摘要:

BackgroundDahl salt-sensitive (DS) rats are characterized by enhanced NaCl reabsorption in the loop of Henle, but the responsible ion transport protein is unknown.ObjectiveTo investigate renal Na–K–Cl cotransporter NKCC2 function and expression in DS rats under a low-salt diet.MethodsNKCC2 functioning was assessedin vitroby measuring bumetanide-sensitive rubidium uptake and cytosolic chloride concentration in isolated medullary thick ascending limb (mTAL) tubules, andin vivoby measuring the salidiuretic action of orally given bumetanide. NKCC2 expression was assessed by Western blot analysis of outer medullary proteins using T4 monoclonal antibody.ResultsmTAL tubules from DS rats exhibited significantly higher bumetanide-sensitive rubidium uptake (85.1 ± 4.8 versus 66.2 ± 4.4 nmol/min per mg protein in DS and DR, (Dahl salt-resistant) rats, respectively;P= 0.011) and significantly higher cytosolic chloride (32.8 ± 1.7 versus 25.0 ± 1.5 mmol/l in DS and DR rats, respectively). Moreover, DS rats showed a significantly higher (P< 0.001) natriuretic response to bumetanide (1.13 ± 0.05 versus 0.64 ± 0.09 mmole/3 h in DS and DR rats, respectively). Finally, Western blot analysis revealed less NKCC2 expression in DS rats.ConclusionsWe conclude that DS rats have increased renal NKCC2 activity, thus explaining, at least in part, their genetic renal inability to excrete sodium. Moreover, DS rats have a decreased renal NKCC2 expression, which can be a compensatory phenomenon against NKCC2 hyperactivity.

ISSN:0263-6352    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

ObjectiveGuidelines recommend lower threshold and goal blood pressure (BP) for patients with proteinuria. BP reduction could be accompanied by a different fall in proteinuria depending of the antihypertensive drug. The objective was to compare proteinuria reduction when BP is lowered to the same level with different drugs.DesignProspective, randomized, double-blind, controlled trial.Setting12 Spanish centres.PatientsA total of 119 patients with primary renal disease, blood pressure>130/85 mmHg, proteinuria>1 g/day, and creatinine clearance⩾50 ml/min.InterventionAfter a 4-week run-in placebo period, patients were randomized to: atenolol 50 mg/day; trandolapril 2 mg/day; verapamil 240 mg/day or verapamil 180 + trandolapril 2 mg/day combination; forced double-dose titration was carried out at the 4th week. Treatment duration was 6 months.Outcome measuresChanges in BP, 24 h proteinuria, serum albumin and calcium.ResultsBP was significantly reduced with the four treatments [SBP/DBP (mmHg]: atenolol 12.2/9.9; trandolapril 12.9/9.3; verapamil 8.2/7.9 and verapamil + trandolapril 13.6/11.3) without differences between them. A significant fall in proteinuria was seen in the trandolapril, 40.2% [95% confidence interval (CI) 24.3–56.2%], and verapamil + trandolapril groups, 48.5% (95% CI, 31.7–64.3%) accompanied with increases in serum albumin (trandolapril: from 3.86±0.64 to 4.03±0.67 g/dl; verapamil + trandolapril: from 4.15±0.58 to 4.40±0.51 g/dl).ConclusionsIn patients with proteinuric primary renal disease, adequate dose titration of antihypertensive drugs may provide a substantial BP reduction. Only angiotensin-converting enzyme inhibitor (trandolapril) treatment, alone or better combined with verapamil, reduces proteinuria and increases serum albumin.

ISSN:0263-6352    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

ObjectiveAngiotensin-converting enzyme inhibitors (ACEI) show an antiproteinuric and thus nephroprotective effect in patients suffering from glomerulonephritis. Angiotensin II-receptor-antagonists (AT1RA) are also efficacious in reducing proteinuria. The study was performed to investigate the antiproteinuric effect of AT1RA candesartan in patients diagnosed with chronic glomerulonephritis by biopsy, and who were already being treated with an ACEI.MethodsA total of 12 patients with a persistent proteinuria of at least 1 g/day who were already being treated with an ACEI for more than 3 months were included. The study was performed using a double-blind, placebo-controlled and randomized method with two treatment periods of 8 weeks (placebo or candesartan 8 mg/day) and a wash-out period of 4 weeks in between. Glomerular filtration rate (GFR) and effective renal plasma flow (ERPF) were measured by inulin- and PAH-clearances at the beginning and the end of each treatment period.ResultsProteinuria significantly decreased from 2±0.4 g/day to 1.3±0.3 g/day (P<0.05) with the addition of candesartan treatment, whereas it remained unchanged (from 1.8±0.3 g/day to 1.9±0.3 g/day) under placebo. GFR (candesartan: from 66±13 to 58±11 ml/min per 1.73 m2, placebo: from 64±11 to 62±13 ml/min per 1.73 m2) and ERPF (candesartan: from 329±44 to 304±37 ml/min per 1.73 m2, placebo: from 362±48 to 315±46 ml/min per 1.73 m2) did not alter significantly after 8 weeks of treatment. The addition of candesartan treatment significantly reduced systolic blood pressure (from 129±3 to 123±2 mmHg,P<0.05) and diastolic blood pressure (from 79±2 to 76±2 mmHg,P<0.05) compared with placebo (systolic: 128±3 to 127±3 mmHg, diastolic: 79±2 to 79±2 mmHg).ConclusionCandesartan promotes a complementary antiproteinuric and a small antihypertensive effect after a treatment period of 8 weeks in patients with chronic glomerulonephritis when given in conjunction with an ACEI. Renal hemodynamics did not vary significantly.

ISSN:0263-6352    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

BackgroundGrowth factors such as transforming growth factor-beta (TGFβ) are believed to have an essential role in cardiac fibrosis. Tranilast (N(3,4-dimethoxycinnamoyl) anthranilic acid) attenuates the increased expression of TGFβ mRNAin vitro.ObjectiveTo investigate whether tranilast reduces cardiac fibrosis in rats with two-kidney, one-clip (2K1C) renovascular hypertension. In addition, we tested the in-vitro effects of tranilast on cardiac myocytes and non-myocyte cells.MethodsWe analysed hearts from four groups of rats: sham-operated controls; rats with 2K1C renovascular hypertension; rats with 2K1C renovascular hypertension treated for 12 weeks with the angiotensin converting enzyme (ACE) inhibitor, quinapril (6 mg/kg per day); rats with 2K1C renovascular hypertension treated for 12 weeks with tranilast (400 mg/kg per day).ResultsSystolic blood pressure was reduced after quinapril treatment. Tranilast did not alter blood pressure (2K1C: 223±19 mmHg; 2K1C + quinapril: 149±15 mmHg (P<0.01 compared with 2K1C); 2K1C + tranilast: 204±32 mmHg). Left ventricular weight was likewise reduced significantly by quinapril, but not significantly by tranilast (2K1C: 1.52±0.2 g; 2K1C + quinapril: 1.26±0.18 g (P<0.05 compared with 2K1C); 2K1C + tranilast: 1.37±0.27 g). Using a computer-aided image analysis system, we demonstrated that tranilast prevented cardiac fibrosis in a blood-pressure-independent manner (P<0.01 compared with 2K1C). Determination of the cardiac hydroxyproline content similarly revealed a significant reduction in cardiac fibrosis by tranilast (2K1C: 4.92±0.48 mg/mg; 2K1C + tranilast: 3.97±0.46 mg/mg;P<0.05). The effect of tranilast on cardiac fibrosis was comparable to the effects of a blood-pressure-decreasing dose of the ACE inhibitor, quinapril. Cell culture experiments revealed that tranilast significantly decreased the proliferation of cardiac non-myocyte cells. Proliferation of cardiac myocytes was not altered.ConclusionThis study revealed that long-term treatment with tranilast markedly attenuated left ventricular fibrosis in rats with renovascular hypertension. This was most probably the result of an antiproliferative effect of tranilast on cardiac non-myocyte cells. Tranilast thus offers a unique new therapeutic approach to the reduction of TGFβ-mediated cardiac fibrosisin vivo.

ISSN:0263-6352    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

ObjectivesDespite the clinical frequency of diastolic heart failure, its therapeutic strategy has not been established. Our recent study demonstrated activation of the endothelin (ET) system in a diastolic heart failure model with hypertension. Several studies have reported that ET type A (ETA) receptor antagonist improves systolic function and prevents systolic heart failure; however, its effects on diastolic heart failure are unknown. We investigated the effects of chronic administration of ETAreceptor antagonist in diastolic heart failure.Design and methodsDahl-Iwai salt-sensitive rats fed on a high-salt diet from 7 weeks of age, in which congestive heart failure develops following hypertension without cardiac chamber dilatation or systolic dysfunction, were divided into groups with and without administration of a subdepressor dose of ETAreceptor antagonist.ResultsHypertension induced compensatory left ventricular (LV) hypertrophy at 13 weeks in six untreated rats. Persistent pressure overload developed progressive LV hypertrophy and fibrosis from 13 to 19 weeks, resulting in elevated LV filling pressure and increased lung weight. Chronic ETAreceptor blockade did not restrain compensatory LV hypertrophy at 13 weeks; however, it attenuated LV hypertrophy and fibrosis thereafter (n= 6). These beneficial effects resulted in the maintenance of normal LV filling pressure without changes in LV end-diastolic diameter, indicating prevention of LV stiffening.ConclusionsChronic ETAreceptor blockade is likely to exert beneficial effects in diastolic failure through attenuation of the progression of LV hypertrophy and fibrosis.

ISSN:0263-6352    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

ObjectiveRacemic propranolol attenuates cardiac hypertrophy secondary to abdominal aortic banding-induced pressure overload by a mechanism independent of its effect on cardiac work load. This was only observed, however, using doses of propranolol that were much higher than those needed to induce β-adrenoceptor blockade. Thus, the question remains as to whether the antihypertrophic effect of propranolol depends on its ability to antagonize cardiac β-adrenoceptor-mediated action (positive chronotropic effect, trophic effect) or on β-adrenoceptor-independent action.MethodsIn a rat model of chronic pressure overload induced by abdominal aortic banding, we evaluated the effects on left ventricular hypertrophy (LVH) of the propranolol isomers, l-propranolol and d-propranolol, which compared to l-isomer is approximately 50-fold less potent as a β-adrenoceptor antagonist, but is similarly potent as a membrane-stabilizer, as well as of timolol, a non-selective β-adrenergic antagonist devoid of membrane stabilizing activity, and disopyramide, which is a membrane stabilizer, but not a β-adrenoceptor blocker.ResultsCompared to sham-operated rats, banded rats had 30% greater left ventricular to body weight (LVW/BW) ratio (P<0.01). The increase in LVW/BW ratio was significantly attenuated by treatment with 40 and 80 (but not 10) mg/kg per day of l-propranolol. Left ventricular hypertrophy was also prevented by d-propranolol, 40 and 80 mg/kg per day, and disopyramide, 50 mg/kg per day, whereas timolol, 30 and 60 mg/kg per day, showed no antihypertrophic effect. In separate groups of banded rats in which the reduction in heart rate induced by propranolol (80 mg/kg per day) was prevented by chronic cardiac pacing at 375 b.p.m., hypertrophy was again prevented, indicating that the effects of l-propranolol on LVH are not related to a reduction in cardiac work load.ConclusionsIn the aortic banding-induced model of LVH: (i) the antihypertrophic effect of propranolol is independent of its β-adrenergic blocking activity; and Iii) since disopyramide and D-propranolol also proved to be able to antagonize banding-induced LVH, the hypothesis is proposed that membrane-stabilizing activity, among the ancillary properties of propranolol, most likely accounts for the antihypertrophic effect of this drug.

ISSN:0263-6352    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

ObjectiveHypertension guidelines recommend initial treatment with a β-blocker or diuretic and adding the other drug where blood pressure is not controlled. We hypothesized that systematic rotation through the major classes of antihypertensive drugs would demonstrate substantial differences in the pattern of an individual patient's response, and suggest a more rational approach to choosing best treatment.DesignThirty-four young hypertensives (age 28–55, median 47) rotated in a double-blind, Latin-square, crossover fashion through 6 weeks of treatment each with amlodipine, doxazosin, lisinopril, bisoprolol, bendrofluazide and placebo. Blood pressure was measured at each visit. ‘Best’ drug, defined by efficacy and tolerability, was repeated at the end.ResultsRotation doubled the number of patients reaching target blood pressure (systolic<140 mmHg) on one drug (P= 0.03). All five drugs were represented among the ‘best’ drugs. In six patients, the blood pressure on ‘best’ drug was at least 10 mmHg lower than on any other. Response to the ‘best’ drug was highly correlated (r= 0.79) with its previous administration. By contrast, there were only weak correlations between responses to pairs of drugs, except for angiotensin-converting enzyme (ACE) inhibitor (A) with β-blocker (B), and calcium blocker (C) with diuretic (D) – eachr= 0.71,P<0.005). In these young patients, the majority of patients (23/34) responded best to a drug suppressing the renin system (A and B).ConclusionsPatients vary reproducibly in their response to initial treatment, and switching among drugs can increase the efficacy of monotherapy. The results support an AB/CD scheme for choosing therapy, in which the first drug is taken from one of these pairs, and uncontrolled patients switch to one of the other pair.

ISSN:0263-6352    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

ObjectiveTo determine whether blood pressure control in a general practice setting is influenced by the presence of additional risk factors, and to analyse the role of antihypertensive therapy in this relationship.DesignA cross-sectional study was conducted with a sample of 3153 general practitioners.SettingPrimary care.ParticipantsThe first five hypertensive patients presenting at the practitioner's office were included.Main outcome measuresCardiovascular risk factors, antihypertensive drugs and cardiovascular history were reported. Blood pressure was measured. The analysis was conducted in treated patients who were divided in three groups: no other risk factors (group I); 1–2 risk factors (group II); 3 or more risk factors or target-organ damage or diabetes or associated cardiovascular disease (group III).ResultsData were available for all variables in the 14 066 treated hypertensive individuals who form the basis of this report. Blood pressure control had been achieved in a lower percentage of individuals in group III (27%) than in group I (42.9%). To control hypertension, combination therapies were more frequently required in group III (55.8%) than in group II (43.5%) or group I (34.2%). Among individuals with uncontrolled hypertension, about 39% of patients in group III were receiving monotherapy and the percentage receiving two-drug treatments identified as effective in the 1999 WHO guidelines was significantly lower in group III.ConclusionThe study shows that, in general practice, control of blood pressure decreases as the number of risk factors present increases. An underuse of combination therapy, especially effective two-drug treatment in patients with several risk factors, may account for this finding.

ISSN:0263-6352    

出版商:OVID    

年代:2002

数据来源: OVID