Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.10.1 (ERK)
95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The aim of the present study was to determine, in rats with myocardial infarction, the systemic and cardiac hemodynamic effects of aladotrilat and of its prodrug, aladotril, both of which display inhibitory activity toward both neutral endopeptidase (NEP, EC. 3.4.24.11) and angiotensin I-converting enzyme (ACE). The effects of acute intravenous injection of aladotrilat (30 mg/kg bolus injection plus 30 mg/kg/hr infusion) were measured for 1 hr in conscious infarcted rats and compared with the effects of SQ 28,603, a selective NEP inhibitor (30 mg/kg bolus injection plus 30 mg/kg/hr infusion), and captopril, a selective ACE inhibitor (10 mg/kg bolus injection plus 10 mg/kg/hr infusion). Unlike SQ 28,603, aladotrilat and captopril produced a slight fall in mean arterial blood pressure. The three treatments had no significant effect on heart rate and rate of increase of left ventricular pressure (LV + dP/dt) but caused significant decreases in left ventricular end-diastolic pressure (LVEDP). The effect of aladotrilat on decreasing LVEDP was faster than those of captopril or SQ 28,603. In chronic experiments, groups of rats received orally, twice daily, captopril (10 mg/kg), aladotril (100 mg/kg) or vehicle. Treatments were started 18 to 20 hr after coronary artery ligation and continued for 4 weeks. Hemodynamic parameters and cardiac hypertrophy were measured at the end of therapy. Unlike aladotril, captopril treatment resulted in significant decreases in mean arterial blood pressure and left ventricular systolic pressure (approximately 15 mm Hg) and produced renal vasodilation.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Hemodynamic effects of acute and chronic treatment with aladotril, a mixed inhibitor of neutral endopeptidase and angiotensin I-converting enzyme, in conscious rats with myocardial infarction. 853 Oct 99

Myocardial infarction in consequence of a coronary artery occlusion presents a serious problem. It is the aim of any emergency revascularization to minimize the ischemia-induced damage or to salvage reversibly injured myocardium. In experiments on 8 anesthetized pigs, myocardial protection by orthograde perfusion with a high-volume cardioplegic solution was studied under controlled conditions. The left anterior descending artery (LAD) was occluded for 60 min. Then cardiopulmonary bypass was instituted and cardioplegia induced by 8 min perfusion of Bretschneider HTK solution into the aortic root. After 15 min global ischemia, the LAD was "revascularized' and 150 min reperfusion followed. Except for the early relaxation (dP/dtmin) and mean thickening velocity in the ischemic myocardium, all variables remained essentially unchanged during LAD occlusion. During the entire reperfusion, heart rate was significantly increased compared to control: 93 +/- 23 vs. 126 +/- 20/min. Left-ventricular (LV) peak pressure was significantly decreased at the end of the reperfusion, 104 +/- 33 and 77 +/- 22 mmHg, as was dP/dtmax:2155 +/- 655 vs. 1720 +/- 895 mmHg/s. Cardiac output was insignificantly decreased at the end of reperfusion, 2.6 +/- 0.6 vs. 2.4 +/- 0.5 L/min, whereas stroke-work index exhibited a significant deterioration: 1.2 +/- 0.6 vs. 0.5 +/- 0.3 mmHg.ml/kg. LV dP/dtmin was significantly impaired after ischemia and at the end of reperfusion, -1575 +/- 385 vs. -855 +/- 310 mmHg/s, while LV end-diastolic pressure exhibited only a moderate increase: 8 +/- 5 vs. 9 +/- 3 mmHg. MVO2, in turn, remained almost constant throughout the protocol for each of two methods by which it was predicted. The results show that global work, MVO2, and external efficiency were unchanged during early and late occlusion compared to control. During the entire reperfusion the myocardium was stunned, i.e. cardiac work was decreased at maintained MVO2. Thus, external efficiency was decreased. From these results we conclude that in reperfused myocardium after cardioplegic arrest, the oxygen is only inefficiently converted to develop force.
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PMID:Cardiac efficiency during coronary occlusion and during reperfusion after emergency revascularization under cardioprotection. 872 96

Ventricular arrhythmias remain a major problem, in particular in patients with left ventricular dysfunction or heart failure. In this group of patients, Class I drugs were shown to be ineffective, and they even increased mortality during chronic treatment. New antiarrhythmic agents should preferably not only have pure antiarrhythmic effects, but should also be free from adverse autonomic properties. In the present study, the electrophysiological, rate dependent and autonomic effects of intravenously administered almokalant, a new Class III antiarrhythmic drug, were investigated in nine pigs surviving a myocardial infarction. The ventricular effective refractory period (VERP) increased after almokalant (loading dose: 0.05 mumol.kg-1.min-1, continuous infusion: 0.0025 mumol.kg-1.min-1) from 292 +/- 25 to 308 +/- 13 ms (pacing cycle length [PCL] 500 ms + 1 extrasystole [ES]), from 249 +/- 19 to 261 +/- 16 ms (PCL 400 ms +1ES), and from 209 +/- 18 to 219 +/- 18 ms (PCL 300 ms +1ES). The VERPs increased most after three ES at PCL 400 ms: from 167 +/- 27 to 186 +/- 29 ms (P < 0.05) and at PCL 300 ms: from 150 +/- 29 to 174 +/- 27 ms (P < 0.05). The ventricular monophasic action potential durations (MAPD) were similarly prolonged and the ratio VERP/MAPD did not change. Prolongation of MAPD after almokalant remained present at short pacing cycle lengths. Before almokalant infusion, sustained monomorphic ventricular tachycardia (VT) was inducible in two pigs, and nonsustained VT in a third animal. After almokalant, only one pig remained inducible. Two weeks after myocardial infarction, heart rate variability and baroreflex sensitivity were reduced. Furthermore, subsequent electrophysiological testing transiently reduced these parameters of autonomic activity. During almokalant however, no changes in autonomic functions were observed after programmed stimulation. Heart rate variability decreased after myocardial infarction from 6.3 +/- 2.5 ms to 5.4 +/- 4.2 ms (P = NS). After programmed stimulation, it further decreased to 2.8 +/- 2.0 ms (P = 0.028). Almokalant infusion prevented autonomic deterioration: 3.3 +/- 2.2 ms before stimulation and 3.3 +/- 1.3 after stimulation (P = NS). In postinfarct pigs, almokalant prolongs VERP and MAPD at shorter pacing cycle lengths. The results indicate absence of reverse rate dependence and of adverse autonomic changes.
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PMID:Electrophysiological, rate dependent, and autonomic effects of the class III antiarrhythmic almokalant after myocardial infarction in the pig. 873 47

Myocardial infarction was induced by rats by ligation of the left coronary artery. Treatment with TM1, a prodrug of SQ 28,603, an inhibitor of neutral endopeptidase (NEP, EC 3.4.24.11), was started 18-20 hours after ligation and was continued for 4 weeks (100 mg/kg, orally, twice daily). Morphological and biochemical parameters were assessed at the endo of therapy. The treatment resulted in a significant reduction of heart hypertrophy, which was restricted to the parts of myocardium hemodynamically upstream of the infarcted left ventricle. The weights of the right ventricle and atria were reduced by 15-20%, whereas the treatment had no effect on the left ventricle and septum weights. Treatment led to an almost complete inhibition of plasma NEP activity and to a slight decrease (-14%, p < 0.05) in plasma ACE activity. Plasma ANF level increased 3.8-fold after ligation, and treatment resulted in a slight ( + 29%) and nonsignificant additional increase in the ANF level. The amount of hydroxyproline in the right ventricle was enhanced by + 207% in control ligated rats and by +140% (NS) in treated rats. These data indicated that prolonged NEP inhibition exerts a favorable effect in heart failure by reducing the development of right ventricular and atrial hypertrophy. These effects may result from an improvement in hemodynamic conditions, leading to a reduction in cardiac preload.
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PMID:Effect on prolonged inhibition of neutral endopeptidase on cardiac hypertrophy in rats with myocardial infarction. 895 76

During myocardial ischemia, inhibition of the carnitine-mediated transportation of fatty acid may be beneficial because it facilitates glucose utilization and prevents an accumulation of fatty acid metabolites. We orally administered 3-(2,2,2-trimethyl hydrazinium) propionate (MET), an inhibitor of carnitine synthesis, for 20 days to rats. Then we evaluated left ventricular (LV) function during brief ischemia by using a buffer-perfused isovolumic heart model. After 15 min of reoxygenation after the transient ischemia, LV peak systolic pressure (PSP) almost completely returned to the baseline level in rats given MET (96 +/- 4%), whereas it was only partially (77 +/- 16%) recovered in the placebo-treated rats. We induced myocardial infarction in other rats by ligating the left anterior descending coronary artery. Then the animals were given MET for 20 days, and LV function was compared. In the placebo-treated rats (with myocardial infarction, but without drug treatment), LVPSP was lower than that in the sham group [108 +/- 19 (n = 10) vs. 136 +/- 15 mm Hg (n = 13); p < 0.05], and the time constant (T) of LV pressure decay was elongated (36 +/- 4 vs. 30 +/- 7 ms; p < 0.05). In MET-treated groups, however, neither PSP nor T differed from those in the sham group. In conclusion, inhibition of the carnitine-mediated transportation of fatty acid by MET protected against left ventricular dysfunction in acute and chronic myocardial ischemia.
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PMID:Inhibition of carnitine synthesis protects against left ventricular dysfunction in rats with myocardial ischemia. 933 6

One important promoter element at the 5' end of the c-fos gene is the serum response element (SRE). SRE is the site of attachment of the 67-kDa protein serum response factor (SRF) and several accessory proteins (Elk1, SAP1, SAP2/NET), termed the ternary complex factors. The binding of SRF to SRE plays an integral role in c-fos transcription and may occur independently of the association of the ternary complex factors. In the current study, we found that SRF protein expression was increased in the hearts of the old vs young adult rats in the basal condition. The hearts of old rats may have posttranslationally modified SRF proteins that are different compared to that of the young adults. The SRF increase was present both in the cytoplasm as well as in the nucleus in the old hearts. To test whether SRF protein levels in response to acute stress might be altered with age, we studied hearts of young adult and old rats during myocardial infarction. The young adult rat hearts responded to acute ischemic stress with an increase in both p62 and p67 SRF. The hearts of the old rats, however, did not exhibit a significant change in SRF protein expression. These findings demonstrate qualitative as well as quantitative age differences in SRF protein levels, both at baseline and following stimulation. The reduced SRF expression in response to acute cardiac ischemic stress in the old rats might contribute to the observed age-related decrease in the induction of immediate early genes such as c-fos in the heart.
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PMID:SRF binding to SRE in the rat heart: influence of age. 946 16

The extent and distribution of myocardial edema induced by perfusion with cardioprotective solutions is of great interest. Domestic pig hearts (n = 12) were perfused in situ after aortic cross clamping either with Bretschneider's cardioplegic solution (HTK, 4 degrees C, n = 3), with a heparinized Krebs-Henseleit solution containing 30 mmol/L 2,3 Butanedionemonoxime (BDM, 4 degrees C, n = 3) or with heparinized pig blood (HPB, 24 degrees C, n = 3). After a three-hours storage period, magnetic resonance tomography (MRI) was carried out. The acquired T1-weighted data were used for the subsequent three-dimensional reconstruction based on the "Heidelberg ray-tracing technique". The small myocardial tissue blocks (n = 216) were excised from these hearts for dry weight measurements for 9 preselected regions in duplicate including ventricular papillary muscle, ventricular free wall, ventricular septum, apex, and atrial tissue. In control hearts (n = 3), dry weight was measured immediately after explantation (no MRI). The results of dry-weight measurements and three dimensional visualization were compared. Dry-weight measurements revealed that considerable myocardial edema is induced by any of the experimental procedures. The effects were most pronounced after BDM perfusion. Regardless how the edema was induced, there were significant differences of the water content within the heart: the water content in the heads of the papillary muscles and in the interventricular septum was always smaller than that of the free left- and right-ventricular walls. The heterogeneity of myocardial edema and its spatial distribution pattern could be qualitatively visualized. The experimental data (biophysical data and 3D visualization) clearly show a heterogeneity of myocardial edema induced by different types of cardioprotective solutions. As the presence of myocardial edema represents one of the crucial events in the pathophysiology of myocardial dysfunction occurring during myocardial infarction, ischemia, heart transplantation, and extracorporeal circulation, the present study represents an interesting contribution towards intravital detection and distribution of myocardial edema.
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PMID:Heterogeneity of myocardial edema in isolated pig hearts after perfusion with different types of cardioprotective solutions. 988 20

This study evaluated the prognostic significance of reinfarction location by considering the previous site or type of myocardial infarction (MI) among 1601 patients with a history of previous MI who took part in the International (non-Italian) tPA/STK trial and/or the Israeli GUSTO study population. These patients were accordingly divided and hospital mortality was compared by six location groups as follows: acute inferior with previous inferior (8.1% hospital mortality), acute inferior with previous anterior (12.8%), acute anterior with previous inferior (13.3%), acute anterior with previous anterior (11.1%), acute inferior with previous non-Q-wave MI (7.6%), and acute anterior with previous non-Q-wave MI (11.2%) (p = 0.17 for comparison between the six groups). Hospital mortality tended to increase among patients with an anterior reinfarction compared with those with an inferior one (12.1% vs. 9.5%, p = 0.12). Among patients with a reinfarction at a different ECG location from the previous event, mortality tended to be higher compared with patients with two MIs at the same location (13.1% vs. 9.7%, p = 0.07). Recurrent MI following a previous Q-wave MI did not cause a higher mortality compared with a previous non-Q-wave type of MI (11.5% vs. 9.5%, p = 0.24). Among patients sustaining reinfarction, overall mortality did not differ between STK- and tPA-treated patients (11.0% vs. 11.4%, p = NS). In conclusion, the current study identified trends for higher mortality rates in patients with anterior compared with inferior reinfarction, with remote compared with the same ECG location of the two infarctions but not following a previous non-Q-wave compared with Q-wave MI. However, no particular combination of successive MIs location was significantly associated with a higher risk for hospital mortality.
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PMID:Prognostic Importance of Previous Myocardial Infarction in Patients Receiving Thrombolytic Therapy for Acute Infarction. 1060 69

Myocardial ischemia can cause myocardial infarction and as a consequence, heart failure. 3-(2,2,2-trimethylhydrazinium) propionate (MET-88) inhibits gamma-butyrobetaine hydroxylase and has cardioprotective effects on the ischemic heart. We now examined the effects of MET-88 in rats with congestive heart failure following myocardial infarction. Congestive heart failure was produced by left coronary artery ligation in rats. MET-88 at 100 mg/kg/day was orally administered from the 2nd day after surgery. We performed a survival study for 181 days, and measured ventricular remodeling, cardiac function, and myocardial high-energy phosphate levels after treatment for 20 days. MET-88 prolonged survival with a median 50% survival of 103 days compared to 79 days for the heart-failure control rats. The expansion of the left ventricular cavity (ventricular remodeling) in heart-failure rats was prevented by treatment with MET-88, and the effect of MET-88 was similar to that of captopril at 20 mg/kg. MET-88 attenuated the rise in right atrial pressure in heart-failure rats and augmented cardiac functional adaptability against an increased load. Also, MET-88 improved the myocardial energy state in heart-failure rats. The present results indicate that MET-88 improves the pathosis in rats with heart failure induced by myocardial infarction.
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PMID:Beneficial effects of MET-88, a gamma-butyrobetaine hydroxylase inhibitor in rats with heart failure following myocardial infarction. 1081 52

It was previously reported that inhibition of carnitine synthesis by 3-(2,2,2-trimethyl-hydrazinium) propionate (MET-88) restores left ventricular (LV) systolic and diastolic function in rats with myocardial infarction (MI). Preservation of the calcium uptake function of sarcoplasmic reticulum Ca2+-ATPase (SERCA2) is one of the possible mechanisms by which MET-88 alleviates hemodynamic dysfunction. To test this hypothesis, the effects of MET-88 on protein content of SERCA2 were evaluated using the same rat model of heart failure. Myocardial protein content of hexokinase, which is one of the key enzymes of glucose utilization, was also measured. Either MET-88 (MET-88 group) or a placebo (MI group) was administered for 20 days to rats with MI induced by coronary artery ligation. The control group underwent sham surgery (no ligation) and received placebo. In LV myocardial homogenates, the myocardial SERCA2 protein content was 32% lower (p<0.05) in the MI group than in the control group. However, in the MET-88 group myocardial SERCA2 content was the same as in the control group. Hexokinase I protein content was 29 % lower (p<0.05) in the MI group compared with the control. In contrast, hexokinase II protein content did not differ significantly among the three groups. Consequently, inhibition of carnitine synthesis ameliorates depression of SERCA2 and hexokinase I protein content which may reduce tissue damage caused by MI.
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PMID:Inhibition of carnitine synthesis modulates protein contents of the cardiac sarcoplasmic reticulum Ca2+-ATPase and hexokinase type I in rat hearts with myocardial infarction. 1109 60


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