temocapril-hydrochloride and Myocardial-Infarction

Both angiotensin-converting enzyme (ACE) inhibitors and angiotensin II type 1 (AT1) receptor blockers have been demonstrated to improve symptoms and prognosis in heart failure (HF). We compared the effects of ACE inhibition and AT1 receptor blockade on myocardial beta-adrenoceptor desensitization in rabbits with HF established 3 weeks after myocardial infarction (MI) with left circumflex coronary artery ligation. Rabbits with MI were randomized to no treatment, the ACE inhibitor temocapril (0.5 mg/kg/day) or AT1 receptor blocker valsartan (3 mg/kg/day). Echocardiographic examinations showed that, relative to rabbits with untreated MI, rabbits receiving temocapril or valsartan had a limitation of cardiac remodeling and prevention of the development of systolic dysfunction. Circulating plasma norepinephrine levels that were markedly elevated in MI animals were strongly inhibited by temocapril or valsartan therapy. beta-Adrenoceptor density, beta-adrenoceptor proportion showing high-affinity agonist binding, and basal and isoproterenol-stimulated adenylate cyclase activities were significantly reduced in MI rabbits. These defects were similarly reversed by temocapril or valsartan. Importantly, as found in human HF, myocardial protein levels of beta-adrenoceptor kinase 1 and G(i alpha) were significantly elevated in MI rabbits, suggesting that these molecules are contributing to the defects in myocardial beta-adrenoceptor signaling. The expression levels of these molecules were normalized equally by both treatments. The results suggest that pharmacologically different interventions in the renin-angiotensin system can equivalently improve the derangements in the beta-adrenoceptor signaling system in the failing heart. This may be important for the beneficial effects of these agents in HF.

Topics: Adenylyl Cyclases; Adrenergic beta-Agonists; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; beta-Adrenergic Receptor Kinases; Blotting, Western; Cyclic AMP-Dependent Protein Kinases; Down-Regulation; Echocardiography; GTP-Binding Protein alpha Subunits, Gi-Go; Heart Failure; Hemodynamics; In Vitro Techniques; Iodocyanopindolol; Male; Membranes; Myocardial Infarction; Myocardium; Norepinephrine; Organ Size; Rabbits; Radioligand Assay; Receptor, Angiotensin, Type 1; Receptors, Adrenergic, beta; Signal Transduction; Thiazepines

Angiotensin-converting enzyme (ACE) inhibitor and angiotensin II type I receptor blockers (ARB) prevent cardiac remodeling after myocardial infarction (MI). However, it is controversial whether combination therapy of ACE inhibitor and ARB is more effective on cardiac remodeling than each agent alone. In this study, we compared the effects of an ACE inhibitor (temocapril), an ARB (CS-866), and their combination on cardiac remodeling after MI.. Temocapril at 3 or 30 mg/kg/day, CS-866 at 1 or 10 mg/kg/day, or combined temocapril and CS-866 at 1.5 and 0.5 mg/kg/day or at 15 and 5 mg/kg/day, respectively, were administered to rats after MI. At 4 weeks after MI, we assessed hemodynamics, cardiac function by Doppler echocardiography and non-infarcted myocardial mRNA expression.. Animals treated with a combination of the two drugs had hemodynamics, heart weights and dimensions similar to the other treated animals. However, the combination of the two drugs suppressed ANP, BNP and other gene expressions related to contractile proteins of fetal type and collagens more effectively than ACE inhibitor or ARB alone.. These data suggest that combination of the two drugs, independent of the hemodynamic effect, may improve left ventricular phenotypic change, collagen accumulation and diastolic function.

Topics: Angiotensin II; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Atrial Natriuretic Factor; Blotting, Northern; Collagen; Diastole; Drug Therapy, Combination; Echocardiography, Doppler; Imidazoles; Male; Models, Animal; Myocardial Infarction; Myocardium; Natriuretic Peptide, Brain; Olmesartan Medoxomil; Rats; Rats, Wistar; RNA, Messenger; Tetrazoles; Thiazepines; Ventricular Remodeling

Based on currently available clinical evidence, we should use high-dose angiotensin converting enzyme inhibitor (ACE-I) for patients with acute myocardial infarction (MI), initiating it at incremental doses to avoid excessive hypotension. Recent animal studies with acute MI models failed to demonstrate the superiority of the combination therapy of ACE-I and angiotensin receptor blocker (ARB) to high-dose ACE-I treatment with comparable blood pressure reductions, which however might be attributed to the initiation of the targeted doses from the beginning. The aim of this study was to compare the effect of increasing the dose of ACE-I with that of adding ARB following a relatively low dose of ACE-I on the survival and left ventricular (LV) remodeling after MI.. Rats underwent left coronary artery ligation and were treated with either ACE-I temocapril (5 mg/kg/day) or vehicle for 2 weeks, which was initiated 3 days after the surgery. The rats treated with temocapril were further randomly assigned to receive either high-dose temocapril (10 mg/kg/day) or combination therapy (temocapril 5 mg/kg/day+olmesartan 2.5 mg/kg/day), which was continued for another 6 weeks.. Both treatments similarly reduced the blood pressure, improved survival and ameliorated LV enlargement. In contrast, several parameters of LV function were significantly ameliorated only by the high-dose ACE-I but not by the combination therapy.. After the initiation of a relatively low dose of ACE-I in acute MI, increasing the dose of ACE-I or adding ARB may equally improve survival and LV remodeling in the setting of an equal hypotensive effect. Further study with a longer treatment protocol is required to determine whether the several favorable effects on LV function elicited only by the high-dose ACE-I treatment provide further beneficial effects on survival and LV remodeling compared with the combination therapy.

Topics: Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Atrial Natriuretic Factor; Bradykinin; Collagen Type I; Collagen Type III; Drug Administration Schedule; Drug Therapy, Combination; Glyceraldehyde-3-Phosphate Dehydrogenases; Imidazoles; Male; Models, Animal; Myocardial Infarction; Myocardium; Norepinephrine; Olmesartan Medoxomil; Random Allocation; Rats; Rats, Wistar; RNA, Messenger; Tetrazoles; Thiazepines; Transforming Growth Factor beta; Ventricular Dysfunction, Left

Inhibition of the renin-angiotensin system has been shown to prevent left ventricular remodeling after myocardial infarction. However, the effect of angiotensin on the signal transduction pathway of left ventricular remodeling after myocardial infarction is as yet unknown. The purpose of this study was to measure myocardial MAPKs and AP-1, NF- kappa B, and Sp-1 DNA-binding activities after myocardial infarction. Moreover, we evaluated the effects of angiotensin converting enzyme (ACE) inhibitor and angiotensin receptor blocker (ARB) on signal transduction pathway. Myocardial infarction was produced by ligation of the coronary artery in Wistar rats. Temocapril (ACE inhibitor) (3 and 30 mg/kg/day) and candesartan cilexitil (ARB) (1 and 10 mg/kg/day) were orally administered once a day. After ligation of the left descending coronary artery, JNKs (p46JNK and p55JNK) increased to 2.0- (P<0.01) and 2.8-fold (P<0.01) at 7 days, respectively. ERKs (p44ERK and p42ERK) and p38 activities did not increase significantly. AP-1 and NF- kappa B binding activities increased at 5 days, reached their peak 2.2- and 2.0-fold at 7 days. Sp-1 did not change. ACE inhibitor and ARB inhibited JNKs, NF- kappa B and AP-1 activities. Increased JNKs, AP-1, NF- kappa B, and Sp-1 DNA-binding activities were suppressed by both drugs in the infarcted region. Doppler-echocardiography showed that ACE inhibitor and ARB prevented the dilatation of left ventricular cavity at 14 days and improved diastolic filling pattern. JNKs, AP-1 and NF- kappa B activation in myocardial infarcted rats could be responsible for left ventricular remodeling after myocardial infarction and angiotensin may be related to the activation of these signals.

Topics: Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Benzimidazoles; Biphenyl Compounds; DNA; Echocardiography, Doppler, Color; Heart Ventricles; Hemodynamics; JNK Mitogen-Activated Protein Kinases; Male; Mitogen-Activated Protein Kinases; Myocardial Infarction; NF-kappa B; p38 Mitogen-Activated Protein Kinases; Rats; Rats, Wistar; Signal Transduction; Sp1 Transcription Factor; Tetrazoles; Thiazepines; Time Factors; Transcription Factor AP-1

This study examined whether chronic inhibition of the angiotensin-converting enzyme (ACE) lowers the threshold of preconditioning (PC) and potentiates cardio-protection of subthreshold PC. Rabbits were orally administered either 0.5 mg/kg/day temocapril or placebo for 14 days and were randomly subjected to subthreshold PC (i.e., PC with 2 minutes ischemia/5 minutes reperfusion) or no PC before a 30-minute coronary artery occlusion and a 3-hour reperfusion. The size of the infarct was determined by tetrazolium staining and was expressed as the percent of the area at risk (%IS/AR). At the end of the experiment, the lungs were sampled for a tissue ACE activity assay. There was no significant difference in %IS/AR among the rabbits given placebo alone, placebo plus 2 minutes PC, and temocapril alone (%IS/AR = 59.5 +/- 5.8%, 43.6 +/- 3.7%, and 56.7 +/- 7.1%, respectively). However, %IS/AR was significantly reduced in the group that received temocapril and 2 minutes PC before infarction (%IS/AR = 35.4 +/- 4.8%, P < 0.05 vs. placebo control and temocapril control). The lung tissue ACE activity did not differ in the placebo-treated rabbits with and without PC (12.6 +/- 2.8 vs. 13.7 +/- 2.0 nmol/g protein/min) but was suppressed in temocapril-treated rabbits despite 2 minutes PC (0.9 +/- 0.1 vs. 1.5 +/- 0.2 nmol/g protein/min, both P < 0.05 vs. placebo-treated groups). The present results suggest that chronic inhibition of ACE is beneficial for potentiating the anti-infarct effect of subthreshold PC.

Topics: Administration, Oral; Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Pressure; Heart Rate; Ischemic Preconditioning, Myocardial; Lung; Myocardial Infarction; Rabbits; Single-Blind Method; Thiazepines; Time Factors