trandolapril and Chronic-Disease

Angiotensin II (ANG II) is an important factor for the progression of renal diseases. ANG II has many pleiotropic effects on the kidney such as pro-inflammatory and profibrotic actions besides the well-known blood pressure-increasing effect.. Organs have local ANG II-generating systems that work independently from their classic systemic counterpart. Renal proximal tubular cells could generate and secrete ANG II into the urine in concentrations that are 10,000 times higher than those found in serum. These local systems are only incompletely blocked by currently used doses of ACE inhibitors or AT(1) antagonists. There are other enzyme systems besides ACE that contribute to the formation of ANG II. Alternative pathways generate peptides such as angiotensin 1-7 that have antagonistic effect compared with ANG II. Degradation products of ANG II such as angiotensin IV bind at separate receptors and could mediate fibrosis. The discovery of AT(1) receptor dimers and agonistic antibodies against AT(1) receptors contributes to the complexity of the system.. The complexity of the renin-angiotensin-aldosterone system (RAAS) implies that dual blockade with ACE inhibitors and AT(1) receptor antagonists makes sense for pathophysiological reasons. First clinical studies have shown that such as dual therapy reduces progression of chronic renal disease more efficiently that the respective monotherapies in certain risk populations. This shows that novel pathophysiological data could lead to innovative clinical treatment strategies.

Topics: Angiotensin I; Angiotensin II; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Chronic Disease; Chymases; Clinical Trials as Topic; Diabetic Nephropathies; Disease Progression; Drug Therapy, Combination; Humans; Indoles; Kidney Diseases; Kidney Tubules, Proximal; Losartan; Prospective Studies; Receptors, Angiotensin; Renin-Angiotensin System; Risk Factors; Serine Endopeptidases

Evidence suggests that the effectiveness of angiotensin-converting enzyme (ACE) inhibition diminishes with time, resulting in increasing angiotensin II levels, the action of which can be inhibited by the addition of an angiotensin receptor blocker (ARB). In the present study, the renal protective effects of ACE inhibitors and ARBs were compared over a five-year period in a prospective, randomized, open-blind study in 68 nondiabetic Japanese patients with elevated serum creatinine levels.. Japanese patients with renal insufficiency were randomly assigned to receive either an ACE inhibitor (benazepril 1.25 to 5 mg daily or trandolapril 0.5 to 4 mg daily) or ARB (candesartan 2 to 8 mg daily or losartan 25 to 100 mg daily) at the Kidney Disease Center at Saitama Medical School Hospital. The primary study endpoint was a change in glomerular filtration rate (GFR) between the baseline value and the last available value obtained during the five-year treatment period, as estimated by the Cockcraft-Gault equation. Secondary endpoints included the annual changes in GFR, serum creatinine level, urinary protein excretion, and blood pressure, as well as the rate of development of endstage renal disease.. There were no significant differences in the primary endpoint between the two groups. However, after 4 years, the decline in GFR in patients treated with ARBs was significantly greater than that seen in patients treated with an ACE inhibitor (p<0.05). Furthermore, the rate of introduction of dialysis therapy was also significantly greater in the ARB-treated patients (52.7% in ACE inhibitor and 81.2% in ARB group at year 5. p<0.01).. While our data suggested that ARB, like ACE, treatment might slow the progression of renal dysfunction, it also pointed to the necessity to be alerted to the progression to endstage renal disease with longterm medication.

Topics: Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Benzazepines; Benzimidazoles; Biphenyl Compounds; Blood Pressure; Chronic Disease; Creatinine; Female; Glomerular Filtration Rate; Glomerulonephritis; Humans; Indoles; Losartan; Male; Middle Aged; Prospective Studies; Renal Insufficiency; Tetrazoles

Patients with reduced renal function are at increased risk for adverse cardiovascular outcomes. In the post-myocardial infarction setting, angiotensin-converting enzyme (ACE) inhibitors have been shown to be as effective in patients with impaired renal function as in those with preserved renal function.. We assessed the relation between renal function and outcomes, the influence of ACE inhibition on this relation, and whether renal function modifies the effectiveness of ACE inhibition in patients with stable coronary artery disease and preserved systolic function enrolled in the Prevention of Events with ACE inhibition trial (PEACE). Patients (n=8290) were randomly assigned to receive trandolapril (target, 4 mg/d) or placebo. Clinical creatinine measures were available for 8280 patients before randomization. The estimated glomerular filtration rate (eGFR) was calculated with the 4-point Modification of Diet in Renal Disease equation. Renal function was related to outcomes, and the influence of ACE-inhibitor therapy was assessed with formal interaction modeling. The mean eGFR in PEACE was 77.6+/-19.4, and 1355 (16.3%) patients had reduced renal function (eGFR <60 mg.mL(-1).1.73 m(-2)). We observed a significant interaction between eGFR and treatment group with respect to cardiovascular and all-cause mortality (P=0.02). Trandolapril was associated with a reduction in total mortality in patients with reduced renal function (adjusted HR, 0.73; 95% CI, 0.54 to 1.00) but not in patients with preserved renal function (adjusted HR, 0.94; 95% CI, 0.78 to 1.13).. Although trandolapril did not improve survival in the overall PEACE cohort, in which mean eGFR was relatively high, trandolapril reduced mortality in patients with reduced eGFR. These data suggest that reduced renal function may define a subset of patients most likely to benefit from ACE-inhibitor therapy for cardiovascular protection.

Topics: Aged; Angiotensin-Converting Enzyme Inhibitors; Cardiovascular Diseases; Chronic Disease; Coronary Artery Disease; Female; Glomerular Filtration Rate; Humans; Indoles; Male; Middle Aged; Renal Insufficiency; Survival Analysis; Treatment Outcome

Experimental studies suggest that angiotensin-converting enzyme (ACE) inhibitors with high tissue affinity confer a greater degree of vascular renin-angiotensin system suppression than those with low tissue affinity despite similar suppression of the circulating renin-angiotensin system. To test this hypothesis in a clinical setting, we randomized subjects with chronic heart failure to receive the low tissue affinity ACE inhibitor enalapril or the high tissue affinity ACE inhibitor trandolapril, and assessed the degree of circulating and vascular renin-angiotensin system suppression. Vascular renin-angiotensin system suppression was determined by measuring the pressor response to intravenous injections of angiotensin I. Circulating renin-angiotensin system suppression was determined by measuring plasma angiotensin II. Vascular and circulating renin-angiotensin system suppression, endothelial function (flow-mediated vasodilation), and maximal exercise capacity (peak oxygen uptake) were assessed after a 4-week run-in period on open-label enalapril 40 mg/day and after 8 weeks of randomized double-blind treatment with enalapril 40 mg/day or trandolapril 4 mg/day. Twenty-six men and 4 women (mean age 52 +/- 11 years; mean left ventricular ejection fraction 25 +/- 9%; New York Heart Association class II [n = 16] and III [n = 14]) were studied. After a 2-month randomized treatment period, vascular renin-angiotensin system suppression, circulating renin-angiotensin system suppression, endothelial function, and exercise capacity did not differ between subjects treated with enalapril and those treated with trandolapril. Despite substantial differences in the tissue affinity of enalapril and trandolapril, the degree of vascular renin-angiotensin system suppression achieved with these agents did not differ in subjects with chronic heart failure during long-term therapy.

Topics: Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Chronic Disease; Double-Blind Method; Enalapril; Endothelium, Vascular; Exercise Tolerance; Female; Heart Failure; Humans; Indoles; Male; Middle Aged; Renin-Angiotensin System

Trandolapril is a newly developed angiotensin converting enzyme inhibitor (ACEI) whose characteristic is that it undergoes hepatic excretion. ACEI appears to have a specific reno-protective and antiproteinuric role in patients with chronic glomerulonephritis(CGN). Although renally excreted ACEI tend to accumulate and cause side-effects in patients with renal dysfunction, the pharmacokinetics of trandolapril were not affected by renal dysfunction. We compared the effect of other renally excreted ACEI with those of trandolapril on serum creatinine (s-Cr), creatinine clearance(Ccr), proteinuria and total protein(TP) in CGN patients who switched from another ACEI to trandolapril. Twelve hypertensive patients with chronic renal failure(nine males and three females, ranging from 30 to 72 years of age) who were treated by other renally excreted ACEIs for long periods(2 to 8 years) with some effects on proteinuria and renal function, were enrolled in the present study. After ACEI therapy, s-Cr had decreased(2.09 to 1.80 mg/dl, p < 0.01) as well as proteinuria(1.65 to 0.71 g/day, p < 0.01). A single daily oral dose of 1 mg of trandolapril was administered to these patients regardless of their blood pressure status and renal functions. After change to trandolapril therapy, s-Cr(2.25 to 2.06 mg/dl, p < 0.01) and urinary protein(1.82 to 1.34 g/day, p < 0.05) significantly decreased. On the contrary, both Ccr and TP significantly increased at the level of 39.4 to 44.4 ml/min(p < 0.05) and 6.80 to 7.02 g/dl (p < 0.01), respectively. No apparent side effects, such as hyperkalemia, hyponatremia, anemia or worsening of the existing renal dysfunction except for coughing, were observed in these patients. Furthermore, none of the 12 patients treated with trandolapril required discontinuation of the compound. In conclusion, it was shown from this study that trandolapril is effective for the treatment of hypertensive patients with renal insufficiency irrespective of the original diseases. Thus, it can be envisaged that trandolapril is one of the most appropriate agents compared to other renally excreted ACEI for these patients with renal insufficiency. We recommend the change from other ACEIs to trandolapril, when renal dysfunction might be due to ACEI accumulation.

Topics: Adult; Aged; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Chronic Disease; Female; Glomerulonephritis; Humans; Hypertension, Renal; Indoles; Male; Metabolic Clearance Rate; Middle Aged; Proteinuria; Renal Insufficiency

To examine the effects of drug treatment on laboratory exercise tests in relation to measures of daily activity in patients with chronic heart failure.. University teaching hospital.. 18 patients with mild to moderate chronic heart failure (New York Heart Association functional class II-III) and 10 age matched healthy controls.. Assessments were made before and after 12 weeks of vasodilator drug treatment. Exercise capacity was measured during two different types of treadmill exercise, one using a ramp protocol and the other a fixed work load. Corridor walk tests at three self selected speeds were also undertaken and measures of customary activity assessed from pedometer scores.. Exercise times were significantly increased from baseline (P < 0.01) with both treadmill protocols after 12 weeks of drug treatment, with a positive correlation between the duration of treadmill exercise for both protocols (r = 0.69, P < 0.01). Corridor walk tests of 100 m at a self selected slow speed also improved (P < 0.02) but these did not correlate with the changes in treadmill exercise time. The pedometer scores of the patients with heart failure were greatly reduced compared with those of the controls (258 (45) x 10(2) v 619 (67) x 10(2) steps/week, P < 0.001) and after 12 weeks of treatment were unchanged (261 (42) x 10(2) steps/week).. These data confirm the need to use different exercise protocols when assessing the benefits of drug treatment in patients with chronic heart failure. Treatments that seem effective with conventional laboratory based exercise tests may not improve daily activities. This may reflect a failure of apparently successful treatment and should be considered when interpreting clinical trials.

Topics: Activities of Daily Living; Aged; Angiotensin-Converting Enzyme Inhibitors; Captopril; Chronic Disease; Deoxyepinephrine; Dopamine Agonists; Exercise Test; Exercise Tolerance; Female; Heart Failure; Humans; Indoles; Isosorbide Dinitrate; Male; Middle Aged; Single-Blind Method; Treatment Failure; Vasodilator Agents

Changes in heat shock protein (Hsp) 60 of the viable left ventricular muscle (viable LV) after myocardial infarction in rats and the effect of the angiotensin I-converting enzyme inhibitor (ACEI) trandolapril were examined. Myocardial infarction was induced in rats by ligation of the left coronary artery. The coronary artery-ligated (CAL) and sham-operated (Sham) rats were orally treated with 3 mg/kg/d trandolapril from the 2nd to 8th week after surgery. Hemodynamic parameters and tissue weights of the left and right ventricles of the animals at the 8th week after CAL (8w-CAL rats) showed signs indicating chronic heart failure. An increase in Hsp60 content, a decrease in mitochondrial oxygen consumption rate (OCR), and an increase in the mitochondrial thiobarbiturate-reacting substance (TRS) of the viable LV were detected. Eight weeks after CAL. Long-term treatment of the CAL rats with trandolapril improved the hemodynamic parameters, attenuated the CAL-induced increase in Hsp60 content, the decrease in mitochondrial OCR, and the increase in the mitochondrial TRS content of the viable LV at the 8th week after myocardial infarction. The increase in Hsp60 content was closely related to the decrease in the mitochondrial OCR and to a rise in the LVEDP of the CAL animal at the 8th week after myocardial infarction. These results suggest that a series of pathophysiological alterations, including a reduction in mitochondrial function, appearance of reactive oxygen stress, and production of Hsp60 is involved in the development of cardiac failure and that trandolapril is beneficial for preventing these alterations.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Blood Pressure; Chaperonin 60; Chronic Disease; Disease Models, Animal; Heart; Heart Failure; Heart Rate; Indoles; Male; Mitochondria, Heart; Myocardial Infarction; Myocardium; Oxidative Stress; Oxygen Consumption; Rats; Rats, Wistar; Thiobarbituric Acid Reactive Substances; Time Factors; Ventricular Function, Left; Ventricular Remodeling

A 48-year-old African-American woman with both sickle cell anemia and chronic pain was treated with a hydrophobic angiotensin I-converting enzyme (ACE) inhibitor. This resulted in the complete resolution of her pain. When the ACE inhibitor was deliberately stopped, her pain recurred, only to cease again after the ACE inhibitor was deliberately resumed. The activation of ACE may be an early step in the arterial vaso-occlusion typical of sickle cell disease.

Topics: Anemia, Sickle Cell; Angiotensin-Converting Enzyme Inhibitors; Black or African American; Cell Hypoxia; Chronic Disease; Female; Gene Frequency; Genotype; Humans; Indoles; Middle Aged; Pain; Peptidyl-Dipeptidase A; Vasoconstriction

Hypertension is present in nearly 80% of dialysis patients yet adequately controlled in less than half. We designed a stepped antihypertensive regimen using long-acting antihypertensives (trandolapril, atenolol and amlodipine) administered thrice a week (TIW) after each hemodialysis, and compared blood pressure (BP) control, medication cost and pill burden to each patient's prior daily antihypertensive prescriptions.. Patients were continued on their daily medications, pre-dialysis sitting BP was measured and a 44-hour interdialytic ambulatory BP monitoring (ABPM) was obtained. Then, their medications were stopped and replaced with trandolapril (2 mg TIW). Atenolol and/or amlodipine were also given TIW if the patients had any member of these classes of drugs as part of their daily regimen. Medications were titrated every 2 weeks to achieve a pre-dialysis mean arterial pressure (MAP) of <107 mm Hg. After 2 consecutive weeks with a pre-dialysis MAP of <107 mm Hg, a second 44-hour ABPM was obtained.. Ten patients completed the study. A persistent MAP of <107 was maintained in all 10 patients after conversion to TIW dosing. The systolic BP decreased from 122.2 +/- 7.1 to 116.4 +/- 11.6, and the diastolic BP decreased from 75.3 +/- 10.4 to 70.4 +/- 11.4 mm Hg. Pill burden and cost of medications were also significantly less.. This pilot study found that ACE inhibitor-based, directly observed TIW therapy to be effective in hemodialysis patients with mild to moderate hypertension. Larger trials of directly observed therapy for hypertension in dialysis patients are warranted.

Topics: Adrenergic beta-Antagonists; Adult; Aged; Amlodipine; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Atenolol; Blood Pressure; Calcium Channel Blockers; Chronic Disease; Delayed-Action Preparations; Drug Administration Schedule; Drug Therapy, Combination; Female; Humans; Hypertension; Indoles; Kidney Diseases; Male; Middle Aged; Pilot Projects; Renal Dialysis; Severity of Illness Index; Treatment Outcome

Patients with chronic kidney disease are at increased risk for cardiovascular morbidity and mortality. We assessed the association between albuminuria and the risks for death and cardiovascular events among patients with stable coronary disease.. We studied patients enrolled in the Prevention of Events with an ACE inhibitor (PEACE) trial, in which patients with chronic stable coronary disease and preserved systolic function were randomized to trandolapril or placebo and followed up for a median of 4.8 years. The urinary albumin to creatinine ratio (ACR) assessed in a core laboratory in 2977 patients at baseline and in 1339 patients at follow-up (mean 34 months) was related to estimated glomerular filtration rate and outcomes. The majority of patients (73%) had a baseline ACR within the normal range (<17 mug/mg for men and <25 mug/mg for women). Independent of the estimated glomerular filtration rate and other baseline covariates, a higher ACR, even within the normal range, was associated with increased risks for all-cause mortality (P<0.001) and cardiovascular death (P=0.01). The effect of trandolapril therapy on outcomes was not modified significantly by the level of albuminuria. Nevertheless, trandolapril therapy was associated with a significantly lower mean follow-up ACR (12.5 versus 14.6 mug/mg, P=0.0002), after adjustment for baseline ACR, time between collections, and other covariates. An increase in ACR over time was associated with increased risk of cardiovascular death (hazard ratio per log ACR 1.74, 95% CI 1.08 to 2.82).. Albuminuria, even in low levels within the normal range, is an independent predictor of cardiovascular and all-cause mortality.

Topics: Aged; Albuminuria; Angiotensin-Converting Enzyme Inhibitors; Chronic Disease; Coronary Disease; Creatinine; Death; Female; Follow-Up Studies; Glomerular Filtration Rate; Humans; Indoles; Kidney Diseases; Male; Middle Aged; Predictive Value of Tests; Randomized Controlled Trials as Topic; Risk Factors; Survival Rate

Specific endothelin A (ET(A))-receptor blockade and ACE inhibition attenuate chronic transplant nephropathy (CTN) in the 'Fisher-to-Lewis' rat model. It is unknown (i) which of both pharmacological interventions attenuates CTN more effectively and (ii) whether combination therapy exerts additive nephroprotection.. We compared (i) the effects of specific ET(A)-receptor blockade with LU 302146 (30 mg/kg bw/day) and ACE inhibition with trandolapril (0.3 mg/kg bw/day) and (ii) the effect of a combination therapy of both drugs on the development of CTN. Kidneys of Fisher rats were orthotopically grafted to Lewis rats. Untreated 'Fisher-to-Lewis' allografts served as controls (TX). All animals received low-dose cyclosporin A (1.5 mg/kg body weight) for 10 days post-transplant to inhibit early acute rejection episodes. The duration of the experiment was 36 weeks. Blood pressure (BP) was measured every other week by tail plethysmography. Indices of glomerulosclerosis (GS), tubulointerstitial and vascular damage, number of glomeruli, total glomerular volume and mean glomerular volume were measured using morphometric and stereological techniques, respectively. Albuminuria, blood chemistry and haematology were measured at the end of the experiment.. LU 302146 did not affect systolic BP. In contrast, trandolapril and combination treatment significantly reduced systolic BP. Histological signs of CTN were almost completely prevented by LU 302146 and trandolapril as compared to TX, e.g. GS=0.8+/-0.08 and 0.9+/-0.20 vs 1.8+/-0.21* (arbitrary unit; *P<0.001 vs treated groups). Allograft weight was significantly lower in treated vs TX animals. Trandolapril and combination therapy, but not LU 302146 alone, abrogated glomerular hypertrophy, i.e. mean glomerular volume: TX 2.22+/-0.43, trandolapril 1.61+/-0.38**, LU 302146 2.22+/-0.11, trandolapril+LU 302146 1.78+/-0.28* (microm(3); *P<0.05 vs control and LU 302146, **P<0.01 vs control and LU 302146). Albuminuria was lower in treated compared to TX animals. Combination therapy did not confer additional benefit compared to the respective monotherapies.. We conclude that ET(A)-receptor blockade abrogates GS, tubulointerstitial and vascular damage in the 'Fisher-to-Lewis' model of CTN to a similar extent as ACE inhibition. However, only ACE inhibition inhibits glomerular hypertrophy. In contrast to ACE inhibition, the effect of ET(A)-receptor blockade is independent of BP. This finding is consistent with the notion that ET(A)-receptor mediated events play a partly BP-independent role in the genesis of CTN. Combination therapy exerts no additive nephroprotection.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Pressure; Chronic Disease; Drug Therapy, Combination; Endothelin Receptor Antagonists; Indoles; Kidney; Kidney Diseases; Kidney Transplantation; Male; Rats; Rats, Inbred F344; Rats, Inbred Lew; Receptor, Endothelin A

Persistent dry cough is well known as the most common side-effect of angiotensin-converting enzyme (ACE) inhibitors. We examined the relationship between a cough and ACE gene polymorphism, plasma bradykinin (BK), substance P (SP) and ACE inhibitor concentrations in patients with hypertension or chronic nephritis. First, ACE genotyping was carried out in 96 patients, 42 with coughs and 54 without coughs, which had been treated with various kinds of ACE inhibitors. However, no significant difference in the ACE genotypes was observed between the two groups. Second, the plasma concentrations of BK, SP and ACE inhibitor were measured in 12 patients, which were treated with trandolapril at a daily dose of 1 mg for 4-33 weeks. In 3 patients, the cough was induced during the trandolapril therapy, while it was induced not in 9 patients. The plasma levels of BK and SP did not significantly change after trandolapril administration in the patients with and without coughs. Between the two groups, there were no significant differences in the plasma levels of BK and SP either before or after the trandolapril therapy. Also the plasma concentrations of trandolapril and trandolaprilat, the active metabolite of trandolapril, did not significantly differ between the two groups. These results suggest that there is no significant relationship between the ACE inhibitor-induced cough and ACE gene polymorphism, plasma BK, SP and ACE inhibitor concentrations in patients with hypertension or chronic nephritis.

Topics: Aged; Angiotensin-Converting Enzyme Inhibitors; Bradykinin; Chronic Disease; Cough; Female; Humans; Hypertension; Indoles; Male; Middle Aged; Nephritis; Peptidyl-Dipeptidase A; Polymorphism, Genetic; Substance P

1. Inhibition of the renin-angiotensin system (RAS) improves symptoms and prognosis in heart failure. The experimental basis for these benefits remains unclear. We examined the effects of inhibition of ACE or blockade of angiotensin II type 1 (AT1) receptor on the haemodynamics, cardiac G-proteins, and collagen synthesis of rats with coronary artery ligation (CAL), a model in which chronic heart failure (CHF) is induced. 2. Rats were orally treated with the ACE inhibitor trandolapril (3 mg kg(-1) day(-1)) or the AT1 receptor blocker L-158809 (1 mg kg(-1) day(-1)) from the 2nd to 8th week after CAL. CAL resulted in decreases in the left ventricular systolic pressure and its positive and negative dP/dt, an increase in the left ventricular end-diastolic pressure, and the rightward shift of the left ventricular pressure-volume curve. Long-term treatment with either drug improved these signs of CHF to a similar degree. 3. Cardiac Gsalpha and Gqalpha protein levels decreased, whereas the level of Gialpha protein increased in the animals with CHF. Long-term treatment with trandolapril or L-158809 attenuated the increase in the level of cardiac Gialpha protein of the animals with CHF without affecting Gsalpha and Gqalpha protein levels. Cardiac collagen content of the failing heart increased, whose increase was blocked by treatment with either drug. 4. Exogenous angiotensin I stimulated collagen synthesis in cultured cardiac fibroblasts, whose stimulation was attenuated by either drug. 5. These results suggest that blockade of the RAS, at either the receptor level or the synthetic enzyme level, may attenuate the cardiac fibrosis that occurs after CAL and thus affect the remodelling of the failing heart.

Topics: Angiotensin I; Angiotensin II; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Body Weight; Chronic Disease; Collagen; Dose-Response Relationship, Drug; Fibroblasts; GTP-Binding Proteins; Heart; Heart Failure; Heart Septum; Heart Ventricles; Hemodynamics; Imidazoles; Indoles; Lung; Male; Organ Size; Peptidyl-Dipeptidase A; Rats; Rats, Wistar; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Tetrazoles

1 Calcium transport activity of isolated cardiac sarcoplasmic reticulum (SR) including Ca2+ uptake and release is decreased in animals with chronic heart failure (CHF) following myocardial infarction. The present study was undertaken to determine whether an angiotensin converting enzyme (ACE) inhibitor, trandolapril, improves cardiac sarcoplasmic reticular function in animals with CHF following myocardial infarction. 2 CHF was induced by left coronary artery ligation in rats, which resulted in an infarction of approximately 45% of the left ventricle. Aortic flow and cardiac output index were decreased, and left ventricular end-diastolic pressure was increased 8 weeks after the operation, suggesting the development of CHF. 3 The developed force transients of cardiac skinned fibres of the rats with CHF were decreased when the skinned fibre was preloaded for 0.25-1 min with 10(-5) M Ca2+ (48-88%) and when preloaded with 10(-6) M Ca2+ and then exposed to 0.1-1 mM caffeine (45-93%). 4 The [3H]-ryanodine-binding activity in SR-enriched fractions was reduced by 23% in the CHF group. These results suggest that the amount of Ca2+ released from SR is decreased due to a reduced rate of SR Ca2+ uptake and a downregulation of the SR Ca2+-release channel. 5 Rats were treated orally with 3 mg kg(-1) day(-1) trandolapril from the 2nd to the 8th week after the coronary artery ligation. Treatment with trandolapril attenuated the reduction in aortic flow and cardiac output index and the increase in left ventricular end-diastolic pressure, and improved the developed force transients of the skinned fibre of the animal with CHF without causing a reduction of infarct size. Treatment with trandolapril also attenuated the reduction in ryanodine receptor density in the viable left ventricle of the rat with CHF. 6 It is concluded that long-term treatment with trandolapril attenuates cardiac SR dysfunction in rats with CHF and that the mechanism underlying this effect is, at least in part, attributed to prevention of downregulation of Ca2+ release channel.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Calcium; Cardiac Output, Low; Chronic Disease; Heart; Hemodynamics; Indoles; Male; Myocardial Infarction; Myocardium; Rats; Rats, Wistar; Ryanodine; Sarcoplasmic Reticulum

To investigate clinical efficacy of angiotensin-converting enzyme inhibitor trandolapril and its effects on myocardial function.. 20 patients with ischemic heart disease (IHD) aged 33-74 years with chronic cardiac failure NYHA class II-IV. 4 of them survived myocardial infarction. In addition to the routine tests, the patients underwent echocardiography, radionuclide ventriculography. Trandolapril was given once a day for 28 days in a dose 2 mg, then a repeat examination was performed.. Trandolapril produced a subjective effect in 80% of patients. There was also improvement of hemodynamic parameters, an increase in the ejection fraction, sensitivity to nitroglycerin, decline of asynchrony. The drug was well tolerated.. Trandolapril (Gopten) is effective in IHD patients with chronic cardiac failure.

Topics: Adult; Aged; Angiotensin-Converting Enzyme Inhibitors; Chronic Disease; Drug Evaluation; Female; Heart Failure; Humans; Indoles; Male; Middle Aged; Myocardial Contraction; Myocardial Ischemia