imidapril and Heart-Failure

Imidapril (Tanatril), through its active metabolite imidaprilat, acts as an ACE inhibitor to suppress the conversion of angiotensin I to angiotensin II and thereby reduce total peripheral resistance and systemic blood pressure (BP). In clinical trials, oral imidapril was an effective antihypertensive agent in the treatment of mild to moderate essential hypertension. Some evidence suggests that imidapril also improves exercise capacity in patients with chronic heart failure (CHF) and reduces urinary albumin excretion rate in patients with type 1 diabetes mellitus. Imidapril was well tolerated, with a lower incidence of dry cough than enalapril or benazepril, and is a first choice ACE inhibitor for the treatment of mild to moderate essential hypertension.

Topics: Angiotensin-Converting Enzyme Inhibitors; Clinical Trials as Topic; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Heart Failure; Humans; Hypertension; Imidazolidines; Molecular Structure; Treatment Outcome

To review whether brain natriuretic peptides (BNP) can be used as a surrogate for the traditional methods of assessing functional status in interventional studies of patients with left ventricular systolic dysfunction (LVSD).. The traditional methods for assessing functional status including New York Heart Association (NYHA) class, exercise intolerance and quality of life were reviewed in relation to BNP measurements in patients with LVSD. A meta-analysis of four studies evaluating BNP levels versus exercise peak oxygen uptake or 6-minute walking distance showed a significant correlation, but a low R-value of -0.59. Studies using BNP levels for optimisation of heart failure therapy showed conflicting results concerning the correlation between the functional improvement and changes in BNP levels. Conflicting results were also found concerning the utility of BNP levels as a surrogate to predict efficacy of the various anti-congestive therapies on heart failure outcome.. The results of the studies examining BNP measurement as a surrogate for functional status and drug efficacy in patients with LVSD are conflicting. Further studies are necessary to settle the place of BNP measurement as surrogate marker for exercise tolerance, NYHA classification and in assessing efficacy of different interventions in the clinical trials.

Topics: Angiotensin-Converting Enzyme Inhibitors; Biomarkers; Carbazoles; Carvedilol; Clinical Trials as Topic; Data Collection; Drug Administration Schedule; Enalapril; Exercise Test; Exercise Tolerance; Health Status; Heart Failure; Humans; Imidazolidines; Meta-Analysis as Topic; Metoprolol; Natriuretic Peptide, Brain; Propanolamines; Quality of Life; Statistics as Topic; Treatment Outcome; Ventricular Dysfunction, Left

Imidapril hydrochloride (imidapril) is a long-acting, non-sulfhydryl angiotensin-converting enzyme (ACE) inhibitor, which has been used clinically in the treatment of hypertension, chronic congestive heart failure (CHF), acute myocardial infarction (AMI), and diabetic nephropathy. It has the unique advantage over other ACE inhibitors in causing a lower incidence of dry cough. After oral administration, imidapril is rapidly converted in the liver to its active metabolite imidaprilat. The plasma levels of imidaprilat gradually increase in proportion to the dose, and decline slowly. The time to reach the maximum plasma concentration (T(max)) is 2.0 h for imidapril and 9.3 h for imidaprilat. The elimination half-lives (t(1/2)) of imidapril and imidaprilat is 1.7 and 14.8 h, respectively. Imidapril and its metabolites are excreted chiefly in the urine. As an ACE inhibitor, imidaprilat is as potent as enalaprilat, an active metabolite of enalapril, and about twice as potent as captopril. In patients with hypertension, blood pressure was still decreased at 24 h after imidapril administration. The antihypertensive effect of imidapril was dose-dependent. The maximal reduction of blood pressure and plasma ACE was achieved with imidapril, 10 mg once daily, and the additional effect was not prominent with higher doses. When administered to patients with AMI, imidapril improved left ventricular ejection fraction and reduced plasma brain natriuretic peptide (BNP) levels. In patients with mild-to-moderate CHF [New York Heart Association (NYHA) functional class II-III], imidapril increased exercise time and physical working capacity and decreased plasma atrial natriuretic peptide (ANP) and BNP levels in a dose-related manner. In patients with diabetic nephropathy, imidapril decreased urinary albumin excretion. Interestingly, imidapril improved asymptomatic dysphagia in patients with a history of stroke. In the same patients it increased serum substance P levels, while the angiotensin II receptor antagonist losartan was ineffective. These studies indicate that imidapril is a versatile ACE inhibitor. In addition to its effectiveness in the treatment of hypertension, CHF, and AMI, imidapril has beneficial effects in the treatment of diabetic nephropathy and asymptomatic dysphagia. Good tissue penetration and inhibition of tissue ACE by imidapril contributes to its effectiveness in preventing cardiovascular complications of hypertension. The major advantages of imidapril are

Topics: Angiotensin-Converting Enzyme Inhibitors; Arrhythmias, Cardiac; Cardiomegaly; Cardiovascular Diseases; Clinical Trials as Topic; Deglutition Disorders; Heart Failure; Humans; Hypertension; Imidazoles; Imidazolidines; Kidney Failure, Chronic; Myocardial Ischemia

Angiotensin II and insulin resistance (IR) have clinical implications in the pathophysiology of chronic heart failure (CHF). However, it is still unclear whether the combination of an angiotensin-receptor blocker and angiotensin-converting enzyme inhibitor (ACEI) improves IR in CHF patients who do not receive β-blockers. Thus, the aim of the present study was to evaluate the effects of losartan on glucose metabolism and inflammatory cytokines in CHF patients treated with ACEI but not β-blockers.. The effect of losartan treatment for 16 weeks on IR was analyzed in 16 CHF patients in a randomized crossover trial. Insulin level and homeostasis model IR index (HOMA-IR) decreased significantly (P<0.05), but fasting plasma glucose did not change significantly. Serum tumor necrosis factor (TNF)-α, interleukin (IL)-6, and monocyte chemoattractant protein (MCP)-1 levels were significantly decreased with losartan (P<0.05). Furthermore, the changes in IL-6 and MCP-1 levels were significantly correlated with the reduction in HOMA-IR (P<0.05), but the change in TNF-α levels was not significantly correlated.. The addition of losartan to ACEI therapy improved IR and decreased inflammatory cytokines in CHF patients who did not receive β-blockers.

Topics: Adrenergic beta-Antagonists; Aged; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Biomarkers; Blood Glucose; Chemokine CCL2; Chronic Disease; Cross-Over Studies; Drug Therapy, Combination; Enalapril; Female; Heart Failure; Humans; Imidazolidines; Inflammation Mediators; Insulin; Insulin Resistance; Interleukin-6; Japan; Lisinopril; Losartan; Male; Middle Aged; Time Factors; Treatment Outcome; Tumor Necrosis Factor-alpha

The clinical efficacy and safety of imidapril were evaluated in dogs that presented with mild to severe congestive heart failure (New York Heart Association stage II to IV) by comparing the success rate of imidapril with a positive control by a non-inferiority approach.. This good, clinical practice compliant, multicentre study (EFFIC study) enrolled 142 client-owned dogs and was conducted in 20 locations in France, Belgium and Germany. Dogs of various breed, age and weight were included in the study. These dogs were randomised into two groups that were treated for 84 days with either the test product, imidapril, or the positive control, benazepril, and followed up in parallel over this period. Both treatments were administered at a dose of 0.25 mg/kg once a day with the possibility of doubling this dose to 0.5 mg/kg if considered necessary from a clinical point of view. In addition, concomitant treatment was given to dogs presenting with pulmonary oedema and/or ascites, supraventricular tachyarrhythmia and/or dilated cardiomyopathy. The evolution of the New York Heart Association stage and the "functional signs" score were evaluated as primary efficacy criteria.. The success rate in the imidapril group was 66 compared with 68 per cent in the benazepril group. Regarding safety, 35 dogs in each group experienced at least one adverse event. Nine dogs in each group experienced at least one serious adverse event. The difference between these results was not statistically significant.. Imidapril is as efficacious and safe as the reference product, benazepril.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Benzazepines; Dog Diseases; Dogs; Female; Heart Failure; Imidazolidines; Male; Safety; Severity of Illness Index; Treatment Outcome

To determine dose-related clinical and neurohumoral effects of angiotensin-converting enzyme (ACE) inhibitors in patients with chronic heart failure (CHF), we conducted a double-blind, placebo-controlled, randomized study of three doses (2.5 mg, 5 mg and 10 mg) of the long-acting ACE inhibitor imidapril.. The ACE inhibitors have become a cornerstone in the treatment of CHF, but whether high doses are more effective than low doses has not been fully elucidated, nor have the mechanisms involved in such a dose-related effect.. In a parallel group comparison, the effects of three doses of imidapril were examined. We studied 244 patients with mild to moderate CHF (New York Heart Association class II-III: +/-80%/20%), who were stable on digoxin and diuretics. Patients were treated for 12 weeks, and the main end points were exercise capacity and plasma neurohormones.. At baseline, the four treatment groups were well-matched for demographic variables. Of the 244 patients, 25 dropped out: 3 patients died, and 9 developed progressive CHF (3/182 patients on imidapril vs. 6/62 patients on placebo, p < 0.05). Exercise time increased 45 s in the 10-mg group (p = 0.02 vs. placebo), but it did not significantly change in the 5-mg (+16 s), and 2.5-mg (+11 s) imidapril group, compared to placebo (+3 s). Physical working capacity also increased in a dose-related manner. Plasma brain and atrial natriuretic peptide decreased (p < 0.05 for linear trend), while (nor)epinephrine, aldosterone and endothelin were not significantly affected. Renin increased in a dose-related manner, but plasma ACE activity was suppressed similarly (+/-60%) on all three doses.. Already within 3 months after treatment initiation, high-dose ACE inhibition (with imidapril) is superior to low-dose. This is reflected by a more pronounced effect on exercise capacity and some of the neurohormones, but it does not appear to be related to the extent of suppression of plasma ACE.

Topics: Adult; Aged; Angiotensin-Converting Enzyme Inhibitors; Atrial Natriuretic Factor; Double-Blind Method; Exercise Test; Female; Heart Failure; Humans; Imidazoles; Imidazolidines; Male; Middle Aged; Natriuretic Peptide, Brain; Renin-Angiotensin System

To study the haemodynamic profile and tolerability of imidapril, a new long-acting ACE inhibitor, and to investigate the effect of inhibition of circulating ACE on blood pressure in patients with stable chronic heart failure.. Twenty-four patients with stable, chronic heart failure (New York Heart Association (NYHA) functional Class II-III) were randomised to receive either 2.5 mg or 5 mg imidapril. Other vasodilators were withheld for > or = 5 half-lives. Blood pressure and ACE activity were carefully monitored for 24 h after dosing.. Both 2.5 mg and 5 mg imidapril decreased systolic blood pressure, while diastolic blood pressure fell only after 5 mg imidapril. The two doses produced a significant and similar inhibition of circulating (serum) ACE. No serious adverse effects were observed, although symptomatic hypotension occured in 1 patient (5 mg). The decrease in blood pressure was not related to baseline ACE activity, serum sodium or serum creatinine concentration.. Imidapril significantly lowered systolic blood pressure and was well tolerated. The difference in the first dose response to the two doses with respect to diastolic blood pressure suggests that this haemodynamic effect of ACE-inhibition is not related to inhibition of circulating ACE.

Topics: Administration, Oral; Aged; Analysis of Variance; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Blood Pressure; Chronic Disease; Double-Blind Method; Female; Heart Failure; Humans; Imidazoles; Imidazolidines; Male; Middle Aged

Symptoms of cancer cachexia (CC) include fatigue, shortness of breath, and impaired exercise capacity, which are also hallmark symptoms of heart failure (HF). Herein, we evaluate the effects of drugs commonly used to treat HF (bisoprolol, imidapril, spironolactone) on development of cardiac wasting, HF, and death in the rat hepatoma CC model (AH-130).. Tumour-bearing rats showed a progressive loss of body weight and left-ventricular (LV) mass that was associated with a progressive deterioration in cardiac function. Strikingly, bisoprolol and spironolactone significantly reduced wasting of LV mass, attenuated cardiac dysfunction, and improved survival. In contrast, imidapril had no beneficial effect. Several key anabolic and catabolic pathways were dysregulated in the cachectic hearts and, in addition, we found enhanced fibrosis that was corrected by treatment with spironolactone. Finally, we found cardiac wasting and fibrotic remodelling in patients who died as a result of CC. In living cancer patients, with and without cachexia, serum levels of brain natriuretic peptide and aldosterone were elevated.. Systemic effects of tumours lead not only to CC but also to cardiac wasting, associated with LV-dysfunction, fibrotic remodelling, and increased mortality. These adverse effects of the tumour on the heart and on survival can be mitigated by treatment with either the β-blocker bisoprolol or the aldosterone antagonist spironolactone. We suggest that clinical trials employing these agents be considered to attempt to limit this devastating complication of cancer.

Topics: Adrenergic beta-1 Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Bisoprolol; Body Composition; Body Weight; Cachexia; Glycogen Synthase Kinase 3; Heart Failure; Imidazolidines; Liver Neoplasms; Mineralocorticoid Receptor Antagonists; Myocytes, Cardiac; Myosin Heavy Chains; Rats; Signal Transduction; Spironolactone; Survival Analysis; Ventricular Dysfunction, Left; Wasting Syndrome

This study was designed to test the hypothesis that blockade of the renin-angiotensin system improves cardiac function in congestive heart failure by preventing changes in gene expression of sarcoplasmic reticulum (SR) proteins. We employed rats with myocardial infarction (MI) to examine effects of an angiotensin-converting enzyme inhibitor, imidapril, on SR Ca(2+) transport, protein content, and gene expression. Imidapril (1 mg.kg(-1).day(-1)) was given for 4 wk starting 3 wk after coronary artery occlusion. Infarcted rats exhibited a fourfold increase in left ventricular end-diastolic pressure, whereas rates of pressure development and decay were decreased by 60 and 55%, respectively. SR Ca(2+) uptake and Ca(2+) pump ATPase, as well as Ca(2+) release and ryanodine receptor binding activities, were depressed in the failing hearts; protein content and mRNA levels for Ca(2+) pump ATPase, phospholamban, and ryanodine receptor were also decreased by approximately 55-65%. Imidapril treatment of infarcted animals improved cardiac performance and attenuated alterations in SR Ca(2+) pump and Ca(2+) release activities. Changes in protein content and mRNA levels for SR Ca(2+) pump ATPase, phospholamban, and ryanodine receptor were also prevented by imidapril treatment. Beneficial effects of imidapril on cardiac function and SR Ca(2+) transport were not only seen at different intervals of MI but were also simulated by another angiotensin-converting enzyme inhibitor, enalapril, and an ANG II receptor antagonist, losartan. These results suggest that blockade of the renin-angiotensin system may increase the abundance of mRNA for SR proteins and, thus, may prevent the depression in SR Ca(2+) transport and improve cardiac function in congestive heart failure due to MI.

Topics: Animals; Antihypertensive Agents; Calcium; Calcium-Transporting ATPases; Cardiomegaly; Enalapril; Gene Expression; Heart Failure; Imidazolidines; Losartan; Male; Myocardial Infarction; Rats; Rats, Sprague-Dawley; Ryanodine Receptor Calcium Release Channel; Sarcoplasmic Reticulum; Sarcoplasmic Reticulum Calcium-Transporting ATPases; Tritium; Ventricular Pressure

1. Adenosine 5'-triphosphate (ATP) is known to augment cardiac contractile activity and cause an increase in intracellular Ca(2+) concentration ([Ca(2+)](i)) in isolated cardiomyocytes. However, no information regarding the ATP-mediated signal transduction in the myocardium in congestive heart failure (CHF) is available. 2. CHF due to myocardial infarction (MI) in rats was induced by the occlusion of the left coronary artery for 8 weeks. The positive inotropy due to ATP was depressed in failing hearts. Treatment of 3 weeks infarcted animals with imidapril (1 mg kg(-1) day(-1)) for a period of 5 weeks improved the left ventricle function and decreased the attenuation of inotropic response to ATP. 3. ATP-induced increase in [Ca(2+)](i) was significantly depressed in cardiomyocytes isolated from the failing heart and this change was partially attenuated by imidapril treatment. However, the binding characteristics of (35)S-labeled adenosine 5'-(gamma-thio) triphosphate in sarcolemma isolated from the failing heart remained unaltered. 4. ATP-induced increase in [Ca(2+)](i) was depressed by verapamil and cibacron blue in both control and failing heart cardiomyocytes; however, the ATP response in the failing hearts, unlike the control preparations, was not decreased by ryanodine. This insensitivity to ryanodine was attenuated by imidapril treatment. 5. Treatment of infarcted rats with enalapril and losartan produced effects similar to imidapril. 6. These findings indicate that the positive inotropic response to ATP and ATP-induced increase in [Ca(2+)](i) in cardiomyocytes are impaired in heart failure. Furthermore, blockade of renin angiotensin system prevented the impairment of the ATP-mediated inotropic and [Ca(2+)](i) responses in the failing heart.

Topics: Adenosine Triphosphate; Animals; Heart Failure; Imidazolidines; Intracellular Fluid; Male; Myocardial Contraction; Myocardial Infarction; Rats; Rats, Sprague-Dawley

The activities of both sarcolemmal (SL) Na(+)-K(+)-ATPase and Na(+)/Ca(2+) exchanger, which maintain the intracellular cation homeostasis, have been shown to be depressed in heart failure due to myocardial infarction (MI). Because the renin-angiotensin system (RAS) is activated in heart failure, this study tested the hypothesis that attenuation of cardiac SL changes in congestive heart failure (CHF) by angiotensin-converting enzyme (ACE) inhibitors is associated with prevention of alterations in gene expression for SL Na(+)-K(+)-ATPase and Na(+)/Ca(2+) exchanger. CHF in rats due to MI was induced by occluding the coronary artery, and 3 wk later the animals were treated with an ACE inhibitor, imidapril (1 mg.kg(-1).day(-1)), for 4 wk. Heart dysfunction and cardiac hypertrophy in the infarcted animals were associated with depressed SL Na(+)-K(+)-ATPase and Na(+)/Ca(2+) exchange activities. Protein content and mRNA levels for Na(+)/Ca(2+) exchanger as well as Na(+)-K(+)-ATPase alpha(1)-, alpha(2)- and beta(1)-isoforms were depressed, whereas those for alpha(3)-isoform were increased in the failing heart. These changes in SL activities, protein content, and gene expression were attenuated by treating the infarcted animals with imidapril. The beneficial effects of imidapril treatment on heart function and cardiac hypertrophy as well as SL Na(+)-K(+)-ATPase and Na(+)/Ca(2+) exchange activities in the infarcted animals were simulated by enalapril, an ACE inhibitor, and losartan, an angiotensin receptor antagonist. These results suggest that blockade of RAS in CHF improves SL Na(+)-K(+)-ATPase and Na(+)/Ca(2+) exchange activities in the failing heart by preventing changes in gene expression for SL proteins.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Ca(2+) Mg(2+)-ATPase; Gene Expression Regulation; Heart; Heart Failure; Heart Rate; Imidazolidines; Losartan; Male; Rats; Rats, Sprague-Dawley; Renin-Angiotensin System; Sarcolemma; Sodium-Calcium Exchanger; Sodium-Potassium-Exchanging ATPase; Ventricular Function, Right

In order to understand the mechanisms of exercise intolerance and muscle fatigue, which are commonly observed in congestive heart failure, we studied sarcoplasmic reticulum (SR) Ca(2+)-transport in the hind-leg skeletal muscle of rats subjected to myocardial infarction (MI). Sham-operated animals were used for comparison. On one hand, the maximal velocities (Vmax) for both SR Ca(2+)-uptake and Ca(2+)-stimulated ATPase activities in skeletal muscle of rats at 8 weeks of MI were higher than those of controls. On the other hand, the Vmax values for both SR Ca(2+)-uptake and Ca(2+)-stimulated ATPase activities were decreased significantly at 16 weeks of MI when compared with controls. These alterations in Ca(2+)-transport activities were not associated with any change in the affinity (1/Ka) of the SR Ca(2+)-pump for Ca2+. Furthermore, the stimulation of SR Ca(2+)-stimulated ATPase activity by cyclic AMP-dependent protein kinase was not altered at 8 or 16 weeks of MI when compared with the respective control values. Treatment of 3-week infarcted animals with angiotensin-converting enzyme (ACE) inhibitors such as captopril, imidapril, and enalapril or an angiotensin receptor (AT1R) antagonist, losartan, for a period of 13 weeks not only attenuated changes in left ventricular function but also prevented defects in SR Ca(2+)-pump in skeletal muscle. These results indicate that the skeletal muscle SR Ca(2+)-transport is altered in a biphasic manner in heart failure due to MI. It is suggested that the initial increase in SR Ca(2+)-pump activity in skeletal muscle may be compensatory whereas the depression at late stages of MI may play a role in exercise intolerance and muscle fatigue in congestive heart failure. Furthermore, the improvements in the skeletal muscle SR Ca(2+)-transport by ACE inhibitors may be due to the decreased activity of renin-angiotensin system in congestive heart failure.

Topics: Angiotensin II; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Animals; Apoptosis; Calcium; Calcium-Transporting ATPases; Captopril; Cyclic AMP-Dependent Protein Kinases; Enalapril; Heart Failure; Imidazolidines; Losartan; Male; Muscle, Skeletal; Muscular Atrophy; Myocardial Infarction; Rats; Rats, Sprague-Dawley; Sarcoplasmic Reticulum; Time Factors

Earlier studies have revealed an improvement of cardiac function in animals with congestive heart failure (CHF) due to myocardial infarction (MI) by treatment with angiotensin converting enzyme (ACE) inhibitors. Since heart failure is also associated with attenuated responses to catecholamines, we examined the effects of imidapril, an ACE inhibitor, on the beta-adrenoceptor (beta-AR) signal transduction in the failing heart. Heart failure in rats was induced by occluding the coronary artery, and 3 weeks later the animals were treated with g/(kg x day) (orally) imidapril for 4 weeks. The animals were assessed for their left ventricular function and inotropic responses to isoproterenol. Cardiomyocytes and crude membranes were isolated from the non-ischemic viable left ventricle and examined for the intracellular concentration of Ca2+ [Ca2+]i and beta-ARs as well as adenylyl cyclase (AC) activity, respectively. Animals with heart failure exhibited depressions in ventricular function and positive inotropic response to isoproterenol as well as isoproterenol-induced increase in [Ca2+]i in cardiomyocytes; these changes were attenuated by imidapril treatment. Both beta1-AR receptor density and isoproterenol-stimulated AC activity were decreased in the failing heart and these alterations were prevented by imidapril treatment. Alterations in cardiac function, positive inotropic effect of isoproterenol, beta1-AR density and isoproterenol-stimulated AC activity in the failing heart were also attenuated by treatment with another ACE inhibitor, enalapril and an angiotensin II receptor antagonist, losartan. The results indicate that imidapril not only attenuates cardiac dysfunction but also prevents changes in beta-AR signal transduction in CHF due to MI. These beneficial effects are similar to those of enalapril or losartan and thus appear to be due to blockade of the renin-angiotensin system.

Topics: Adenylyl Cyclases; Angiotensin-Converting Enzyme Inhibitors; Animals; Disease Models, Animal; Enalapril; Heart Failure; Imidazolidines; Isoproterenol; Kinetics; Losartan; Male; Myocardial Infarction; Myocardium; Rats; Rats, Sprague-Dawley; Receptors, Adrenergic, beta; Renin-Angiotensin System; Signal Transduction

Although it is generally accepted that the efficacy of imidapril, an angiotensin-converting enzyme inhibitor, in congestive heart failure (CHF) is due to improvement of hemodynamic parameters, the significance of its effect on gene expression for sarcolemma (SL) and sarcoplasmic reticulum (SR) proteins has not been fully understood. In this study, we examined the effects of long-term treatment of imidapril on mortality, cardiac function, and gene expression for SL Na+/K+ ATPase and Na+ -Ca2+ exchanger as well as SR Ca2+ pump ATPase, Ca2+ release channel (ryanodine receptor), phospholamban, and calsequestrin in CHF due to myocardial infarction. Heart failure subsequent to myocardial infarction was induced by occluding the left coronary artery in rats, and treatment with imidapril (1 mg.kg(-1).day(-1)) was started orally at the end of 3 weeks after surgery and continued for 37 weeks. The animals were assessed hemodynamically and the heart and lung were examined morphologically. Some hearts were immediately frozen at -70 degrees C for the isolation of RNA as well as SL and SR membranes. The mortality of imidapril-treated animals due to heart failure was 31% whereas that of the untreated heart failure group was 64%. Imidapril treatment improved cardiac performance, attenuated cardiac remodeling, and reduced morphological changes in the heart and lung. The depressed SL Na+/K+ ATPase and increased SL Na+-Ca2+ exchange activities as well as reduced SR Ca2+ pump and SR Ca2+ release activities in the failing hearts were partially prevented by imidapril. Although changes in gene expression for SL Na+/K+ ATPase isoforms as well as Na+-Ca2+ exchanger and SR phospholamban were attenuated by treatments with imidapril, no alterations in mRNA levels for SR Ca2+ pump proteins and Ca2+ release channels were seen in the untreated or treated rats with heart failure. These results suggest that the beneficial effects of imidapril in CHF may be due to improvements in cardiac performance and changes in SL gene expression.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Blotting, Northern; Calcium; Calcium-Binding Proteins; Calcium-Transporting ATPases; Calsequestrin; Gene Expression; Heart; Heart Failure; Imidazolidines; Lung; Male; Myocardial Infarction; Myocardium; Rats; Rats, Sprague-Dawley; RNA; Ryanodine Receptor Calcium Release Channel; Sarcolemma; Sarcoplasmic Reticulum; Sarcoplasmic Reticulum Calcium-Transporting ATPases; Sodium-Calcium Exchanger

An 8-yr-old male meerkat (Suricata suricatta) presented with sudden lethargy. A globular-shaped heart associated with pleural effusion on chest thoracic radiographs was consistent with congestive heart failure, and echocardiography was performed under general anesthesia. It revealed an Ebstein anomaly, with mild pericardial effusion and marked right heart enlargement. The animal was treated with imidapril chlorydrate. After 4 mo of treatment, thoracic radiographs still showed right-sided cardiomegaly; however, the animal appeared clinically normal.

Topics: Animals; Antihypertensive Agents; Carnivora; Ebstein Anomaly; Echocardiography; Heart Failure; Imidazolidines; Male; Pericardial Effusion; Treatment Outcome

The activities of cardiac protein kinase C (PKC) were examined in hemodynamically assessed rats subsequent to myocardial infarction (MI). Both Ca(2+)-dependent and Ca(2+)-independent PKC activities increased significantly in left ventricular (LV) and right ventricular (RV) homogenates at 1, 2, 4, and 8 wk after MI was induced. PKC activities were also increased in both LV and RV cytosolic and particulate fractions from 8-wk infarcted rats. The relative protein contents of PKC-alpha, -beta, -epsilon, and -zeta isozymes were significantly increased in LV homogenate, cytosolic (except PKC-alpha), and particulate fractions from the failing rats. On the other hand, the protein contents of PKC-alpha, -beta, and -epsilon isozymes, unlike the PKC-zeta isozyme, were increased in RV homogenate and cytosolic fractions, whereas the RV particulate fraction showed an increase in the PKC-alpha isozyme only. These changes in the LV and RV PKC activities and protein contents in the 8-wk infarcted animals were partially corrected by treatment with the angiotensin-converting enzyme inhibitor imidapril. No changes in protein kinase A activity and its protein content were seen in the 8-wk infarcted hearts. The results suggest that the increased PKC activity in cardiac dysfunction due to MI may be associated with an increase in the expression of PKC-alpha, -beta, and -epsilon isozymes, and the improvement of heart function in the infarcted animals by imidapril may be due to partial prevention of changes in PKC activity and isozyme contents.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Cyclic AMP-Dependent Protein Kinases; Cytosol; Heart Failure; Heart Ventricles; Hemodynamics; Imidazoles; Imidazolidines; Immunoblotting; Isoenzymes; Male; Myocardial Infarction; Myocardium; Protein Kinase C; Rats; Rats, Sprague-Dawley; Time Factors

Phospholipase D 2 (PLD2) is the major PLD isozyme associated with the cardiac sarcolemmal (SL) membrane. Hydrolysis of SL phosphatidylcholine (PC) by PLD2 produces phosphatidic acid (PA), which is then converted to 1,2 diacylglycerol (DAG) by the action of phosphatidate phosphohydrolase type 2 (PAP2). In view of the role of both PA and DAG in the regulation of Ca(2+) movements and the association of abnormal Ca(2+) homeostasis with congestive heart failure (CHF), we examined the status of both PLD2 and PAP2 in SL membranes in the infarcted heart upon occluding the left coronary artery in rats for 1, 2, 4, 8 and 16 weeks. A time-dependent increase in both SL PLD2 and PAP2 activities was observed in the non-infarcted left ventricular tissue following myocardial infarction (MI); however, the increase in PAP2 activity was greater than that in PLD2 activity. Furthermore, the contents of both PA and PC were reduced, whereas that of DAG was increased in the failing heart SL membrane. Treatment of the CHF animals with imidapril, an angiotensin-converting enzyme (ACE) inhibitor, attenuated the observed changes in heart function, SL PLD2 and PAP2 activities, as well as SL PA, PC and DAG contents. The results suggest that heart failure is associated with increased activities of both PLD2 and PAP2 in the SL membrane and the beneficial effect of imidapril on heart function may be due to its ability to prevent these changes in the phospholipid signaling molecules in the cardiac SL membrane.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Coronary Stenosis; Disease Models, Animal; Enzyme Activation; Guanosine 5'-O-(3-Thiotriphosphate); Heart Failure; Heart Ventricles; Imidazoles; Imidazolidines; Male; Myocardium; Oleic Acid; Phosphatidate Phosphatase; Phosphatidylinositol 4,5-Diphosphate; Phospholipase D; Rats; Rats, Sprague-Dawley; Sarcolemma; Time Factors

Reactive oxygen species have an important pathogenic role in organ damage. We investigated the role of oxidative stress via nicotinamide adenine dinucleotide phosphate (NAD[P]H) oxidase in the kidney of the Dahl salt-sensitive (DS) rats with heart failure (DSHF). Eleven-week-old DS rats fed an 8%-NaCl diet received either vehicle or imidapril (1 mg/kg per day) for 7 weeks. The renal expression of the NAD(P)H oxidase p47phox and endothelial NO synthase were evaluated. In DSHF rats, associated with increased renal angiotensin II, mRNA and protein expression of NAD(P)H oxidase p47phox were enhanced with an increase in renal lipid peroxidation production (0.33+/-0.03 versus 0.22+/-0.01 nmol/mg protein, P<0.05) and urinary excretion of hydrogen peroxide (26.9+/-6.6 versus 9.5+/-2.1 U/mg creatinine, P<0.01) compared with levels in Dahl salt-resistant rats. The endothelial NO synthase expression was decreased in the kidney. Treatment with imidapril reduced renal angiotensin II and NAD(P)H oxidase expression and the oxidative products (kidney lipid peroxidation product: 0.16+/-0.02, P<0.001; urinary hydrogen peroxide: 3.1+/-0.2, P<0.01 versus DSHF rats). Imidapril significantly decreased albuminuria and reduced glomerulosclerosis without changes in the blood pressure. In conclusion, DSHF rats showed increased oxidative stress in the kidney via NAD(P)H oxidase. Blockade of local angiotensin II with subpressor dose of imidapril inhibited NAD(P)H oxidase and prevented renal damage.

Topics: Albuminuria; Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Animals; Blotting, Western; Disease Models, Animal; Gene Expression; Heart Failure; Heart Ventricles; Hydrogen Peroxide; Imidazoles; Imidazolidines; Kidney; Male; NADPH Oxidases; Nitric Oxide Synthase; Nitric Oxide Synthase Type III; Oxidative Stress; Phosphoproteins; Rats; Rats, Inbred Dahl; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger

Eighteen patients with heart failure were studied to clarify whether angiotensin-converting enzyme inhibitor treatment improves excess ventilation during exercise. Treatment with angiotensin-converting enzyme inhibitors had a beneficial effect on excess ventilation during exercise, without significant improvement in exercise capacity in patients with moderate congestive heart failure.

Topics: Angiotensin-Converting Enzyme Inhibitors; Cardiomyopathy, Dilated; Enalapril; Exercise Test; Exercise Tolerance; Heart Failure; Humans; Imidazoles; Imidazolidines; Middle Aged; Pulmonary Ventilation; Time Factors

We have examined the changes in quantity and activity of cardiac sarcolemmal (SL) phosphoinositide-phospholipase C (PLC)-beta(1), -gamma(1), and -delta(1) in a model of congestive heart failure (CHF) secondary to large transmural myocardial infarction (MI). We also instituted a late in vivo monotherapy with imidapril, an ANG-converting enzyme (ACE) inhibitor, to test the hypothesis that its therapeutic action is associated with the functional correction of PLC isoenzymes. SL membranes were purified from the surviving left ventricle of rats in a moderate stage of CHF at 8 wk after occlusion of the left anterior descending coronary artery. SL PLC isoenzymes were examined in terms of protein mass and hydrolytic activity. CHF resulted in a striking reduction (to 6-17% of controls) of the mass and activity of gamma(1)- and delta(1)-isoforms in combination with a significant increase of both PLC beta(1) parameters. In vivo treatment with imidapril (1 mg/kg body wt, daily, initiated 4 wk after coronary occlusion) improved the contractile function and induced a partial correction of PLCs. The mass of SL phosphatidylinositol 4,5-bisphosphate and the activities of the enzymes responsible for its synthesis were significantly reduced in post-MI CHF and partially corrected by imidapril. The results indicate that profound changes in the profile of heart SL PLC-beta(1), -gamma(1), and -delta(1) occur in CHF, which could alter the complex second messenger responses of these isoforms, whereas their partial correction by imidapril may be related to the mechanism of action of this ACE inhibitor.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Cytosol; Heart Failure; Imidazoles; Imidazolidines; Isoenzymes; Male; Myocardial Infarction; Rats; Rats, Sprague-Dawley; Sarcolemma; Type C Phospholipases

Topics: Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Double-Blind Method; Heart Failure; Humans; Imidazoles; Imidazolidines; Randomized Controlled Trials as Topic