imidapril and Myocardial-Infarction

Matrix metalloproteinase (MMP) plays a critical role in the development of ventricular remodeling after acute myocardial infarction (AMI). Imidapril, an angiotensin-converting enzyme inhibitor, has been shown to inhibit MMP activity. We investigated whether imidapril inhibits plasma MMP activities and attenuates ventricular remodeling in patients with AMI in comparison with enalapril. We enrolled 70 patients with AMI. All patients underwent primary percutaneous coronary intervention and were randomly assigned either to imidapril (n = 35) or to enalapril (n = 35) treatment. Left ventriculography was performed in acute (day 14) and chronic (6 months) phases, and plasma MMP-2 and MMP-9 activities were measured by zymography. Any changes in left ventricular end-diastolic volume index and ejection fraction from acute to chronic phases did not differ between the 2 groups. The plasma MMP-2 and MMP-9 activities at day 14 were both significantly decreased compared with those at day 1 in both groups (all P < 0.05). At 6 months, MMP-9 activity still remained decreased in both groups (P < 0.05 vs. day 1). Overall, there were no differences between the 2 groups both in plasma MMP-2 and MMP-9 activities. These results demonstrate that imidapril exerts inhibitory effects on plasma MMP activities and attenuates left ventricular remodeling in patients with AMI similar to enalapril.

Topics: Aged; Angiotensin-Converting Enzyme Inhibitors; Enalapril; Female; Humans; Imidazolidines; Male; Matrix Metalloproteinase Inhibitors; Matrix Metalloproteinases; Middle Aged; Myocardial Infarction; Ventricular Remodeling

Although angiotensin-converting enzyme inhibitor attenuates ventricular enlargement, whether beta-blocker therapy induces regression of left ventricular remodeling is not known. The purpose of this study was to compare the effects of bisoprolol therapy with those of imidapril therapy on left ventricular remodeling after acute myocardial infarction (AMI).. Sixty patients with AMI who underwent reperfusion therapy were randomly assigned to an imidapril group (20 patients), a bisoprolol group (20 patients), or a control group (20 patients). Administration was started within 24 hours. Left ventricular function on admission and 3 months and 1 year after AMI was investigated.. Baseline characteristics on admission were similar in the 3 groups except for sex distribution. Mean pulmonary capillary wedge pressure and left ventricular end-diastolic pressure in the bisoprolol group were higher than those in the imidapril group 1 year after admission (pulmonary capillary wedge pressure: 12 +/- 7 vs 8 +/- 2 mm Hg, left ventricular end-diastolic pressure: 17 +/- 8 vs 11 +/- 4 mm Hg, P <. 01). Left ventricular end-diastolic volume index (EDVI) increased in the bisoprolol group throughout the 1-year period (P <.01), whereas EDVI in the imidapril group decreased (P <.01). The increases in EDVI during 1 year in the bisoprolol group were greater than those of the other 2 groups (bisoprolol: 12 +/- 10, imidapril: -9 +/- 7, control: 4 +/- 11 mL/m2, P <.01).. Early treatment with bisoprolol in AMI cannot prevent left ventricular remodeling, whereas imidapril attenuates left ventricular dilation by decreasing preload.

Topics: Adrenergic beta-Antagonists; Adult; Aged; Aged, 80 and over; Angiotensin-Converting Enzyme Inhibitors; Bisoprolol; Coronary Angiography; Coronary Circulation; Female; Heart Ventricles; Hemodynamics; Humans; Imidazolidines; Longitudinal Studies; Male; Middle Aged; Myocardial Infarction; Myocardial Reperfusion; Vascular Patency; Ventricular Remodeling

Treatment with an angiotensin-converting enzyme (ACE) inhibitor in patients with myocardial infarction has been shown to modify endogenous fibrinolysis.. We investigated the effects of the ACE inhibitor imidapril on endogenous fibrinolysis in association with the serum ACE activity.. In a randomized, double-blind, placebo-controlled study beginning 4 weeks after uncomplicated myocardial infarction, 15 patients received imidapril (5 mg daily) (imidapril group) and another 15 received placebo therapy (placebo group) for 4 weeks. Blood sampling was performed before the start of administration and on Days 3, 7, and 28 after the start of administration. Serum ACE activity and plasma fibrinolytic variables [plasminogen activator inhibitor (PAI) activity, plasminogen activator inhibitor type 1 (PAI-1) antigen level, and tissue type plasminogen activator (TPA) antigen level] were measured.. There was no difference between the imidapril and placebo groups in serum ACE activity or plasma fibrinolytic variables before administration. Serum ACE activity decreased significantly on Days 3, 7, and 28 in the imidapril group. The decrease of PAI activity and PAI-1 antigen levels was significantly less on Days 7 and 28, but not on Day 3. The TPA antigen level in the imidapril group was unchanged. None of the parameters in the placebo group was changed.. The ACE inhibitor imidapril modified fibrinolysis, but the effects occurred after the inhibition of serum ACE activity.

Topics: Administration, Oral; Aged; Angiotensin-Converting Enzyme Inhibitors; Antigens; Biomarkers; Double-Blind Method; Enzyme-Linked Immunosorbent Assay; Female; Fibrinolysis; Humans; Imidazoles; Imidazolidines; Male; Myocardial Infarction; Peptidyl-Dipeptidase A; Plasminogen Activator Inhibitor 1; Tissue Plasminogen Activator; Treatment Outcome

This study sought to determine whether early treatment with angiotensin-converting enzyme (ACE) inhibitors in patients with acute myocardial infarction (AMI) is useful for the improvement of fibrinolytic function, as well as left ventricular function. This study was designed to examine the levels of plasma plasminogen activator inhibitor (PAI) activity and serum ACE activity during the course of 2 weeks in 40 patients with AMI within 12 hours after the onset of the symptom and who randomly received early treatment with either the ACE inhibitor imidapril or a placebo (20 patients in the imidapril group and 20 in the placebo group). The levels of serum ACE activity in the imidapril group decreased significantly (p < 0.01) 8 hours after the administration of imidapril, and the levels 24 hours after administration were significantly lower than those in the placebo group (3.6 +/- 0.6 IU/L vs 7.4 +/- 0.8 IU/L; p < 0.001). The plasma PAI activity increased gradually to peak levels 16 hours after the administration of imidapril and placebo. The levels in the placebo group decreased gradually but remained high during the study period. On the other hand, the levels of PAI activity in the imidapril group decreased rapidly and those 48 hours after administration were significantly lower than those in the placebo group (7.9 +/- 1.9 IU/ml vs 18.4 +/- 3.5 IU/ml; p < 0.01). The levels of left ventricular ejection fraction about 2 weeks after admission were significantly higher in the imidapril group than in the placebo group (65.9% +/- 2.5% vs 49.1% +/- 4.4%; p < 0.01). This study showed that imidapril, an ACE inhibitor, might be useful for the improvement of fibrinolytic function and left ventricular function in the acute phase of myocardial infarction.

Topics: Aged; Angiotensin-Converting Enzyme Inhibitors; Female; Fibrinolysis; Humans; Imidazoles; Imidazolidines; Male; Middle Aged; Myocardial Infarction; Plasminogen Inactivators; Thrombolytic Therapy; Ventricular Function, Left

Plasma levels of B-type natriuretic peptide (BNP) are markedly increased in patients with heart failure and acute myocardial infarction. The changes in plasma BNP levels in the treatment of acute myocardial infarction with angiotensin-converting enzyme inhibitors have not been examined well. This study was designed to examine the effects of early angiotensin-converting enzyme inhibitor therapy on plasma BNP levels in patients with acute myocardial infarction.. We measured the plasma levels of B-type natriuretic peptide over the time course for 2 weeks in 30 patients with acute myocardial infarction in whom either imidapril (n = 15) or placebo (n = 15) was given at random immediately after admission. Plasma BNP levels increased and reached a peak of 192 +/- 28 pg/ML 16 hours after administration; thereafter, the levels decreased and then again increased, forming the second peak of 217 +/- 38 pg/ML on the fifth day (biphasic pattern). On the other hand, plasma BNP levels increased and reached a peak level of 190 +/- 22 pg/ML 16 hours after admission and then decreased from 2 days after admission until the second week in the imidapril group (monophasic pattern). Left ventricular ejection fraction measured in the second week was significantly higher in the imidapril group than in the control group (62.2 +/- 1.1% vs 51.2 +/- 3.6%, P < .01).. It is concluded that plasma BNP levels followed a monophasic pattern after imidapril treatment, whereas a biphasic pattern was followed after placebo, and that plasma BNP levels constitute a marker of ventricular dysfunction in the treatment of acute myocardial infarction with angiotensin-converting enzyme inhibitors.

Topics: Adult; Aged; Aged, 80 and over; Angiotensin-Converting Enzyme Inhibitors; Biomarkers; Female; Hemodynamics; Humans; Imidazoles; Imidazolidines; Male; Middle Aged; Myocardial Infarction; Natriuretic Peptide, Brain; Nerve Tissue Proteins; Peptidyl-Dipeptidase A; Treatment Outcome; Ventricular Dysfunction

Angiotensin converting enzyme inhibitors have been used clinically to prevent myocardial infarction (MI). The angiotensin converting enzyme inhibitors attenuated ventricular remodeling and improved cardiac function by inhibition of matrix metalloproteinases after MI. Although the effect is thought to be a class effect, there are significant differences among the drugs. The aim of this study was to compare the effects of imidapril and ramipril on ventricular remodeling after MI.. The middle portion of left anterior descending artery was ligated to induce a moderate size MI in rats (moderate MI group). The proximal portion of the artery was ligated to induce a large size MI (large MI group). The animals were assigned to subgroups in moderate MI group and large MI group: (1) nontreated group, (2) ramipril group (1 mg/kg daily), and (3) imidapril group (1 mg/kg daily). All rats were killed on day 28 after the MI operation.. Although the nontreated MI group showed impaired ventricular contraction and severe fibrosis, imidapril significantly negated ischemia-induced changes. Imidapril had a superior effect for preventing ventricular remodeling characterized by fibrosis and collagen accumulation in left ventricle compared with ramipril in the moderate and large MI groups, even though the dosage used in this study was too small to reduce systemic blood pressure.. Imidapril can be used as a substitute for ramipril to prevent ventricular remodeling after MI.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Collagen; Disease Models, Animal; Fibrosis; Imidazolidines; Male; Myocardial Contraction; Myocardial Infarction; Ramipril; Rats; Rats, Sprague-Dawley; Ventricular Remodeling

To investigate the inhibitory specificity of angiotensin converting enzyme (ACE) inhibitors to matrix metalloproteinase (MMP)-9, we predicted molecular interactions between an ACE inhibitor imidapril and MMP-9 active site based on recent X-ray structural analyses. Two binding modes differing in the orientation of imidapril on the active site were identified, and its hydrophobic group appeared to preferentially interact with the S1 site compared with the S1' site. Compared with the lisinopril-MMP-9 model in our previous study, imidapril was stabilized effectively on the active site with less of molecular distortions. We also measured ACE and MMP-9 inhibitory activities of imidapril and lisinopril after myocardial infarction. Imidapril had a stronger inhibitory activity against MMP-9 than lisinopril. These findings show that imidapril inhibits MMP-9 directly like lisinopril and its hydrophobic interactions with the S1 site of MMP-9 would be important for enhancing inhibitory activity.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Binding Sites; Cricetinae; Heart Ventricles; Imidazolidines; Lisinopril; Male; Matrix Metalloproteinase Inhibitors; Mesocricetus; Models, Molecular; Myocardial Infarction

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

To investigate the effects of imidapril (IMI) on effective refractory period (ERP) and sodium current (I(Na)) of myocytes in ventricular noninfarction zone of healed myocardial infarction (HMI) in rabbit models.. Rabbits with left coronary artery ligation were prepared and IMI (0.625 mg x kg(-1) x d(-1), 8 weeks) was orally administered. The ERP and sodium current were recorded.. The ERP in HMI heart was prolonged. The ERP in IMI group was lower significantly than that of HMI group. The I(Na) density of myocyte in HMI ventricle decreased obviously. V 1/2 of steady state inactivation of I(Na) shifted to hyperpolarization, and time constant (tau) of recovery from inactivation in HMI ventricular myocyte was longer than that of sham ventricular myocyte. I(Na) density in IMI group increased markedly as compared with that of HMI group.. IMI was shown to reverse the abnormal prolongation of ERP in rabbit heart with the HMI and increase I(Na) density. It may be the mechanism of IMI preventing against antiarrhythmia in healed myocardical infarction.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Calcium Channels; Female; Heart Ventricles; Imidazolidines; Male; Myocardial Infarction; Myocytes, Cardiac; Rabbits; Refractory Period, Electrophysiological

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

To investigate the effects of chronic treatment with imidapril on the electrophysiologic heterogeneous change of the noninfarcted myocardium of rabbits after myocardial infarction and the mechanism of its antiarrhythmic efficacy.. Rabbits with left coronary artery ligation were prepared and allowed to recover for 8 weeks. Myocytes were isolated from subendocardial, midmyocardial, and subepicardial regions of the noninfarcted left ventricular wall. Action potentials and calcium current were recorded using whole-cell patch clamp technique.. The action potential duration of repolarization 90 % (APD90) was more prolonged in midmyocardium rather than in subepicardium and subendocardium with healed myocardial infarction. The transmural dispersion of repolarization (TDR) was increased in the three ventricular regions. The amplitude of I(Ca-L) [was enhanced but its density was decreased in noninfarcted ventricular myocytes due to increased cell membrane capacitance. The increased differences of calcium currents among subepicardium, midmyocardium, and subendocardium were also discovered. Normalization of heterogeneous changes in repolarization after treatment with imidapril was observed and decrease of TDR in noninfarcted area was measured. Early after depolarization (EAD) events of noninfarcted midmyocardium were markedly decreased by imidapril.. Imidapril reduced the electrophysiologic heterogeneities in noninfarcted area in rabbits after myocardial infarction. This ability of imidapril may contribute to its antiarrhythmic efficacy.

Topics: Action Potentials; Adrenergic beta-Antagonists; Animals; Anti-Arrhythmia Agents; Calcium Channels, L-Type; Cell Separation; Heart Ventricles; Imidazolidines; Myocardial Infarction; Myocytes, Cardiac; Rabbits

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

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

The beneficial effects of imidapril, an angiotensin converting enzyme (ACE) inhibitor were investigated on changes in myofibrillar ATPase as well as myosin heavy chain (MHC) content and gene expression due to myocardial infarction (MI). Three weeks after occluding the left coronary artery, rats were treated with or without imidapril (1 mg/kg/day), for 4 weeks. The infarcted hearts exhibited depressed rates of left ventricular (LV) pressure development (57+/-2.4% reduction) and pressure decay (55.5+/-1.6% reduction). LV myofibrillar Ca(2+) ATPase activity, unlike that in the right ventricle (RV), was decreased in the infarcted animals compared with controls (6.8+/-0.4 vs 10.3+/-0.6 micromol Pi/mg/hr). MHC alpha-isoform contents were decreased by 47 and 41% whereas those of MHC beta-isoform were increased by 823 and 1200% in the LV and RV due to MI, respectively. MHC alpha-isoform mRNA levels were decreased by 55 and 35% whereas those for MHC beta-isoform were increased by 50 and 30% in the infarcted LV and RV, respectively. Imidapril treatment partially prevented the changes due to MI in LV function (rate of pressure development, 24+/-2.3% reduction and rate of pressure decay, 14+/-1.8% reduction), myofibrillar Ca(2+) ATPase activity (8.2+/-0.7 micromol Pi/mg/hr), MHC protein content (alpha-MHC, 24% reduction and beta-MHC, 525% increase) and MHC gene expression (alpha-MHC, 18% reduction and beta-MHC, 15% increase). The results suggest that the beneficial effects of ACE inhibition on the failing heart are associated with improvements in myofibrillar ATPase activities as well as prevention of changes in MHC isozyme protein contents and their gene expression.

Topics: Adenosine Triphosphatases; Angiotensin-Converting Enzyme Inhibitors; Animals; Gene Expression Regulation; Imidazoles; Imidazolidines; Male; Myocardial Infarction; Myofibrils; Myosins; Protein Isoforms; Rats; Rats, Sprague-Dawley; RNA, Messenger

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

The in vivo activation of transcription factors, which is important for cell regulation by gene expression, has not been well examined in myocardial infarcted heart. The purpose of this study was to determine whether myocardial signal transducer and activator of transcription (STAT) pathway is activated as sis-inducing factor (SIF) in infarcted heart, and to assess the angiotensin blockade on SIF activity in ischemic and non-ischemic myocardium of rat. Myocardial infarction was made by ligation of the coronary artery in Wistar rats. In electrophoretic mobility shift assay, myocardial SIF DNA binding activities gradually increased and reached to peak at 1 week in infarcted and non-infarcted regions after myocardial infarction. Imidapril and candesartan cilexitil significantly prevented the increase in SIF DNA binding activity in infarcted and non-infarcted regions. This increased SIF DNA complex was supershifted by specific anti-STAT3 antibody, indicating that increased SIF complex at least contained activated STAT3 proteins in myocardial infarcted heart. Furthermore, immunoprecipitation-Western blot analysis revealed that STAT3 of infarcted and non-infarcted regions were tyrosine-phosphorylated at 1 week after myocardial infarction. Imidapril and candesartan cilexitil prevented the increase in phosphorylated STAT3. Thus, the transcriptional activation of STAT3 through AT1 receptor may be partially involved in cardiac remodeling after myocardial infarction.

Topics: Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Angiotensins; Animals; Benzimidazoles; Biphenyl Compounds; DNA-Binding Proteins; Heart Ventricles; Hemodynamics; Imidazoles; Imidazolidines; Male; Myocardial Infarction; Organ Size; Phosphorylation; Rats; Rats, Wistar; Sp1 Transcription Factor; STAT3 Transcription Factor; Tetrazoles; Time Factors; Trans-Activators; Tyrosine

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

For this study, we used (NZW x BXSB)F1 male mice as a model of myocardial infarction. The animals were kept on water containing imidapril or enalapril at 60 mg/kg/day from 10 to 27 weeks of age. Imidapril and enalapril significantly reduced the blood pressure. Imidapril reduced the mortality rate more significantly than enalapril did. In the second experiment where imidapril, enalapril and captopril were administered to the mice at 5 mg/kg/day, p.o., both imidapril and captopril significantly reduced the mortality, but enalapril did not. Blood pressure was slightly reduced by these ACE inhibitors. These data suggest that imidapril and captopril are efficacious for the treatment of myocardial infarction and blood pressure reduction hardly contributes to its mechanism of action.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Pressure; Coronary Disease; Disease Models, Animal; Dose-Response Relationship, Drug; Female; Heart Rate; Imidazoles; Imidazolidines; Male; Mice; Mice, Inbred Strains; Myocardial Infarction