imidapril and Myocardial-Ischemia

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

Imidapril is an angiotensin I converting enzyme inhibitor, a class of drugs with known cardioprotective activity. It is now known that this is due not only to their antihypertensive activity, but also to the fact that they decrease cellular and tissue levels of angiotensin II, a potent vasoconstrictor and inducer of myocardial fibrosis. These mechanisms may explain the good clinical results of this class of drugs in the treatment of coronary artery disease and heart failure, two diseases whose etiopathogenesis is closely related to the activation of the renin-angiotensin-aldosterone system. However, the impact of this class of drugs on cardiac mitochondrial function during acute myocardial ischemia is still largely unknown. With the aim of studying the effect of imidapril on cardiac mitochondrial function during acute ischemia, we used an ex-vivo animal model, perfused in a Langerdorff system and then subjected to ischemia in the presence or absence of imidapril. We evaluated mitochondrial membrane electrical potential, respiratory chain O2 consumption, and rate and amplitude of mitochondrial swelling. We conclude that imidapril did not significantly change oxygen consumption by cardiac mitochondria, as assessed by the rate of respiratory state 3 (the state that corresponds to the active phosphorylation phase). However, imidapril significantly increased transmembrane electrical potential and, in ischemic cardiac mitochondria, was able to prevent the calcium-induced increase in the rate and amplitude of mitochondrial swelling, thus enabling better preservation of mitochondrial membrane structure, with consequent improvement of electrical potential after the phosphorylation cycle. These findings enabled a better understanding of the mechanisms behind the cytoprotection provided by imidapril during ischemic cardiomyopathy, clearly highlighting, at a cellular biology level, the importance of pharmacological modulation of cardiac mitochondrial function during acute ischemia.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Imidazolidines; In Vitro Techniques; Male; Mitochondria, Heart; Myocardial Ischemia; Rats; Rats, Wistar

There have been many studies concerning the hemodynamics and physiological mechanisms in ischemic heart disease, little is known about molecular mechanisms during myocardial ischemia in in vivo study. As the signal transduction pathway responsible for myocardial hypertrophy and apoptosis, janus kinase (JAK) and signal transducers and activators of transcription (STAT) are suggested to play an important role. However, whether in vivo activation of JAK-STAT pathway occurs during myocardial ischemia is still unknown. The purpose of this study was to determine whether myocardial JAK or STAT is activated in ischemic heart, and to evaluate the angiotensin blockade on the pathway. Myocardial infarction was produced by ligation of the coronary artery in Wistar rats. After myocardial ischemia, we analysed both activated levels and total amounts of JAK1, JAK2, STAT1 and STAT3 by Western blot analyses at 0, 5, 15, 30, 60, 120 and 240 min. Compared with JAK activities at 0 min, JAK1 activities were significantly increased at 60 and 120 min (3.0- and 3.7-fold, respectively, P<0.01). JAK2 and STAT1 activities of ischemic myocardium were unchanged through the time course. STAT3 activities were increased at 5 min (3.3-fold, P<0.01) and markedly enhanced at 30, 60 and 120 min (4.6-, 7.7- and 8.7-fold, respectively, P<0.01). Pretreatment with imidapril (ACE inhibitor) and candesartan cilexitil (AT1 receptor antagonist) significantly prevented the increase in the phosphorylation of JAK1 at 120 min and STAT3 at 30 and 120 min. Sis-inducing factor (SIF) DNA complex was supershifted by specific anti-STAT3 antibody, indicating that increased SIF complex at least contained activated STAT3 proteins in ischemic myocardium. Imidapril and candesartan cilexitil inhibited the activation of SIF DNA binding at 1 day after coronary ligation. In conclusion, we showed that JAK1 and STAT3 were activated by ischemia from the basal activities in in vivo rat myocardial ischemia model. Imidapril and candesartan cilexitil prevented the increase in phosphorylated JAK1 and STAT3, thereby suggesting that angiotensin II, especially angiotensin II type I receptor, partially mediates activation of myocardial JAK-STAT pathway in acute myocardial ischemia.

Topics: Angiotensin II; Animals; Antihypertensive Agents; Benzimidazoles; Biphenyl Compounds; Blotting, Western; Coronary Vessels; DNA; DNA-Binding Proteins; Drosophila Proteins; Electrophoresis, Polyacrylamide Gel; Enzyme Activation; Enzyme Inhibitors; Guanine Nucleotide Exchange Factors; Imidazoles; Imidazolidines; Immunoblotting; Janus Kinase 1; Janus Kinase 2; Male; Myocardial Infarction; Myocardial Ischemia; Peptidyl-Dipeptidase A; Phosphorylation; Precipitin Tests; Protein-Tyrosine Kinases; Proto-Oncogene Proteins; Rats; Rats, Wistar; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Receptors, Angiotensin; Signal Transduction; STAT1 Transcription Factor; STAT3 Transcription Factor; Tetrazoles; Time Factors; Trans-Activators

Our laboratory previously reported that the end-systolic force-length relationship of the left ventricle provides a better method of evaluating myocardial contractile properties than the left ventricular end-systolic pressure-volume relationship, because it avoids deficiencies of the latter parameter such as dependence of its slope (E(max)) on the volume intercept (V(0)). The slope (E(c)) of the left ventricular end-systolic force-length relationship represents the contractility of functioning myocardium, while its length intercept (L(0)) reflects the length of non-functioning myocardium. However, the effect of regional myocardial ischemia on these parameters, as evaluated by the force-length relationship, remains unknown. To clarify the effects of regional ischemia and angiotensin-converting enzyme inhibition on the myocardium during ischemia-reperfusion, the changes in E(c) and L(0) were determined in anesthetized open-chest dogs. (1) Control group (n=26): Before and after 15 min of complete coronary artery occlusion, as well as after 15 min of reperfusion, left ventricular pressure and volume were simultaneously recorded during inferior vena cava occlusion. The left ventricular force-length relationship was obtained from the pressure and volume of three cylindrical segments of the ventricle, and E(c) and L(0) were calculated. (2) Imidapril group (n=14): Imidaprilat (1 microg/kg/min) was continuously infused from 30 min before ischemia to the end of the experiment, and the same procedures were followed as in the control group. Fourteen out of the 26 dogs (54%) in the control group died of reperfusion-induced ventricular arrhythmias, while only two of the 14 dogs (14%) in the imidapril group did so (P<0.05). In the control group, E(c) was increased during ischemia and remained at the same level after reperfusion. However, E(c) was not altered in the imidapril group. Although L(0) was increased during ischemia and decreased after reperfusion in both groups, the percent increase of L(0) in the imidapril group was significantly smaller than in the control group (8% vs. 32%, P<0.05). With the improvement of these indices, the bradykinin concentration of coronary venous blood increased in the imidapril group (P<0.01). These findings suggest that regional myocardial ischemia increased the average contractility of overall functioning myocardium despite the increased non-functioning myocardium. Moreover, imidapril has a cardioprotective effect against ischemia-r

Topics: Adrenergic beta-Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Atropine; Blood Pressure; Bradykinin; Dogs; Imidazoles; Imidazolidines; Infusions, Intravenous; Muscarinic Antagonists; Myocardial Contraction; Myocardial Ischemia; Myocardial Reperfusion Injury; Myocardium; Nitric Oxide; Propranolol; Stroke Volume; Ventricular Function, Left