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Biomedical subjects

S Oparil

Publications and source records attributed to S Oparil.

At least 55 records · Page 3Linked to original sources
PubMed1999

Candesartan cilexetil in combination with low-dose hydrochlorothiazide is effective in severe hypertension.

This randomized, double-blind, placebo-controlled multicenter study was designed to evaluate the efficacy, tolerability, and safety of candesartan cilexetil in a diverse population of patients with severe systemic hypertension (diastolic blood pressure > or =110 mm Hg). After a placebo run-in period, patients were given hydrochlorothiazide (HCTZ) 12.5 mg once daily for 1 week. A total of 217 patients with sitting diastolic blood pressure >95 mm Hg while receiving HCTZ were then randomized in a 2:1 ratio to receive candesartan cilexetil or placebo once daily for 4 weeks. Candesartan cilexetil was started at 8 mg and titrated to 16 mg if needed for blood pressure control; background HCTZ was continued in both groups. Candesartan cilexetil was significantly more effective than placebo in lowering trough diastolic and systolic blood pressure. The mean change in trough sitting diastolic blood pressure from the end of the HCTZ run-in period to the week 4 endpoint (primary study endpoint) was -9.1 mm Hg with candesartan cilexetil and -3.1 mm Hg with placebo (p = 0.0001). A higher percentage of patients treated with candesartan cilexetil than placebo responded to treatment (53% vs 29%) and achieved diastolic blood pressure <90 mm Hg (32% vs 15%). Subgroup analyses indicated that candesartan cilexetil was especially effective in patients with higher trough diastolic blood pressure at randomization, and it was significantly more effective than placebo in both black and nonblack patients alike as well as in women and men. Candesartan cilexetil was safe and well tolerated, with an adverse-event profile comparable to placebo. These results demonstrate that candesartan cilexetil added to background HCTZ therapy is effective and well tolerated in lowering blood pressure in patients with severe systemic hypertension.

Aged↗
PubMed1999

Estrogen inhibits vascular smooth muscle cell-dependent adventitial fibroblast migration in vitro.

BACKGROUND: Mounting experimental evidence suggests that estrogen treatment protects against neointima formation in response to vascular injury in vivo. Previous studies have suggested that this process includes the activation and migration of adventitial fibroblasts. The present in vitro study was designed to establish a mechanism whereby estrogen attenuates migration of adventitial fibroblasts. METHDS AND RESULTS: Primary cultures of vascular smooth muscle cells (VSMCs) and adventitial fibroblasts were derived from female Sprague-Dawley rats. Reverse transcriptase-polymerase chain reaction and Western blotting were used to determine that expression of the estrogen receptor (ER) was restricted to early-passage VSMCs. Migration of transduced (retrovirally mediated) fibroblasts was determined by counting the number of blue lacZ-expressing cells attached to Boyden-type chambers preconditioned under defined experimental conditions. Compared with growth medium alone, chambers treated with medium conditioned by VSMCs demonstrated a 2-fold increase in fibroblast migration, suggesting that VSMCs release soluble factor(s) competent to bind the Transwell membrane and promote fibroblast migration. In contrast, treatment of VSMCs with 17beta-estradiol (10(-9) to 10(-7) mol/L) before preconditioning of the chamber induced a dose-dependent inhibition of fibroblast migration. Cotreatment of VSMCs with 17beta-estradiol and the ER antagonist ICI-182780 (10(-7) mol/L) blocked the inhibitory effect of estrogen on fibroblast migration. CONCLUSIONS: These observations suggest a novel mechanism of hormonal vasoprotection by which estrogen directly modulates VSMC expression of factor(s) controlling migration of adventitial fibroblasts via an ER-dependent mechanism.

Animals↗
PubMed1999

Effects of candesartan cilexetil in patients with severe systemic hypertension. Candesartan Cilexetil Study Investigators.

The efficacy, tolerability, and safety of the potent angiotensin II receptor blocker candesartan cilexetil were evaluated in 217 adult patients (68% men, 41% black) with severe systemic hypertension on background therapy with hydrochlorothiazide (HCTZ) in a 4-week, multicenter, randomized, double-blind, placebo-controlled study. Patients with sitting diastolic blood pressure (BP) > or =110 mm Hg during the placebo run-in received HCTZ 12.5 mg once daily for 1 week. Those with sitting diastolic BP >95 mm Hg after the HCTZ run-in were randomized (2:1) to receive candesartan cilexetil 8 mg once daily (n = 141) or placebo (n = 76), plus HCTZ 12.5 mg. After 1 week of double-blind treatment, patients with sitting diastolic BP > or =90 mm Hg were uptitrated to candesartan cilexetil 16 mg once daily or matching placebo, plus HCTZ 12.5 mg; 84% required uptitration. Primary efficacy measurement was a change in trough (24+/-3 hours after treatment) sitting diastolic BP from the end of the HCTZ run-in to double-blind week 4. Mean changes in systolic and diastolic BP were significantly greater with candesartan cilexetil than with placebo, -11.3/-9.1 mm Hg versus -4.1/-3.1 mm Hg, p <0.001/p <0.001, respectively. Patients with higher sitting diastolic BP at the end of the HCTZ run-in tended to have greater decreases in BP (p <0.05). Most patients (53%) receiving candesartan cilexetil were responders (diastolic BP <90 mm Hg or > or =10 mm Hg decrease) and 32% were controlled (diastolic BP <90 mm Hg). Tolerability and safety profiles were similar in the candesartan and placebo groups. In conclusion, candesartan cilexetil 8 to 16 mg once daily was an effective and well-tolerated therapy for lowering BP when added to HCTZ 12.5 mg in a diverse population of patients with severe systemic hypertension in the United States.

Adult↗
PubMed1999

Evidence for angiotensin-converting enzyme- and chymase-mediated angiotensin II formation in the interstitial fluid space of the dog heart in vivo.

BACKGROUND: We have previously demonstrated that angiotensin II (Ang II) levels in the interstitial fluid (ISF) space of the heart are higher than in the blood plasma and do not change after systemic infusion of Ang I. In this study, we assess the enzymatic mechanisms (chymase versus ACE) by which Ang II is generated in the ISF space of the dog heart in vivo. METHODS AND RESULTS: Cardiac microdialysis probes were implanted in the left ventricular (LV) myocardium (3 to 4 probes per dog) of 12 anesthetized open-chest normal dogs. ISF Ang I and II levels were measured at baseline and during ISF infusion of Ang I (15 micromol/L, n=12), Ang I+the ACE inhibitor captopril (cap) (2.5 mmol/L, n=4), Ang I+the chymase inhibitor chymostatin (chy) (1 mmol/L, n=4), and Ang I+cap+chy (n=4). ISF infusion of Ang I increased ISF Ang II levels 100-fold (P<0.01), whereas aortic and coronary sinus plasma Ang I and II levels were unaffected and were 100-fold lower than ISF levels. Compared with ISF infusion of Ang I alone, Ang I+cap (n=4) produced a greater reduction in ISF Ang II levels than did Ang I+chy (n=4) (71% versus 43%, P<0.01), whereas Ang I+cap+chy produced a 100% decrease in ISF Ang II levels. CONCLUSIONS: This study demonstrates for the first time a very high capacity for conversion of Ang I to Ang II mediated by both ACE and chymase in the ISF space of the dog heart in vivo.

Angiotensin II↗
PubMed1999

Differential expression of angiotensin-converting enzyme and chymase in dogs with chronic mitral regurgitation.

The current study tested the hypothesis that angiotensin-converting enzyme (ACE) and chymase expression are subject to different regulatory processes in the heart, as well as the lungs and kidneys and, as a result, have an important effect on the efficacy of ACE inhibitor treatment in modulating tissue angiotensin II (ANG II) levels in heart failure. A total of 18 dogs underwent the induction of mitral regurgitation and were followed for 5 months. Eleven dogs were untreated and seven received the ACE-inhibitor ramipril at a dose of 10 mg PO BID. Seventeen dogs underwent a sham-operation: six of these dogs were treated with ramipril for 3 months (10 mg PO BID) and 11 were untreated and followed for 3 months prior to sacrifice. In mitral regurgitation dogs, ANG II levels were increased >2-fold in left ventricle, lungs, and kidney, but were normalized with ACE inhibitor-treatment only in the left ventricle. In the left ventricle and lungs steady state ACE mRNA levels and ACE activities were increased 2-fold in treated and untreated mitral regurgitation dogs compared to shams (P<0.05, ANOVA). In contrast, chymase mRNA levels were decreased by >50% and chymase activity was increased in left ventricle (LV) of mitral regurgitation dogs (P<0.05). Neither chymase mRNA nor chymase activity could be detected in the kidney; however, kidney ACE mRNA and ACE activity were significantly upregulated in treated and untreated mitral regurgitation dogs (P<0. 05). These results suggest that ACE and chymase expression are regulated differentially in the dog in response to chronic mitral regurgitation and ACE inhibitor treatment. Further, these responses, as well as regulation of ANG II formation, are organ specific.

Animals↗
PubMed1999

2-Tetradecylglycidic acid, an inhibitor of carnitine palmitoyltransferase-1, induces myocardial hypertrophy via the AT1 receptor.

Activation of the antiogensin II, type 1 (AT1) receptor mediates the myocardial response to numerous hypertrophic stimuli. This study tested the hypothesis that 2-tetradecylglycidic acid (TDGA), an oxirane carboxylate inhibitor of mitochondrial carnitine plamitoyltransferase-1, induces myocardial hypertrophy via the AT1 receptor system. Male Sprague-Dawley rats treated with 10 mg TDGA/kg/day for 7 days had a heart wet weight:body weight ratio of 3. 58+/-0.16 mg/g compared with a ratio of 2.79+/-0.07 for rats treated with vehicle (P<0.05). The plasma level of antiogensin II was 117. 75+/-17.39 pg/ml in rats treated with 10 mg TDGA/kg/day compared with 54.0+/-11.38 pg/ml for rats treated with vehicle (P<0.05). The plasma level of angiotensin I in these two groups of rats was not different statistically. Rats treated with TDGA and given drinking water containing 1 mg losartan/ml had a heart wet weight:body weight ratio of 2.84+/-0.05 mg/g. This value was not statistically different from the value measured in rats given drinking water containing 1 mg losartan/ml and treated with vehicle alone. No significant difference in the heart wet weight:dry weight ratio occurred among these groups of rats. Finally, treating rats with TDGA or giving rats drinking water that contained 1 mg losartan/ml altered neither their heart rate nor their mean arterial blood pressure when compared with untreated rats. This data, therefore, suggests that oxirane carboxylates induce myocardial hypertrophy by activating the AT1 receptor independent of changes in systemic hemodynamics.

Animals↗
PubMed1999

Differential expression of natriuretic peptides and their receptors in volume overload cardiac hypertrophy in the rat.

Atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) upregulation are genetic markers for the chronic hypertrophic phenotype but also have important acute physiologic effects on salt and water balance and blood pressure control. The presence of a dual NP-system led us to hypothesize a differential expression of ANP and BNP in response to an acute hemodynamic stress of volume overload in the left ventricle (LV) and right ventricle (RV). Accordingly, we examined the temporal relationship between the RV and LV expression of ANP and BNP mRNA and NP receptor mRNA levels on days 1, 2, 3, and 7 after induction of aortocaval fistula in the rat. LV end-diastolic pressure was increased 1.5-fold by day 3 and 2.0-fold by day 7 compared to control (P<0.05). LV weight increased by day 7 compared to control (2.34+/-0.04 vs 3.07+/-0.10 mg/g, P<0.05) while RV weight did not change over the 7 days. There was a 7-fold increase of ANP mRNA in LV at day 1, which was sustained through day 7, while LV BNP mRNA levels did not differ from controls over the 7 days. In contrast, RV mRNA transcript levels for ANP and BNP were increased >2-fold by day 2 and this increase was sustained throughout 7 days. NP clearance receptor was decreased by 75% by day 7 in the LV but did not change in the RV. Thus, LV ANP mRNA levels increased before the onset of LV hypertrophy and RV BNP mRNA levels increased in the absence of RV hypertrophy. The disparate response of BNP and the NP clearance receptor transcript levels in the LV and RV may be related to differences in load and/or differential expression of the NP system in the LV and RV in response to acute haemodynamic stress.

Animals↗
PubMed1999

Nutritionally complete prepared meal plan to reduce cardiovascular risk factors: a randomized clinical trial.

OBJECTIVE: To compare a nutritionally complete prepared meal plan that meets national dietary guidelines to usual-care dietary therapy for hypertension, dyslipidemia, and glycemic control. DESIGN: Randomized, controlled trial. SUBJECTS/SETTING: Outpatients with hypertension, dyslipidemia, or diabetes mellitus (n = 251) were recruited at 6 medical centers in the United States and Canada. INTERVENTION: The prepared meal plan, which was developed by university-based nutrition and cardiovascular scientists and food technologists at Campbell's Center for Nutrition & Wellness (CCNW), provided the optimal levels of macronutrients and micronutrients recommended for cardiovascular risk reduction in a variety of prepackaged meals and snacks. After a 4-week pretrial period to assess baseline state, participants were randomized to the CCNW plan or "usual-care" diet for 10 weeks. MAIN OUTCOME MEASURES: Blood pressure, carbohydrate metabolism, lipoproteins, homocysteine, weight, nutrient intake, compliance. STATISTICAL ANALYSES PERFORMED: Repeated measures analysis of variance. RESULTS: Lipoproteins, carbohydrate metabolism, blood pressure, and weight improved on both plans. Mean differences (+/- standard deviation) between baseline and follow-up for the CCNW plan and the usual-care plan, respectively, were total cholesterol, -0.41 +/- 0.64 and -0.20 +/- 0.50 mmol/L (between-group P < .01); plasma glucose, -0.7 +/- 1.7 and -0.3 +/- 1.3 mmol/L (P < .05); systolic blood pressure, -5.2 +/- 10.0 and -4.7 +/- 9.0 mm Hg (P = .67), diastolic blood pressure, -3.8 +/- 5.9 and -2.2 +/- 5.5 mm Hg (P < .05); and homocysteine, -1.3 +/- 3.8 and 0.2 +/- 3.4 mumol/L (P < .01). The CCNW plan led to greater weight loss than the usual-care diet (-5.5 +/- 3.8 kg vs -3.0 +/- 3.2 kg, P < .0001). APPLICATIONS/CONCLUSION: The nutritionally complete CCNW plan offers greater improvements in lipids, blood sugars, homocysteine, and weight loss than usual-care diet therapy. This prepackaged comprehensive nutrition program can augment both the prescription and practice of optimal dietary therapy.

Adult↗
PubMed1999

Dietary changes favorably affect bone remodeling in older adults.

OBJECTIVE: To determine whether dietary counseling to increase milk intake could produce useful changes in the calcium economy and what, if any, other nutrition-related changes might be produced. DESIGN: Randomized, open trial. SUBJECTS/SETTING: Two hundred four healthy men and women, aged 55 to 85 years, who habitually consumed fewer than 1.5 servings of dairy foods per day. Six academic health centers in the United States. INTERVENTION: Subjects were instructed to consume 3 servings per day of nonfat milk or 1% milk as a part of their daily diets, or to maintain their usual diets, for a 12-week intervention period, which followed 4 weeks of baseline observations. MAIN OUTCOME MEASURES: Energy and nutrient intake assessed from milk intake logs and 3-day food records; serum calciotrophic hormone levels at baseline and at 8 and 12 weeks; urinary excretion of calcium and N-telopeptide at 12 weeks. STATISTICAL ANALYSES: Repeated-measures analysis of variance. RESULTS: In the milk-supplemented group, calcium intake increased by 729 +/- 45 mg/day (mean +/- standard error), serum parathyroid hormone level decreased by approximately 9%, and urinary excretion of N-telopeptide, a bone resorption marker, decreased by 13%. Urine calcium excretion increased in milk-supplemented subjects by 21 +/- 7.6 mg/day (mean +/- standard error), less than half the amount predicted to be absorbed from the increment in calcium intake. All of these changes were significantly different from baseline values in the milk group and from the corresponding changes in the control group. Bone-specific alkaline phosphatase level (a bone formation marker) fell by approximately 9% in both groups. Serum level of insulin-like growth factor-1 (IGF-1) rose by 10% in the milk group (P < .001), and the level of insulin-like growth factor binding protein-4 (IGFBP-4) fell slightly (1.9%) in the milk group and rose significantly (7.9%) in the control group (P < .05). APPLICATIONS/CONCLUSIONS: The changes observed in the calcium economy through consumption of food sources of calcium are similar in kind and extent to those reported previously for calcium supplement tablets. The increase in IGF-1 level and the decrease in IBFBP-4 level are new observations that are beneficial for bone health. Important improvements in skeletal metabolism can feasibly occur in older adults by consumption of food sources of calcium. Dietitians can be confident that food works, and that desired calcium intakes can be achieved using food sources.

Aged↗
PubMed1999

Estrogen attenuates the adventitial contribution to neointima formation in injured rat carotid arteries.

OBJECTIVE: This study tested, in ovariectomized rats, whether (1) adventitial activation plays a role in the vascular injury response, and (2) inhibition of adventitial activation and the subsequent wave of cell proliferation moving from adventitia to neointima contributes to the estrogen-induced attenuation of neointima formation in balloon injured carotid arteries. METHODS: Ovariectomized Sprague-Dawley rats were treated with either 17 beta-estradiol or vehicle beginning 72 h prior to balloon injury of the right common carotid artery and were sacrificed at 0, 3, 7, 14 and 28 days after injury. BrdU was administered 18 h and 12 h prior to sacrifice in order to quantitate mitotic activity in adventitia, media and neointima of the damaged vessel at specified times post injury. RESULTS: Adventitial activation, evidenced by positive BrdU staining, was evident on the day of injury, peaked on day 3 and was resolved by day 7, thus preceding neointima formation. Numbers of BrdU labeled cells in adventitia on day 3 were significantly reduced in estrogen treated rats compared to controls. BrdU labeled cells were undetectable in media on the day of injury, appeared at day 3 and disappeared by day 14. Neointima appeared at day 7 and increased in area throughout the period of observation. Neointimal area and numbers of BrdU labeled cells in neointima were significantly reduced in estrogen treated rats compared to controls. These findings suggest that there is a wave of cell proliferation moving in an adventitia-to-lumen direction following endoluminal injury of the rat carotid artery and that estrogen modulates this proliferative response to injury. CONCLUSION: These results support the hypothesis that adventitial activation contributes to the vascular injury response and that estrogen reduces this contribution.

Analysis of Variance↗
PubMed1999

Management of the hypertensive patient with coronary artery disease.

Hypertension, a major risk factor for cardiovascular disease worldwide, remains inadequately diagnosed and treated, particularly in certain at-risk populations. Hypertension, often in association with other factors, increases the risk for the development of coronary artery disease (CAD). In turn, CAD increases the risk for related morbidity and mortality and presents treatment challenges. The chronobiology of many cardiovascular events offers a pathway for selecting optimal therapy for the hypertensive patient with CAD. Choosing a long-acting agent that achieves high plasma drug levels during critical hours may reduce the risk for cardiovascular morbidity and mortality.

Cardiovascular Agents↗
PubMed1999

Fenoldopam: a new parenteral antihypertensive: consensus roundtable on the management of perioperative hypertension and hypertensive crises.

A panel of clinicians from anesthesiology, surgery, nephrology, hypertension, cardiology, and pharmacology was convened to discuss pharmacologic therapeutics in the management of hypertensive crisis and perioperative hypertension. The panel discussed the advantages and limitations of currently available parenteral drugs, and assessed the potential use of fenoldopam mesylate, a drug in clinical development since 1981, and recently approved by the U.S. Food and Drug Administration (FDA). Fenoldopam is a dopamine receptor (DA1 selective) agonist that is a systemic and renal vasodilator. It was concluded that fenoldopam offers significant advantages as a parenterally administered agent for the management of blood pressure in both hypertensive emergencies and in the perioperative setting.

Acute Disease↗
PubMed1999

A comparison of the angiotensin II antagonists valsartan and losartan in the treatment of essential hypertension.

We compared the angiotensin II receptor antagonist valsartan to losartan as an antihypertensive agent in an 8-week trial. Adults with uncomplicated essential hypertension (baseline seated diastolic blood pressure < 115 mm Hg and > or = 95 mm Hg) were randomized to receive 80 mg valsartan, 50 mg losartan, or placebo once daily. After 4 weeks doses of active medication and placebo were doubled. Seated systolic and diastolic blood pressures were measured and the response rate evaluated. Tolerability was assessed by the incidence of adverse events. Both angiotensin II receptor antagonists produced similar significant reductions in mean blood pressures at 4 and 8 weeks compared to placebo. Valsartan produced a significantly higher number of responders (62%) than losartan (55%, P = .02) at the 8 week treatment endpoint. The incidence of adverse experiences (AE) was similar in all three groups, with headache and dizziness reported most often. Valsartan (80/160 mg) monotherapy in this trial was as effective and well tolerated as 50/100 mg losartan in treating mild to moderate essential hypertension, and at 160 mg has a significantly higher responder rate than 100 mg losartan.

Adolescent↗