endothelin-1 and trandolapril

Circulating biomarkers can offer insight into subclinical cardiovascular stress and thus have the potential to aid in risk stratification and tailoring of therapy.. We measured plasma levels of 4 cardiovascular biomarkers, midregional pro-atrial natriuretic peptide (MR-proANP), midregional pro-adrenomedullin (MR-proADM), C-terminal pro-endothelin-1 (CT-proET-1), and copeptin, in 3717 patients with stable coronary artery disease and preserved left ventricular ejection fraction who were randomized to trandolapril or placebo as part of the Prevention of Events With Angiotensin Converting Enzyme (PEACE) trial. After adjustment for clinical cardiovascular risk predictors and left ventricular ejection fraction, elevated levels of MR-proANP, MR-proADM, and CT-proET-1 were independently associated with the risk of cardiovascular death or heart failure (hazard ratios per 1-SD increase in log-transformed biomarker levels of 1.97, 1.48, and 1.47, respectively; P≤0.002 for each biomarker). These 3 biomarkers also significantly improved metrics of discrimination when added to a clinical model. Trandolapril significantly reduced the risk of cardiovascular death or heart failure in patients who had elevated levels of ≥2 biomarkers (hazard ratio, 0.53; 95% confidence interval, 0.36-0.80), whereas there was no benefit in patients with elevated levels of 0 or 1 biomarker (hazard ratio, 1.09; 95% confidence interval, 0.74-1.59; P(interaction)=0.012).. In patients with stable coronary artery disease and preserved left ventricular ejection fraction, our results suggest that elevated levels of novel biomarkers of cardiovascular stress may help identify patients who are at higher risk of cardiovascular death and heart failure and may be useful to select patients who derive significant benefit from angiotensin-converting enzyme inhibitor therapy.

Topics: Adrenomedullin; Aged; Angiotensin-Converting Enzyme Inhibitors; Atrial Natriuretic Factor; Biomarkers; Cardiovascular Diseases; Coronary Disease; Death; Endothelin-1; Female; Glycopeptides; Heart Failure; Humans; Indoles; Male; Middle Aged; Peptide Fragments; Prognosis; Protein Precursors; Risk; Stress, Physiological; Stroke Volume

The aim of this study was to assess the influence of trandolapril on blood pressure and ET-1 plasma activity in young patients with essential mild-to-moderate hypertension.. 19 persons with essential mild-to-moderate hypertension were enrolled into the study: the average age of this group was 17,6 +/- 1,4 years. The blood pressure and serum concentration of ET-1 in plasma were measured before enrolling and after 42 days of trandolapril (2 mg per day) therapy. The concentration of endothelin-1 was measured using RIA method.. In the studied group, after trandolapril therapy SBP was reduced from 142.6 +/- 9,7 mmHg to 129.3 +/- 8,4 mmHg (p<0,003), DBP from 85.7 +/- 6,9 mmHg to 79.8 +/- 8,6 mmHg (p<0,01). The average serum concentration of endothelin-1 was: before therapy 9,33 +/- 1,9 fmol/ml and after therapy 8,96 +/- 2,2 fmol/ml (non-significant).. 1. Young hypertensives treated with trandolapril (ACEI) showed significant decrease of SBP and DBP 2. 6-weeks trandolapril therapy was associated with the reduction of serum concentration of ET-1, but without statistical significance.

Topics: Adolescent; Adult; Angiotensin-Converting Enzyme Inhibitors; Endothelin-1; Female; Humans; Hypertension; Indoles; Male; Treatment Outcome

Endothelin (ET) is the strongest endogenic substance causing vasoconstriction. The aim of this study was to assess the influence of ACEI therapy on serum concentration of ET-1 plasma activity in young patients with essential mild-to-moderate hypertension.. 19 persons with essential mild-to-moderate hypertension were enrolled into study (14 male and 5 female). The average age of this group was 17.6+/-1.4 years. The patients were untreated or there was a 7 day wash out period. The blood pressure and serum concentration of ET-1 plasma were measured before enrolling and after 6 weeks of trandolapril (2 mg per day) therapy. The concentration of endothelin-1 was measured using RIA methods.. In analyzed group there was a significant both SBP and DBP lowering after the ACEI therapy. SBP was reduced from 142.6+/-9.7 to 129.3+/-8.4 mmHg (p<0.003), DBP from 85.7+/-6.9 to 79.8+/-8.6 mmHg (p<0.01). The average serum concentration of endothelin-1 was: before treatment 9.33+/-1.9 fmol/ml and after therapy 8.96+/-2.2 fmol/ml.. The treatment with ACEI drug (trandolapil) induced the significant decrease of SBP and DBP in young hypertensives. 6-weeks trandolapril therapy was associated with the reduction of serum concentration of ET-1, but not statistically significant.

Topics: Adolescent; Adult; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Blood Pressure; Endothelin-1; Female; Humans; Hypertension; Indoles; Male; Treatment Outcome

There is little information whether cardiac capillary supply is deranged in diabetes. Hyperglycaemia is a potent stimulus for endothelin-1 (ET-1) production. We therefore hypothesised that increased ET-1 production in Streptozotocin-induced Type 1 diabetes causes abnormalities of cardiac capillaries and the aorta. To this end we compared the effects of an ET receptor A blocker (ETA-RB) with that of an ACE-inhibitor (ACE-i) or their combination in rats with Streptozotocin (STZ) diabetes.. Sprague Dawley rats were injected with 65 mg STZ i.v. and subsequently developed diabetes. Rats were left untreated or received daily either the ACE-i Trandolapril, the ETA-RB Darusentan or a combination of both. After 6 months the experiment was terminated and the heart and the aorta were investigated using quantitative morphological techniques.. ACE-i but not ETA-RB lowered blood pressure in STZ Type 1 diabetic rats. Capillary length density was lower in untreated STZ diabetic rats (2932+/-128 mm/mm3) compared to non-diabetic control rats (3410+/-252 mm/mm3). Treatment with ACE-i (3568+/-431 mm/mm3), but not with ETA-RB (2893+/-192 mm/mm3), prevented the decrease in capillary supply. Volume density of the myocardial interstitium was higher in untreated STZ diabetic rats (0.86+/-0.04%) compared to non-diabetic control rats (0.36+/-0.06%). In all three intervention groups the values were lower (ACE-i: 0.53+/-0.05%, ETA-RB: 0.7+/-0.08% and combination: 0.69+/-0.1).. Our study identifies a capillary defect of the heart in STZ diabetes, i.e. decreased capillary supply. This abnormality was reversed by ACE-i, but not by ETA-R blockade. A similar trend, although not complete normalisation, was seen in cardiac fibrosis.

Topics: Albuminuria; Angiotensin-Converting Enzyme Inhibitors; Animals; Aorta, Thoracic; Arterioles; Blood Glucose; Blood Pressure; Body Weight; Cardiovascular Diseases; Collagen Type IV; Coronary Vessels; Diabetes Mellitus, Experimental; Endothelin A Receptor Antagonists; Endothelin-1; Fibrosis; Gene Expression; Heart; Immunohistochemistry; In Situ Hybridization; Indoles; Male; Myocardium; Phenylpropionates; Pyrimidines; Rats; Rats, Sprague-Dawley; Receptor, Endothelin A; Transforming Growth Factor beta

The pathomechanisms that cause renal damage in diabetes have not been completely clarified. Treatment with angiotensin-converting enzyme inhibitors (ACE-i) is highly effective but fails to completely prevent end-stage renal disease. The effects of ET(A)-receptor blockers (ET(A)-RB) on renal damage are controversial and have rarely been investigated in type 2 diabetes. We compared the influence of the selective ET(A)-RB LU135252 and the ACE-i Trandolapril on renal structure in the SHR/N-cp rat model of type 2 diabetes. Three-month-old male SHR/N-cp rats were left untreated or received daily either Trandolapril or LU135252. The experiment was terminated after 6 months. The glomerulosclerosis index; tubulointerstitial damage index; and glomerular geometry, glomerular cell number, and capillary density were investigated. Proliferating cell nuclear antigen and desmin expression of podocytes, renal mRNA expression of endothelin (ET-1) and transforming growth factor-beta, blood pressure, and urine albumin excretion were measured. The glomerulosclerosis index was significantly higher in untreated diabetic animals than in the groups that were treated with ACE-i and ET(A)-RB. There were analogous changes in tubulointerstitial damage index. Treatment with either substance comparably lowered urinary albumin excretion in diabetic SHR/N-cp. Podocyte and endothelial cell numbers per glomerulus decreased in untreated diabetic animals; this was prevented by the ACE-i but not by the ET(A)-RB. Glomerular capillary length density was lower in SHR/N-cp, and this was normalized by ACE-i only. Increased expression of desmin and proliferating cell nuclear antigen expression of podocytes in the SHR/N-cp was abrogated by ACE-i but not by ET(A)-RB. Treatment with ACE-i or ET(A)-receptor antagonist resulted in less structural and functional alterations, but the ET(A)-RB was inferior to the ACE-i. This is particularly the case for podocyte changes pointing to angiotensin II-dependent pathomechanisms.

Topics: Albuminuria; Angiotensin-Converting Enzyme Inhibitors; Animals; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Disease Models, Animal; Endothelin Receptor Antagonists; Endothelin-1; Immunohistochemistry; Indoles; Kidney; Male; Phenylpropionates; Proliferating Cell Nuclear Antigen; Pyrimidines; Rats; RNA, Messenger; Transforming Growth Factor beta

to compare the acute effect of ACEI and ARB's upon the plasmatic endothelin level in heart failure patients.. There were studied 30 patients with congestive heart failure, III-IV functional NYHA class, that were not under ACEI or ARB's treatment. In all the patients the endothelinl-21 plasmatic level was determined. After this, 20 patients, representing group I, received a single dose of 1 mg trandolapril, and 10 patients, representing group II, received a single dose of 40 mg telmisartan. After 24 hours, the plasmatic endothelin 1-21 level was determined again.. The mean endothelial plasmatic level was similar in both groups (group I: 0.358+/-0.04 fmol/ml; group II: 0.345+/-0.038). After 24 hours, the endothelin level decreased to 0.295+/-0.03 fmol/ml for group I (p<0.05) and to 0.287+/-0.029 fmol/ml for group II (p<0.05), suggesting that both ACEI and ARB's are equally efficient in decreasing endothelin. The initial endothelinl-21 level was inversely correlated with LVEF (r = -0.989), and the degree of the decrease of endothelinl-21 after both ACEI and ARB's is directly correlated with the initial endothelinl-21 level (r =0.64).. The acute administration of ACEI and ARB's in heart failure patients decreases the endothelin level, both categories of drugs having the same effects.

Topics: Adult; Aged; Aged, 80 and over; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Benzimidazoles; Benzoates; Endothelin-1; Endothelins; Heart Failure; Humans; Indoles; Middle Aged; Telmisartan

We investigated the effects of long-term endothelin A (ET(A)) receptor blockade and ACE inhibition, either alone or in combination, on the hemodynamics, neurohormonal activation and cardiac remodeling in rats with congestive heart failure (CHF) after extensive myocardial infarction (MI).. Rats were treated with placebo, the ET(A) antagonist LU135252 (30 mg/kg/d), the ACE inhibitor trandolapril (0.3 mg/kg/d), or a combination of both for 11 weeks, starting 7 days after MI.. Despite comparable effects on left ventricular (LV) systolic pressure among all drug treatments, only combined ET(A) and ACE inhibition significantly reduced LV end-diastolic pressure (P<0.01), improved LV dP/dt(max) (P<0.01) and normalized sympathetic activation (P<0.05) in rats with CHF. The combination therapy was more effective in reducing type I and III collagen mRNA levels, MMP-2 zymographic activity and collagen accumulation in the surviving LV myocardium. Moreover, the increases in cardiac beta-myosin heavy chain and skeletal alpha-actin mRNAs, markers of hypertrophy or failure, were attenuated to a greater degree by the combination therapy than monotherapy, whereas right ventricular hypertrophy and ANF mRNA upregulation were significantly (P<0.01) prevented only by combined ET(A) and ACE inhibition.. Long-term combined ET(A) receptor and ACE inhibition improved cardiac failure after extensive MI more effectively than monotherapy. We show additive effects on LV fibrosis and fetal gene expression. ET(A) receptor antagonists could be a therapeutical option in CHF in addition to an ACE inhibitor.

Topics: Actins; Angiotensin-Converting Enzyme Inhibitors; Animals; Atrial Natriuretic Factor; Collagen; Drug Therapy, Combination; Endothelin Receptor Antagonists; Endothelin-1; Gene Expression; Heart Failure; Heart Ventricles; Hemodynamics; Indoles; Male; Matrix Metalloproteinase 2; Models, Animal; Myosin Heavy Chains; Norepinephrine; Phenylpropionates; Pyrimidines; Rats; Rats, Wistar; Renin; Tissue Inhibitor of Metalloproteinase-2; Transforming Growth Factor beta

In the heart of uremic animals and patients, the number of capillaries per volume of myocardium is reduced. Immunohistochemical studies demonstrated increased cardiac endothelin-1 (ET-1) expression in the left ventricle of uremic animals. Therefore, whether treatment with a selective ET(A)-receptor antagonist prevented such capillary-myocyte mismatch was investigated. Twenty-four h after subtotal nephrectomy, rats were left untreated or started on treatment with the ET(A)-receptor antagonist LU 135252 (20 mg/kg per d) and with the angiotensin-converting enzyme (ACE) inhibitor trandolapril (0.3 mg/kg per d), respectively. BP was monitored by telemetry. Myocardial capillary length density was analyzed by stereologic techniques that avoid anisotropy artifacts. In addition, cardiac ET-1 protein and mRNA were measured using immunohistochemistry, in situ hybridization, and quantitative reverse transcription-PCR. Changes in cardiac ET(A)-and ET(B)-PCR. receptor mRNA were measured using reverse transcription-PCR. Fifteen wk after subtotal nephrectomy, significantly reduced left ventricular capillary length density (3307 +/- 535 mm/mm(3)) was found compared with sham-operated controls (3995 +/- 471 mm/mm(3)); this was also seen in animals that were treated with trandolapril (3503 +/- 533 mm/mm(3)) but not in animals that were treated with LU 135252 (3800 +/- 303 mm/mm(3)). The results support a role of ET-1 in the genesis of left ventricular capillary/myocyte mismatch in uremia.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Capillaries; Coronary Circulation; Endothelin Receptor Antagonists; Endothelin-1; Immunohistochemistry; In Situ Hybridization; Indoles; Male; Molecular Biology; Myocardium; Nephrectomy; Phenylpropionates; Pyrimidines; Rats; Rats, Sprague-Dawley; Receptor, Endothelin A; RNA, Messenger; Uremia

We previously showed that chronic administration of an angiotensin converting enzyme (ACE) inhibitor to rats with passive Heymann nephritis (PHN), a model of membranous nephropathy with proteinuria and increased renal synthesis of endothelin-1 (ET-1), reduces urinary proteins and partially limits the exaggerated ET-1 renal synthesis. Here we compared the effect of an ETA receptor antagonist and an ACE-inhibitor given as single therapies with a combination of the two drugs in uninephrectomized PHN rats.. PHN was induced with a single i.v. injection of rabbit anti-Fx1A antibody in 40 male Sprague Dawley rats. To accelerate the onset of renal damage rats underwent uninephrectomy seven days later and were subsequently treated until eight months with the ETA receptor antagonist LU-135252 (50 mg/kg b.i.d. p.o.) or the ACE-inhibitor trandolapril (1 mg/kg in the drinking water) or the combination of the two drugs.. Either LU-135252 or trandolapril given alone prevented the increase in systolic blood pressure (SBP). Combined therapy was even more effective than single drugs. While LU-135252 and trandolapril reduced proteinuria by 23 to 25%, the drug combination resulted in 45% lowering of urinary proteins. Serum creatinine was significantly decreased by the combination, but not by the single drugs. Glomerulosclerosis and tubulointerstitial damage were more reduced by combined therapy than by LU-135252 or trandolapril alone.. These data suggest that contemporary blocking angiotensin II (Ang II) and ET-1 in an accelerated model of PHN had an additive renoprotective effect than single blocking Ang II or ET-1 and would represent a therapeutic advantage for renal disease patients who do not completely respond to ACE inhibitors.

Topics: Angiotensin II; Animals; Blood Pressure; Endothelin-1; Glomerulonephritis; Indoles; Kidney; Male; Phenylpropionates; Proteinuria; Pyrimidines; Rats; Rats, Sprague-Dawley