and efficacy of the new angiotensin-converting enzyme inhibitor moexipril with that of hydrochlorothiazide (HCTZ) in postmenopausal women with mild-to-moderate hypertension. After a 4-week single-blind placebo period, 97 postmenopausal hypertensive women (42-74 years of age) with a sitting diastolic blood pressure (SDBP) of 95-114 mm Hg were randomized to receive either once daily moexipril 15 mg or HCTZ 25 mg for a 12-week double-blind treatment period. At study endpoint, HCTZ caused significantly greater increases from baseline in serum uric acid levels than did moexipril (0.8 +/- 0.1 vs. 0.1 +/- 0.1 mg/dl, p < 0.01). Furthermore, 12-week treatment with HCTZ resulted in significant increases in glucose (+11.0 +/- 4.1 mg/dl) and total cholesterol/HDL ratio (+0.3 +/- 0.1 mg/dl) and a significant decrease in HDL (-3.2 +/- 0.7 mg/dl). In contrast, moexipril treatment was not associated with significant changes in any metabolic parameter. Both drugs efficiently lowered SDBP with reductions of -10.0 +/- 1.3 and -11.8 +/- 1.1 mm Hg in the moexipril and HCTZ group, respectively. Clinical adverse events were reported by a greater percentage of HCTZ patients (53%) than moexipril patients (40%), with headache and rhinitis as the most frequent events. The results indicate that moexipril was better tolerated than HCTZ in postmenopausal women and did not adversely affect metabolic parameters. Both drugs were effective in lowering blood pressure.

Adult↗
PubMed1998

Characteristics of 9194 patients with left ventricular hypertrophy: the LIFE study. Losartan Intervention For Endpoint Reduction in Hypertension.

-Losartan was the first available orally administered selective antagonist of the angiotensin II type 1 receptor developed for the treatment of hypertension. The Losartan Intervention For Endpoint (LIFE) Reduction in Hypertension Study is a double-blind, prospective, parallel group study designed to compare the effects of losartan with those of the beta-blocker atenolol on the reduction of cardiovascular morbidity and mortality. Patients with essential hypertension, aged between 55 and 80 years, and ECG-documented left ventricular hypertrophy (LVH) were included. Altogether, 9223 patients in Scandinavia, the United Kingdom, and the United States were randomized from June 1995 through April 1997, and 9194 remain after exclusion of a study center at which irregularities were discovered. This population of hypertensives (mean systolic/diastolic blood pressure, 174.4/97.8 mm Hg) with LVH comprises women (54.1%) and men, mostly retired from active work (mean age, 66.9 years), with a high prevalence of overweight (mean body mass index, 28.0 kg/m2), diabetes mellitus (12.3%), lipid disorders (18.0%), and symptoms or signs of coronary heart disease (15.1%). There were fewer current smokers (<17%) than in the general population, and approximately 7% were nonwhite. Almost 30% of participants had been untreated for at least 6 months when screened for the study. Only 1557 persons who entered the placebo run-in period of 14 days were excluded, predominantly because of sitting blood pressures above or below the predetermined range of 160-200/95-115 mm Hg and ECG-LVH criteria not met. By application of simple 12-lead ECG criteria for LVH (Cornell voltage QRS duration product formula plus Sokolow-Lyon voltage read by a core laboratory), hypertensive patients with LVH with an average 5-year coronary heart disease risk of 22.3% according to the Framingham score were identified. This population is now being treated (goal, <140/90 mm Hg) in adherence with the protocol for at least 4 years after final enrollment (ie, through April 2001) and until at least 1040 patients suffer myocardial infarction, stroke, or cardiovascular death.

Aged↗
PubMed1997

Estrogen restores endothelial cell function in an experimental model of vascular injury.

BACKGROUND: It has been suggested that reendothelialization of damaged blood vessels protects against the vascular injury response. The goal of the present study was to determine whether estrogen restores endothelial cell function in balloon-injured rat carotid arteries. METHODS AND RESULTS: Ten-week-old male and female Sprague-Dawley rats with intact gonads underwent balloon injury to the right common carotid artery. Female rats were randomized to receive either daily subcutaneous injections of 17beta-estradiol (17betaE[2]; 20 microg x kg[-1] x d[-1]) or vehicle over the course of the study. Vessel morphology was assessed 2 weeks after injury. Significant neointima formation was observed in vehicle-treated males. This response was blunted in vehicle-treated and 17beta-E(2)-supplemented females. Intima-to-media ratios were 1.28+/-0.23 (males), 0.72+/-0.07 (vehicle-treated females), and 0.49+/-0.07 (17beta-E[2]supplemented females). To test whether reductions in neointimal lesion formation were related to the functional reendothelialization of the damaged vessel, endothelium-dependent relaxation was tested in isolated ring segments from the three experimental groups. Vessels were precontracted with phenylephrine followed by cumulative administration of acetylcholine, an endothelium-dependent vasodilator. Maximum relaxation to acetylcholine was 8.13+/-1.70% (males), 22.06+/-4.36% (vehicle-treated females), and 46.47+/-3.48% (17beta-E[2]-supplemented females). The enhanced endothelium-dependent relaxation of rings from 17betaE(2)-supplemented females correlated with reduced neointimal proliferation in this group. The concentration of nitric oxide metabolites in plasma correlated positively with plasma 17beta-E(2) concentration. CONCLUSIONS: These results suggest that estrogen protects against neointimal injury in the balloon-injured rat, at least in part, by facilitating the reendothelialization of the damaged vessel.

Acetylcholine↗
PubMed1997

Antihypertensive effects of mibefradil in the treatment of mild-to-moderate systemic hypertension.

This report summarizes the results of 4 double-blind, placebo-controlled studies designed to determine the efficacy, tolerability, and dose-response characteristics of the novel T-channel-selective calcium antagonist, mibefradil, in the treatment of mild-to-moderate essential hypertension. Two of these studies were conducted in the general population of essential hypertensives, 1 in elderly patients, and 1 in patients on chronic hydrochlorothiazide treatment. A total of 1,116 patients were randomized to receive 1 of 7 doses of mibefradil (6.25-200 mg; n = 927), or placebo (n = 189). Each study demonstrated a significant linear dose response in the reduction of sitting diastolic (SDBP) and sitting systolic (SSBP) blood pressure. In all 4 trials, SDBP was significantly reduced with the recommended doses of 50 and 100 mg mibefradil (placebo-corrected treatment effects of -4.1 to -6.8 mm Hg and -8.8 to -11.1 mm Hg, respectively, for the 50- and 100-mg doses). A similar reduction in SSBP occurred in 3 of 4 studies at the 50-mg dose (-7.5 to -10.7 mm Hg) and in 4 of 4 studies at the 100-mg dose (-6.8 to -16.7 mm Hg). Lower doses did not reduce blood pressure significantly; doses > 100 mg had little additional effect and an increased incidence of adverse events. Overall, response and normalization rates were dose related and averaged 61% and 51%, respectively, for the 50-mg dose and 78% and 65%, respectively, for the 100-mg dose. The onset of the antihypertensive effect was gradual, with no first-dose effect; near maximal response was reached within 1-2 weeks. Trough/peak ratios ranged from 77-86% with the 50-mg dose and from 77-108% with the 100-mg dose, indicating a sustained effect over a 24-hour period. A slight decrease in heart rate was observed, ranging from -2.2 to -5.5 beats/min at the 50-mg dose and from -4.0 to -8.8 beats/min at the 100-mg dose. The efficacy and safety results were similar across all populations studied, including the elderly and hydrochlorothiazide-treated patients, indicating that no dose adjustment is needed for these populations. Thus, the results of these 4 placebo-controlled trials confirm that when taken at the recommended doses of 50 and 100 mg once daily, mibefradil is an effective, safe, and well-tolerated therapy for the treatment of mild-to-moderate hypertension.

Adolescent↗
PubMed1997

Compartmentalization of angiotensin II generation in the dog heart. Evidence for independent mechanisms in intravascular and interstitial spaces.

Angiotensin-converting enzyme inhibitors have beneficial effects that are presumably mediated by decreased angiotensin II (ANG II) production. In this study, we measure for the first time ANG I and ANG II levels in the interstitial fluid (ISF) space of the heart. ISF and aortic plasma ANG I and II levels were obtained at baseline, during intravenous infusion of ANG I (5 microM, 0.1 ml/min, 60 min), and during ANG I + the angiotensin-converting enzyme inhibitor captopril (cap) (2.5 mM, 0.1 ml/min, 60 min) in six anesthetized open-chested dogs. ISF samples were obtained using microdialysis probes inserted into the left ventricular myocardium (3-4 probes/dog). ANG I increased mean arterial pressure from 102+/-3 (SEM) to 124+/-3 mmHg (P < 0.01); addition of cap decreased MAP to 95+/-3 mmHg (P < 0.01). ANG I infusion increased aortic plasma ANG I and ANG II (pg/ml) (ANG I = 101+/-129 to 370+/-158 pg/ml, P < 0.01; and ANG II = 22+/-40 to 466+/-49, P < 0.01); addition of cap further increased ANG I (1,790+/-158, P < 0.01) and decreased ANG II (33+/-49, P < 0.01). ISF ANG I and ANG II levels (pg/ml) were > 100-fold higher than plasma levels, and did not change from baseline (8,122+/-528 and 6,333+/-677), during ANG I (8,269+/-502 and 6, 139+/-695) or ANG I + cap (8,753+/-502 and 5,884+/-695). The finding of very high ANG I and ANG II levels in the ISF vs. intravascular space that are not affected by IV ANG I or cap suggests that ANG II production and/or degradation in the heart is compartmentalized and mediated by different enzymatic mechanisms in the interstitial and intravascular spaces.

Angiotensin I↗
PubMed1997

Sexually dimorphic response of the balloon-injured rat carotid artery to hormone treatment.

BACKGROUND: Estrogen blunts the neointimal response to vascular injury in gonadectomized rats of both sexes; addition of a progestin blocks the estrogen effect. This study tested, in intact rats of both sexes, whether (1) exogenous estrogen has a vasoprotective effect in injured carotid arteries, (2) progestin (medroxyprogesterone acetate, MPA) blocks the vasoprotective effect of estrogen, and (3) any observed sexual dimorphism in the responses to estrogen and/or MPA can be accounted for by differences in serum 17 beta-estradiol levels. METHODS AND RESULTS: Intact male and female Sprague-Dawley rats were randomly divided into four subgroups treated with either (1) 17 beta-estradiol, (2) MPA, (3) 17 beta-estradiol + MPA, or (4) vehicle and were subjected to balloon injury of the right common carotid artery. Two weeks later, rats were killed by an overdose of pentobarbital, and the carotid arteries were evaluated for myointimal thickening. Neither estradiol nor MPA altered the neointimal response in males. In females, estradiol reduced and MPA enhanced the response, whereas addition of MPA to estradiol blocked the vasoprotective effects of estrogen. CONCLUSIONS: Intact male rats but not intact females are resistant to the vasoprotective effects of exogenous estrogen, despite attainment of physiological (for females) serum 17 beta-estradiol levels. MPA enhances the neointimal response in intact females, presumably by blocking the production and thus the vasoprotective effect of endogenous estrogen.

Angioplasty, Balloon↗
PubMed1997

Nutritional management of cardiovascular risk factors. A randomized clinical trial.

BACKGROUND: Adherence to dietary recommendations for disease management is often hindered by the complexity of incorporating them into the daily diet. Nutrition and cardiovascular scientists and food technologists collaborated to develop a prepared meal plan that meets national dietary guidelines for cardiovascular risk reduction. OBJECTIVE: To assess the clinical effects of this plan, which incorporates all National Academy of Sciences National Research Council recommended dietary allowances for vitamins, minerals, and macronutrients, compared with a patient-selected American Heart Association Step I and Step II diet plan. METHODS: This multicenter, randomized, parallel-intervention trial was conducted at 10 medical centers in the United States and Canada and involved 560 men and women with hypertension, dyslipidemia, or diabetes. Following calculation of prescriptions to meet individual nutritional requirements based on the Harris-Benedict equation, participants were randomized to the Campbell's Center for Nutrition and Wellness (CCNW) plan, which is composed of prepackaged breakfast, lunch, and dinner meals provided to participants, or a nutritionist-guided American Heart Association Step I and Step II diet, in which participants self-selected foods to meet their nutrition prescription for 10 weeks. MAIN OUTCOME MEASURES: Blood pressure (BP); lipid, glucose, glycosylated hemoglobin (HbA1c), and insulin levels; body weight; dietary intake; and quality of life. RESULTS: Patients' BP, lipid levels, carbohydrate metabolism, weight, and quality of life (P < or = .001 for all findings except low-density lipoprotein-high-density lipoprotein ratio, P = .25) all improved on both nutrition plans. Mean differences (+/-SD) between baseline and treatment clinical values for the CCNW and the self-selected diet groups (between-group P values), respectively, were as follows: systolic BP, -6.4 +/- 9.2 mm Hg and -4.6 +/- 9.0 mm Hg (P = .02); diastolic BP, -4.2 +/- 5.7 mm Hg and -3.0 +/- 5.1 mm Hg (P = .006); cholesterol, -0.32 +/- 0.58 mmol/L and -0.27 +/- 0.56 mmol/L (-12.4 +/- 22.5 mg/dL and -10.4 +/- 21.9 mg/dL) (P = .30); glucose, -0.65 +/- 1.88 mmol/L and -0.75 +/- 2.03 mmol/L (-11.7 +/- 34.0 mg/dL and -13.5 +/- 36.6 mg/dL) (P = .10); and HbA1c, -0.4% +/- 0.8% and -0.3% +/- 0.7% (P = .66). Weight loss with the CCNW and self-selected plans, respectively, was as follows: men, -4.5 +/- 3.6 kg and -3.5 +/- 3.3 kg; and women, -4.8 +/- 3.0 kg and -2.8 +/- 2.8 kg. Quality of life was significantly improved for daily and work activities (P < .05) and nutritional health perceptions (P < .05) with the CCNW plan relative to the self-selected group. Overall nutrient intake and compliance were both significantly (P < .001) better with the CCNW plan. CONCLUSIONS: Nutritionally balanced meals that meet the recommendations of national health organizations improved multiple risk factors for patients with cardiovascular disease. The CCNW plan resulted in greater clinical benefits, nutritional completeness, and compliance than the self-selected diet. The CCNW is a comprehensive nutrition plan, convenient for both prescription and practice, and appears viable for effecting favorable dietary changes in patients at high risk for cardiovascular disease.

Adult↗
PubMed1997

Blood pressure and metabolic responses to moderate sodium restriction in isradipine-treated hypertensive patients.

This multicenter, randomized, controlled clinical trial assessed the influence of sodium chloride intake on the antihypertensive effect of the calcium channel blocker isradipine. Participants with uncomplicated hypertension controlled by isradipine entered a 4-week sodium-restricted (60 to 80 mmol/24 h) period. Participants with urinary sodium levels < 120 mmol/24 h (n = 99) were randomized to placebo or sodium chloride (100 mmol/24 h) for 4 weeks, and then crossed over to the alternative treatment for an additional 4 weeks. Mean baseline systolic blood pressure was 151.9 +/- 16.7 mm Hg (mean +/- SD). During open-label isradipine treatment, systolic blood pressures for ad libitum sodium chloride and restriction were 134.1 +/- 11.1 and 132.1 +/- 12.2 mm Hg respectively; for double-blind sodium chloride restriction and supplementation: 133.6 +/- 12.6 and 138.5 +/- 12.8 mm Hg (P < .01). Urinary sodium excretion values for open-label isradipine ad libitum versus restricted were 140.6 +/- 61.9 versus 76.9 +/- 32.4 mmol/24 h; for double-blind restricted versus supplemented, sodium excretion was 120.5 +/- 68.9 v 175.9 +/- 68.7 mmol/24 h (P < or = .0001). Changes in urinary sodium excretion were not predictive of variations in blood pressure. Urinary sodium excretion during sodium restriction correlated directly with HDL-cholesterol (P < .02) and inversely with total cholesterol:HDL-cholesterol (P = .02), despite decreased total and saturated fat intake (P < .01). Sodium restriction was associated with significant reductions (P < .01) in virtually all macronutrients and electrolytes, and thus had an adverse impact on overall nutrition. The antihypertensive action of isradipine was not enhanced by dietary sodium chloride restriction, and the lipoprotein profile was least favorable with sodium chloride restriction.

Adult↗
PubMed1997

Dose-response characteristics of mibefradil, a novel calcium antagonist, in the treatment of essential hypertension.

The aim of this study was to determine the dose-response characteristics of the calcium antagonist, mibefradil, and to evaluate its antihypertensive efficacy and safety in varying doses in patients with mild-to-moderate hypertension. Three hundred and three eligible patients were randomized to receive once-daily 6.25-, 12.5-, 25-, 50-, 100-, 150-, or 200-mg mibefradil doses or placebo for 4 weeks. Repeated blood pressure measurements and electrocardiographic recordings were obtained for the 24 h following the last dose of the placebo run-in period and for the first and last doses of randomized treatment. A statistically significant (P < .001 versus placebo) and clinically relevant drop in sitting diastolic blood pressure (SDBP) both at trough and at peak was observed in the 50-, 100-, 150-, and 200-mg mibefradil dose groups (trough placebo-corrected reductions: -4.9, -9.1, -9.9, and -11.9 mm Hg, respectively), with a significant dose-response relationship (P < .001) and high response rates. Trough/peak ratios for the placebo-corrected change from baseline to week 4 in SDBP were >85% for the 50- and 100-mg doses and 68% and 69% for the 150- and 200-mg doses, respectively. The full antihypertensive effect of mibefradil was achieved within 1 week of treatment. Reductions in sitting systolic blood pressure (SSBP) closely paralleled those in SDBP. The antihypertensive effect of mibefradil was associated with a slight dose-dependent decrease in heart rate and increase in the pulse rate (PR) electrocardiographic interval [corrected]. The appropriate therapeutic dose range of mibefradil in the management of mild-to-moderate essential hypertension is 50 to 100 mg.

Adolescent↗
PubMed1997

Dietary compliance and cardiovascular risk reduction with a prepared meal plan compared with a self-selected diet.

Noncompliance with therapeutic diets remains a major obstacle to achieving improvements in cardiovascular disease (CVD) morbidity and mortality. This study compared dietary compliance and CVD risk factor response to two dietary interventions designed to treat hypertension, dyslipidemia, and diabetes mellitus. In a multicenter trial, 560 adults were randomly assigned to either a self-selected, mixed-food plan (n = 277), or a nutrient-fortified prepared meal plan (n = 283); each was designed to provide 15-20% of energy from fat, 55-60% from carbohydrate, and 15-20% from protein. Nutrient intake was estimated from 3-d food records collected biweekly throughout the 10-wk intervention. Compliance was determined by evaluating the participants' ability to meet specific criteria for energy intake [+/-420 kJ (100 kcal) from the midpoint of the prescribed energy range], fat intake (< 20%, < 25%, or < 30% of energy from total fat), and the National Cholesterol Education Program/American Heart Association Step 1 and 2 diet recommendations. Compliance with energy, fat, and Step 1 and 2 criteria was better in participants who followed the prepared meal plan than in those who followed the self-selected diet (P < 0.0001). Compliant participants in both groups achieved greater reductions in body weight, systolic and diastolic blood pressure, and total and low-density-lipoprotein cholesterol than noncompliant participants (P < 0.05). In general, better endpoint responses were observed with lower fat intakes regardless of group assignment. The prepared meal plan is a simple and effective strategy for meeting the many nutrient recommendations for CVD risk reduction and improving dietary compliance and CVD endpoints.

Adult↗
PubMed1997

The orally active nonpeptide endothelin A-receptor antagonist A-127722 prevents and reverses hypoxia-induced pulmonary hypertension and pulmonary vascular remodeling in Sprague-Dawley rats.

Exposure to hypoxia is associated with increased pulmonary artery pressure and plasma endothelin (ET-1) levels and with selective enhancement of ET-1 peptide and messenger RNA (mRNA) and endothelin-A (ET-A) receptor mRNA in rat lung. Our study tested the hypothesis that A-127722, an orally active antagonist of the ET-A receptor, can prevent hypoxia-induced pulmonary hypertension and vascular remodeling in the rat. Pretreatment with A-127722 (3, 10, and 30 mg/kg/day in drinking water for 2 days) caused dose-dependent inhibition of the pulmonary vasoconstrictor response to short-term hypoxia (10% O2, 90 min). Long-term A-127722 treatment (10 mg/kg/day in drinking water for 2 weeks) instituted 48 h before hypoxic exposure attenuated the subsequent development of pulmonary hypertension, the associated right atrial hypertrophy, and pulmonary vascular remodeling. Institution of A-127722 treatment (10 mg/kg/day in drinking water for 4 weeks) after 2 weeks of hypoxia retarded the progression of established hypoxia-induced pulmonary hypertension and right atrial hypertrophy and reversed the pulmonary vascular remodeling despite continuing hypoxic exposure. These findings support the hypothesis that endogenous ET-1 plays a major role in hypoxic pulmonary vasoconstriction/hypertension, right heart hypertrophy, and pulmonary vascular remodeling and suggest that ET-A receptor blockers may be useful in the treatment and prevention of hypoxic pulmonary hypertension in humans.

Animals↗
PubMed1997

Volume-overload cardiac hypertrophy is unaffected by ACE inhibitor treatment in dogs.

We tested the hypothesis that angiotensin-converting enzyme (ACE) inhibitor therapy prevents volume-overload hypertrophy in dogs with chronic mitral regurgitation (MR). Seven adult mongrel dogs receiving ramipril (R; 10 mg orally, twice/day) for 4 mo were compared with 11 dogs receiving no R (N) for 4 mo after induction of MR. Cine-magnetic resonance imaging demonstrated that left ventricular (LV) mass increased in the R-MR dogs [80 +/- 4 (SE) to 108 +/- 7 g, P < 0.01] and in the N-MR dogs (92 +/- 7 to 112 +/- 8 g, P < 0.001). LV myocyte cell length was greater in the R-MR and N-MR dogs (203 +/- 6 and 177 +/- 10 microns, respectively) than in normal (144 +/- 4 microns, P < 0.05) dogs. There was significant loss of the collagen weave pattern by scanning electron microscopy in both R-MR and N-MR dogs. LV ACE and chymase activities were significantly elevated in R-MR and N-MR compared with normal dogs. LV angiotensin II (ANG II) levels in the R-MR dogs (28 +/- 12 pg/g) were reduced to levels seen in normal dogs (28 +/- 4 pg/g) compared with N-MR dogs (72 +/- 11 pg/g, P < 0.05). Steady-state AT1-receptor mRNA levels decreased 66% in N-MR compared with normal dogs (P < 0.001) and increased 1.5-fold in R-MR compared with normal dogs (P < 0.01). Thus upregulation of the AT1 receptor in the R-MR hearts may provide a mechanism by which normal intracardiac ANG II levels could continue to mediate LV hypertrophy. However, the mechanism of dissolution collagen weave in both N-MR and R-MR hearts may be related to the stretch of volume overload.

Angiotensin II↗
PubMed1997

Angiotensin II formation from ACE and chymase in human and animal hearts: methods and species considerations.

The current study examined the contributions of angiotensin-converting enzyme (ACE) vs. chymase to angiotensin II (ANG II) generation in membrane preparations from left ventricles of humans, dogs, rabbits, and rats and from total heart of mice. ACE and chymase activity were measured in membrane preparations extracted with low or high detergent (LD and HD, respectively) concentrations. We hypothesized that ACE, which is membrane bound in vivo, would be preferentially localized to the HD preparation, whereas chymase, which is localized to the cytoplasm and cardiac interstitium, would be localized to the LD preparation. In human heart, ACE activity was 16-fold higher in the HD than in the LD preparation, whereas chymase activity was 15-fold higher in the LD than in the HD preparation. Total ANG II formation was greater in human heart [15.8 +/- 3.4 (SE) micromol ANG II x g(-1) x min(-1)] than in dog, rat, rabbit, and mouse hearts (3.90 +/- 0.35, 0.41 +/- 0.02, 0.61 +/- 0.07, and 1.16 +/- 0.08 micromol ANG II x g(-1) x min(-1), respectively, P < 0.05, by analysis of variance). ANG II formation from ACE was higher in mouse heart (1.09 +/- 0.05 micromol ANG II x g(-1) x min(-1), p < 0.001) than in rabbit, human, dog, and rat hearts (0.55 +/- 0.06, 0.34 +/- 0.01, 0.32 +/- 0.06, and 0.31 +/- 0.02 micromol ANG II x g(-1) x min(-1), respectively). In contrast, chymase activity was higher in human heart (15.3 +/- 3.4 micromol ANG II x g(-1) x min(-1)) than in dog, rat, rabbit, and mouse hearts (3.59 +/- 0.29, 0.10 +/- 0.01, 0.06 +/- 0.01, and 0.07 +/- 0.01 micromol ANG II x g(-1) x min(-1), respectively). Our results demonstrate important species differences in the pathways of intracardiac ANG II generation. Chymase predominated over ACE activity in human heart, accounting for extremely high total ANG II formation in human heart compared with dog, rat, rabbit, and mouse hearts.

Angiotensin II↗
PubMed1997

Hypoxia stimulates human preproendothelin-1 promoter activity in transgenic mice.

Significant elevations in endothelin (ET)-1 levels accompany many diseases, but the underlying regulatory mechanisms are unclear. To investigate the in vivo regulation of human preproendothelin-1 (PPET-1), we examined the activity of the PPET-1 promoter in transgenic mice exposed to hypoxia. Mice expressing one of three PPET-1 promoter-luciferase (PPET-1/LUC) reporter transgenes (approximately 2.5 kb, 138 bp, or none of the 5'-flanking sequences of the PPET-1 gene) were generated. LUC expression was reduced in mice with a truncated 138-bp PPET-1 promoter. Exposure of mice bearing the 2.5-kb PPET-1/LUC transgene to hypoxia (10% O2 for 24 h) increased LUC expression sixfold in pulmonary tissue but only twofold in other tissues. In situ hybridization revealed the strongest transgene expression in the pulmonary vasculature and bronchiolar epithelium. These data are consistent with the hypothesis that hypoxic induction of the PPET-1 gene leads to increased pulmonary production of ET-1 in diseases associated with low O2 tension.

Animals↗
PubMed1997

Blood pressures and cardiovascular homeostasis in mice having reduced or absent angiotensin-converting enzyme gene function.

We studied cardiovascular phenotypes in wild-type (+/+), heterozygous (+/-), and homozygous mutant (-/-) mice for an insertional inactivation of the angiotensin-converting enzyme (ACE) gene (Ace in mice, ACE in humans). Compared with +/+ mice, baseline mean arterial pressure was not significantly altered in +/- mice but was reduced by 51+/-4 mm Hg in -/- mice. Although the pressor response to injected angiotensin II did not differ significantly in the three genotypic groups, the pressor response to angiotensin I was strongly affected by Ace genotype: Compared with the response in the +/+ group (+26% of baseline), the response to Ang I was close to half normal (+12%) in the +/- group and virtually abolished (+1%) in the -/- group. The depressor response to injected bradykinin was significantly enhanced in the +/- and -/- groups compared with the +/+ group. Ace expression and ACE activity were directly related to functional Ace copy number, and renin and angiotensinogen mRNA levels were inversely related to Ace copy number. Angiotensin type 1A receptor mRNA levels were not significantly different in the +/+, +/-, and -/- groups. We conclude that (1) ACE is essential for the maintenance of normal blood pressure; (2) subnormal levels of ACE affect the blood pressure responses to infused angiotensin I and bradykinin in vivo; and (3) compensations for inactivation of one Ace copy, which include increased expression of renin, normalize blood pressure in heterozygotes.

Analysis of Variance↗