摘要:

BackgroundIncreased apoptosis has recently been reported in the heart of spontaneously hypertensive rats (SHRs).ObjectiveTo investigate the molecular basis of apoptosis in the left ventricle of SHRs in terms of the expression of Bcl-2 protein (which protects from apoptosis) and Bax protein (which acts as an apoptotic promoter). In addition, we analysed the involvement of α1-adrenergic receptors in the left ventricular apoptosis of SHRs.MethodsThe study was performed in untreated SHRs (n= 16) and SHRs that were orally treated with doxazosin (10 mg/kg body weight per day, for 15 days), a selective α1-receptor blocker (n= 16). A group of Wistar–Kyoto (WKY) rats (n= 16) was used as the control.ResultsThe left ventricles of untreated SHRs showed a significant increase in Bcl-2 protein expression and a reduced presence of Bax protein. The ratio of Bcl-2:Bax in SHRs was higher than in WKY rats, suggesting an anti-apoptotic state. Paradoxically, both the number of apoptotic cardiac cells and the cleavage of an 85-kDa fragment of the poly (ADP-ribose) polymerase (PARP), a marker of caspase-3 activity, were higher in the left ventricle of SHRs than in WKY rats, suggesting an apoptotic situation. Bax promotes cell apoptosis when it is bound to Bcl-2. We then determined the abundance of Bax–Bcl-2 complexes in the left ventricle of the two groups of animals. Bax–Bcl-2 complexes were more abundant in SHRs than WKY rats. In a second set of experiments, we analysed the role of α1-adrenergic blockade by doxazosin in the above-described mechanisms. Doxazosin treatment reduced the formation of Bax–Bcl-2 complexes in the left ventricle of SHRs, and this was accompanied by a decrease in the levels of 85-kDa PARP and a reduction in apoptotic left ventricular cells.ConclusionsThe present work suggests that the presence of Bax–Bcl-2 complexes in the left ventricle could be a more reliable marker of the apoptotic state than the determination of the absolute expression of Bcl-2 and Bax proteins. Moreover, the inhibition of α1-adrenergic receptors by doxazosin decreased the abundance of Bax–Bcl-2 complexes and promoted a reduction of apoptosis in the left ventricle of SHRs.

ISSN:0263-6352    

出版商:OVID    

年代:2000

数据来源: OVID

摘要:

ObjectiveTo establish the optimal dose of the perindopril/indapamide combination (Per/Ind) in the treatment of mild or moderate hypertension.DesignThis was a randomized, double-blind, placebo-controlled, seven-way parallel-group, dose-ranging study, set in multicenter, outpatient offices/clinics in Europe and Canada.PatientsA total of 438 patients aged between 18 and 75 years whose supine diastolic blood pressure was between 95 and114 mmHg were randomly assigned to an 8-week double-blind treatment with either placebo, Per 2/Ind 0.625, Per 4/Ind 1.25, Per 8/Ind 2.5, Per 0/Ind 1.25, Per 2/Ind 1.25 or Per 8/Ind 1.25 mg.Main outcome measuresSystolic and diastolic blood pressure measured in the clinic approximately 24 h after dosing.ResultsThere was a linear dose–response relationship (P= 0.001) for doubling the dose of Per 2/Ind 0.625 mg up to Per 8/Ind 2.5 mg with a progressive fall in supine diastolic blood pressure (−9.3 to −15.0 mmHg). Combining 1.25 mg Ind with increasing doses of Per (0, 2, 4 and 8 mg) also showed a linear dose–response relationship (P<0.001), with supine diastolic blood pressure falling by −8.0 to −12.0 mmHg compared with a fall of −5.2 mmHg for the placebo group. Similar findings were noted for supine systolic blood pressure, standing blood pressure and ambulatory blood pressure. Hypokalemia was more common (9.7%) in the Per 8/Ind 2.5 mg group than in the groups receiving other doses (0–4.6%).ConclusionThe combinations of Per 2/Ind 0.625 mg and Per 4/Ind 1.25 mg were effective in reducing blood pressure without producing clinically important side effects.

ISSN:0263-6352    

出版商:OVID    

年代:2000

数据来源: OVID

摘要:

ObjectiveTo determine the long-term efficacy and safety of a fixed, very-low-dose tablet combining one-half the standard dose of perindopril with one-quarter the standard dose of indapamide as first-line treatment in elderly patients.DesignDouble-blind, randomized, placebo-controlled study in an outpatient setting.Patients and interventionsFollowing a single-blind, placebo run-in period of 4 weeks, patients [65–85 years, with mild-to-moderate essential hypertension or isolated systolic hypertension (ISH)] were randomized to receive one tablet of perindopril 2 mg/indapamide 0.625 mg (Per/ Ind) (n= 193) or placebo (n= 190), daily for 12 weeks. After this first 12-week period, all patients on Per/Ind (n= 138) and patients responding to placebo (n= 61) were maintained on their previous regimen for a further 48 weeks. Patients in the placebo group whose blood pressure was not normalized, were switched to Per/Ind (n= 60).Main outcome measureThe primary endpoint was the proportion of patients with blood pressure that normalized between weeks 0 and 60.ResultsAfter 1 year of treatment (intention-to-treat) supine systolic and diastolic blood pressure decreased by 23.0 ± 15.3 mmHg and 13.3 ± 9.4 mmHg with Per/Ind (n= 253: 193 from randomized Per/Ind group and 60 from the placebo group switched at week 12). The mean decreases in systolic blood pressure were similar in essential hypertension and ISH (systolic blood pressure 23.2 versus 22.7 mmHg, respectively). Per/Ind treatment (n= 253) achieved an initial normalization of blood pressure in 96.2% [95% confidence interval (CI) 93.6–98.9%; Kaplan-Meier estimate] of Per/Ind-treated patients; 79.8% (95% CI 74.1–85.5%) of these maintained a normalized blood pressure throughout the 1-year follow-up. The incidence of adverse events was similarly low in the placebo and active therapy groups. Efficacy and safety results for the over 75 years subgroup were similar to those for the younger elderly subjectsConclusionsThe fixed, very low-dose combination of perindopril 2 mg/indapamide 0.625 mg results in sustained blood pressure control when used as first line treatment of elderly hypertensive patients over 1-year, and is well-tolerated.

ISSN:0263-6352    

出版商:OVID    

年代:2000

数据来源: OVID

摘要:

IntroductionLosartan is an angiotensin II receptor blocker indicated for treatment of hypertension. It also inhibits platelet agreggation through blockade of thromboxane A2/prostaglandin H2receptors, and has a uricosuric effect. We determined the effect on ambulatory blood pressure (ABP) of 100 mg losartan monotherapy (L100) versus 50 mg losartan/12.5 mg hydrochlorothiazide (HCTZ) combination therapy (L50H12.5C), in patients uncontrolled on 50 mg losartan. We also assessed the effects of losartan on platelet aggregation and serum urate at these clinically relevant doses.MethodsThis was a randomized, double-blind trial of L100 versus L50H12.5C, in moderate hypertensives (sitting diastolic blood pressure (DBP) ≥ 95 mmHg and <120 mmHg). After 4 weeks of placebo run-in, patients received 50 mg losartan for 6 weeks; patients uncontrolled (sitting DBP ≥ 95 mmHg) were randomized to L100 or L50H12.5C for a further 6 weeks. Platelet function was assessed by measuring percentage inhibition of platelet aggregation, and serum uric acid was also measured.ResultsMonotherapy with 50 mg losartan reduced ABP by 16.0/9.9 mmHg during the day and 9.8/5.5 mmHg at night. However, 16 out of 24 (66%) patients had uncontrolled blood pressure on this treatment. L50H12.5C further reduced daytime ABP by 10.7(10.7)/8.4(6.5) mmHg mean (SEM) compared with L100 (25.3(9.7)/22.3(4.8),P= 0.013). 50 mg losartan and L100 did not affect platelet function or uric acid levels beyond placebo values; treatment with L50H12.5C was associated with a significant rise in serum urate above levels obtained on 50 mg losartan (366.9(67.6) versus 331.6(65.0),P= 0.006), to levels similar to placebo (358.8(80.9)).ConclusionL50H12.5C is an effective antihypertensive regimen in patients with moderate hypertension that is uncontrolled on 50 mg losartan monotherapy, and is the preferred treatment option in these patients compared with increasing the dose of losartan. The additional benefit of losartan on platelet inhibition was not evident in our population at these doses; however, there was evidence to suggest that the uricosuric effects of losartan might ameliorate the uric acid retention effects of therapy with hydrochlorothiazide.

ISSN:0263-6352    

出版商:OVID    

年代:2000

数据来源: OVID

ISSN:0263-6352    

出版商:OVID    

年代:2000

数据来源: OVID

ISSN:0263-6352    

出版商:OVID    

年代:2000

数据来源: OVID

ISSN:0263-6352    

出版商:OVID    

年代:2000

数据来源: OVID