Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Positive inotropic agents that increase the sensitivity of myofilaments to calcium have recently been described (Kitada et al., 1987; Cottney et al., 1990; Ferroni et al., 1991; Lee and Allen, 1991; Beier et al., 1992). These drugs appear to augment contractility independently of cAMP or calcium, and thus may have fewer of the adverse side effects seen with other currently available agents (Katz, 1986; Packer 1989). The clinical utility of "calcium-sensitizers" has been questioned on the theoretical grounds that such agents may interfere with relaxation and impair diastolic function (Hajjar and Gwathmey, 1991). Previous studies have shown a small but significant negative lusitropic effect of the calcium sensitizer EMD 53998 in ferret papillary muscle, although this effect was considered to be outweighed by powerful augmentation of contractility. Modelling studies have suggested that the impairment of relaxation by calcium-sensitizers may be even more severe when myocardial calcium is abnormally elevated, such as in hypoxia (Allen and Orchard, 1987; Lodge and Gelband, 1988) and end-stage heart failure (Hajjar and Gwathmey, 1991). We have examined the effects of EMD 53998 and milrinone on contractility and calcium flux in a cell culture model of myocardial hypoxia. The results indicate that increased calcium sensitivity results in marked impairment of relaxation under hypoxic conditions, possibly due to the impaired calcium sequestration and increased calcium availability exhibited by hypoxic myocytes. These studies show that the effects of calcium sensitizers can be strongly influenced by the prevailing status of intracellular calcium handling, and may be deleterious in the diseased or ischemic myocardium.
J Mol Cell Cardiol 1993 Jul
PMID:Negative lusitropy and abnormal calcium handling in hypoxic cardiac myocytes exposed to the calcium-sensitizer EMD 53998. 823 Feb 39

This study examined the potential role of ET-1 and the contribution of protein kinase C (PKC) in the desensitization of the ET-1 transmembrane signaling pathway in the left circumflex coronary artery (CCA) of a dog model of congestive heart failure (CHF). In the CCA of the rapid ventricular pacing-overdrive dog model of CHF, elevated plasma endothelin levels were associated with a decrease in the basal accumulation of inositol phosphates and ET-1 mediated activation of phosphatidylinositol (PI) turnover (P < 0.05). To assess whether elevated plasma ET-1 levels may have contributed to the diminished ET-1 responsiveness in the heart failure dogs, ET-1 generation of inositol phosphates was measured following a one hour pretreatment of normal coronary artery rings with 0.1 nM ET-1. As compared to non-treated rings, ET-1 pretreatment resulted in a 33% decrease of ET-1 (10 nM) production of inositol phosphates. To evaluate the role of PKC in this process, normal coronary rings pretreated for a period of one hour with the phorbol ester, phorbol 12-myristate 13-acetate (PMA, 1 microM), resulted in a similar attenuation (36%) of ET-1 production of inositol phosphates. In the presence of the protein kinase C inhibitor staurosporine, both the agonist and phorbol ester induced decreases in ET-1 mediated PI turnover were reversed. Staurosporine even potentiated (75%) ET-1 induced PI turnover despite ET-1 and PMA pretreatments. These results suggest that agonist-induced desensitization of ET-1 mediated PI turnover can occur and is at least one of the possible mechanisms contributing to the desensitization of the ET-1 transmembrane signaling pathway in the pacing-overdrive model of heart failure in the dog.
J Mol Cell Cardiol 1993 Aug
PMID:Regulation of the endothelin-1 transmembrane signaling pathway: the potential role of agonist-induced desensitization in the coronary artery of the rapid ventricular pacing-overdrive dog model of heart failure. 826 60

To elucidate the relationship between functional alterations and disturbances in myocardial energy metabolism of rats with heart failure following coronary artery ligation, the left coronary artery of the rat was ligated and the time course of changes in cardiac function and myocardial energy state of the animal were examined for 12 weeks after the ligation. Coronary artery ligation resulted in approximately 40% infarction of the left ventricle, an increase in the right ventricular weight, a decrease in left ventricular developed pressure, an increase in left ventricular end-diastolic pressure throughout the experiment, suggesting the development of cardiac failure after the operation. Cardiac output and stroke volume indices were not altered during the first 4 weeks, but were significantly decreased on the 8th and 12th weeks, suggesting that cardiac function had further aggravated by 8 weeks after the operation. Myocardial energy profiles of the scar tissue, the remaining left ventricle and interseptum, and the right ventricle were determined. Tissue ATP (27.54 +/- 0.82 to 26.38 +/- 1.58 mumol/g dry tissue; n = 8-10) and creatine phosphate (26.73 +/- 1.63 to 24.38 +/- 1.83 mumol/g dry tissue; n = 8-10) of the remaining viable left ventricle were lower than control (33.17 +/- 0.73 and 40.04 +/- 1.07 mumol/g dry tissue; n = 8) throughout the experiment. A marked decrease in tissue ATP and CP was seen in the scar tissue throughout the experiment. Increases in tissue lactate of the remaining left ventricle and the right ventricle were detected from 1 to 2 weeks after the operation, but returned to the control levels thereafter. Mitochondrial oxygen consumption rates of isolated myocardial bundles from the 8th and 12th weeks (21.03 +/- 2.22 and 17.79 +/- 3.24 ng oxygen/min/mg dry tissue; n = 8) were lower than control (33.15 +/- 1.95 ng oxygen/min/mg dry tissue; n = 5), and those of the interseptum (23.71 +/- 1.33 ng oxygen/min/mg dry tissue; n = 8) and the right ventricle (22.44 +/- 2.73 ng oxygen/min/mg dry tissue; n = 8) on the 12th week after the operation were lower than control (33.58 +/- 2.80 and 34.83 +/- 2.64 ng oxygen/min/mg dry tissue; n = 5). The results provide evidence for a decline in myocardial energy store and energy producing ability associated with the development of cardiac failure.
J Mol Cell Cardiol 1993 Sep
PMID:Regional energy metabolism of failing hearts following myocardial infarction. 828 76

Ventricular cardiomyocytes represent the most important source of atrial natriuretic factor (ANF) in pathological conditions such as congestive heart failure (CHF). It has been suggested that in cardiomyopathic Syrian hamster ventricles the ANF gene can be reactivated during the hypertrophic stage occurring before heart failure. The present study was undertaken to investigate ANF gene expression during early stages of myocardial damage and its distribution throughout atrial and ventricular myocardium in UM-X7.1 cardiomyopathic Syrian hamsters (CMPH) before hypertrophy and cardiac failure occur. Atria, right and left ventricles, and interventricular septum of hearts of 20-23 days old (young) and 90-95 days old (adult) CMPH were studied. The absence of hypertrophy and cardiac failure was preliminarly ascertained by microscopic and hemodynamic evaluation. ANF-mRNA as well as tissue and plasma immunoreactive ANF were assayed. Moreover, ANF secretion pattern was evaluated by immunocytochemical techniques. Young and adult CMPH hearts were in the necrotic stage of myocardial disease, as demonstrated by histopathological evaluation and by decreased wet weights (mg/g body weight) of different heart regions. Hemodynamic assessment showed no significant changes of left ventricular end-diastolic pressure (LVEDP) and a decrease of the left ventricular peak systolic pressure (LVSP) and +dP/dt. Plasma immunoreactive ANF (IR-ANF) levels were higher in young (3-fold) and adult (6-fold) CMPH than in age-matched normal hamsters. A reduced IR-ANF concentration (per milligram protein) was observed in both young and adult cardiomyopathic atria in respect to healthy controls, whereas a higher IR-ANF concentration was present in ventricles. A 3-fold, 6-fold and 20-fold increase of IR-ANF concentration was found in right ventricular free-wall (RV), left ventricular free-wall (LV) and interventricular septum (IVS), respectively. Northern-blot analysis confirmed that IVS was the major site of ventricular ANF-mRNA transcription in both young and adult CMPH. ANF-mRNA was increased also in atria where a faster peptide secretion can be hypothesized to lower tissue IR-ANF concentration. ANF secretion in ventricular myocardium was achieved via constitutive pathway as demonstrated by immunocytochemistry. Different patterns of ANF gene reactivation occur in CMPH myocardium before intraventricular pressure increases and structural hypertrophic modifications are detectable. The extent of ANF gene reactivation in CMPH ventricles parallels the severity of necrotic damage. Moreover, ANF gene expression is heterogeneously distributed throughout the myocardium, suggesting that interventricular septum, the ontogenically youngest heart region, might preserve foetal characters which can be rapidly reactivated in pathological conditions.
Mol Cell Biochem 1993 Aug 25
PMID:Myocardial expression of atrial natriuretic factor gene in early stages of hamster cardiomyopathy. 828 73

Endocardial endothelium has been shown to modulate the contractile characteristics and alpha-1-adrenergic responsiveness of its adjacent myocardium. This study was designed to evaluate whether this was also the case in the pacing-overdrive model of heart failure in the dog, a model in which changes in contractile characteristics and changes in alpha-1-adrenergic responsiveness similar to those caused by endocardial endothelial removal, occur prior to endocardial endothelial removal. Pacing-overdrive heart failure caused a decrease in total tension (TT) (5.1 +/- 0.5 g/mm2 in controls to 2.2 +/- 0.4 g/mm2 in pacing-overdrive, P < 0.01) and twitch configuration (time to 1/2 tension decline [RT1/2] 659 +/- 23 to 517 +/- 41 ms P < 0.01) to occur in isolated papillary muscles. Endocardial endothelial removal in control muscles caused similar but less marked changes (TT to 3.8 +/- 0.3 g/mm2, and RT1/2 to 563 +/- 21 ms). Endocardial endothelium removal also decreased TT (to 1.6 +/- 0.3 g/mm2) and RT1/2 (459 +/- 28 ms) in pacing-overdrive muscles indicating that even in this model of heart failure, endocardial endothelium continued to modulate the contractile characteristics of its adjacent myocardium. The addition of phenylephrine caused proportionately similar changes in contractile characteristics in both control and pacing-overdrive muscles prior to and after endocardial endothelial removal. However, in control muscles, endocardial endothelial removal caused a rightward shift in phenylephrine concentration-response curve (EC50 0.6 +/- 0.2 x 10(-6)M to 3.4 +/- 1.0 x 10(-6)M, P < 0.05). Pacing-overdrive muscles already had a rightward shift (EC50 = 4.1 +/- 1.0 x 10(-6)M) prior to endocardial endothelium removal, such that endocardial endothelial removal caused no further shift in EC50 (2.8 +/- 1.0 x 10(-6)M) indicating that the decrease in alpha-1-adrenergic responsiveness in this model was endocardial endothelium dependent. Taken together, these results suggest that the direct modulating effects of the endocardial endothelium on its adjacent myocardium are not necessarily related to its modulatory role on the myocardial effects of circulating substances in the plasma and, that in heart failure, the decrease in alpha-1-adrenergic responsiveness that occurs is related to endocardial endothelium dysfunction.
J Mol Cell Cardiol 1993 May
PMID:Endocardial function in pacing-induced heart failure in the dog. 837 13

In human heart failure, an increase in frequency of stimulation is followed by a reduced force of contraction in vivo and in vitro. The present study aimed to investigate whether a different origin of the myocardial sample or pretreatment with the cardioprotective agent 2,3-butanedione-monoxime (BDM) influences the force-frequency-relationship in electrically driven muscle strips taken from failing and nonfailing human myocardium. With as well as without pretreatment with BDM, the altered force-frequency-relationship in failing compared to nonfailing human ventricular myocardium can be observed. The effectiveness and the potency to increase force of contraction following an increase in frequency of stimulation was significantly higher in atrial than in ventricular myocardium in nonfailing and failing tissue. The different observations in atrial and ventricular myocardium provide evidence for functionally relevant differences in the electromechanical coupling between the human atrial and ventricular myocardium.
Mol Cell Biochem 1993 Feb 17
PMID:Force-frequency-relation in human atrial and ventricular myocardium. 845 89

To determine whether calcium channel blockade is effective in the prevention of the cascade of events leading to the thin walled, decompensated ventricle observed in ischemic heart failure, inhibition of transsarcolemmal transport of calcium by nisoldipine was examined in rats in which luminal narrowing of the left main coronary artery was utilized to produce global cardiac ischemia. Coronary artery narrowing was produced in rats at 2 months of age and animals were maintained on nisoldipine (10 mg/kg body weight) (CANN) or water (CANW) until time of sacrifice 1 month later. Surgical intervention resulted in a 50% reduction in coronary artery luminal diameter in both experimental groups and was associated with an increase in kidney and lung weights in only CANW animals. Heart weights were also increased in the water treated coronary artery narrowed group. In CANW rats, systemic arterial and left ventricular systolic pressures were reduced whereas left ventricular diastolic pressures were elevated. Peak rates of pressure rise and decay and cardiac output were also reduced in CANW rats. Treatment with nisoldipine prevented the detrimental impact of ischemic heart disease to an extent that all measured parameters in CANN rats were found to be intermediate between unoperated controls and CANW animals. Thus, calcium channel blockade was therapeutic in the prevention of cardiac dysfunction and failure seen after the onset of ischemic heart disease in rats. Furthermore, the detrimental impact of ischemic heart disease was ameliorated by early and continuous treatment with the calcium channel blocker, nisoldipine.
J Mol Cell Cardiol 1995 Sep
PMID:Nisoldipine improves ventricular function in rats with ischemic heart failure. 852 45

We made acute cardiac failure in excised cross-circulated canine hearts by a new coronary perfusion protocol consisting of Ca2+ free Tyrode perfusion for the first 10 min, high Ca2+ (16 mmol/l) Tyrode perfusion for the next 5 min, and normal Tyrode perfusion for the last 5 min interrupting blood cross circulation. After 50 min from the blood recirculation, left ventricular contractility was stably depressed to 60% of control. We studied mechanoenergetics of these acute failing hearts for the next 1-3 h. Then, we prepared mitochondria from these excised failing hearts and the support dogs' normal hearts to examine their mitochondrial respiratory function by the respiratory control index (RCI) and the oxygen consumption rate in state III (State III O2). RCI and State III O2 were significantly smaller in the failing hearts than in the normal hearts. However, sham protocol consisting of normal Tyrode coronary perfusion for 20 min did not affect RCI and State III O2. These results revealed that the mitochondrial respiratory function was moderately impaired in these acute failing hearts made by the new short-term Ca2+ intervention. However, no ultrastructural injuries of mitochondria were detected in these failing hearts.
J Mol Cell Cardiol 1995 Sep
PMID:Suppression of myocardial mitochondrial respiratory function in acute failing hearts made by a short-term Ca2+ free, high Ca2+ coronary perfusion. 852 60

The objective of this study was to evaluate the tension-frequency relationship in normal and cardiomyopathic myocardium from one species with a negative or biphasic relationship, the hamster, and one with a positive relationship, the dog. Left ventricular papillary muscles from 100-day-old normal Syrian and cardiomyopathic (CHF-147) hamsters and right ventricular papillary muscles or trabeculae from normal mongrel dogs and dog with pacing-induced heart failure were used for the study. Stimulation frequency was varied from 1 to 90/min and isometric contractions recorded at each frequency prior to and after the addition of phenylephrine 10 microM. A tension-frequency relationship at varying extracellular calcium concentrations (1.25, 2.5 and 5.0 mM) was also constructed in normal hamster myocardium. Ryanodine 1.2 microM was added to a bath with normal hamster muscles and a force-frequency relationship constructed prior to and after adding phenylephrine 10 microM. A calcium dose-response curve in normal and cardiomyopathic dog myocardium was also constructed. Normal and cardiomyopathic hamster myocardium had a biphasic tension-frequency relationship with the increase in tension during the second phase being greater in normal v cardiomyopathic hamster myocardium (0.66 +/- 0.19 v 0.12 +/- 0.03 g/mm2, P < 0.05). The initial decrease in tension in response to increasing stimulation frequency was markedly attenuated in normal hamster myocardium by increasing extracellular calcium concentration. Developed tension was eliminated at lower stimulation rates by ryanodine such that when developed tension did occur, it increased with increasing stimulation rates. The addition of phenylephrine to hamster myocardium modified the tension-frequency relationship of both normal and cardiomyopathic dog myocardium and their response to phenylephrine were similar. In each case, tension increased progressively with increasing stimulation rate. Although the absolute increase in tension caused by increasing extracellular calcium was less in cardiomyopathic dog myocardium, the percent increase in tension and shortening was greater. We conclude that the tension-frequency relationship of normal and cardiomyopathic hamster myocardium are biphasic, with the initial negative phase being the result of limitations of sarcoplasmic reticulum calcium handling. Phenylephrine modifies this relationship to a uniphasic positive one, likely by its effects on both the sarcolemma and the sarcoplasmic reticulum. Also, the tension-frequency relationship of normal and cardiomyopathic dog myocardium are similar and unmodified by phenylephrine.
J Mol Cell Cardiol 1995 Jun
PMID:Tension-frequency relationships in normal and cardiomyopathic dog and hamster myocardium. 853 Dec 7

Although pharmacological therapy with angiotensin converting enzyme (ACE) inhibitors has proved to be effective in patients with heart failure (HF), the experimental basis of this effect has not yet been addressed. In the present study, animals with HF were treated with an oral administration of 10 mg/kg/day captopril, 10 mg/kg/day enalapril and 3 mg/kg/day trandolapril from the 2nd to 12th week after the operation. HF was induced by permanent occlusion of the left coronary artery of the rat at 2 mm from its origin. Treatment of the HF rats with the ACE inhibitors enhanced the decrease in mean arterial blood pressure, attenuated the rise in left ventricular end-diastolic pressure, an indirect marker of preload, and diminished the reduction in cardiac output and stroke volume indices of the HF animal. Treatment also reversed the reduction in ATP, creatine phosphate, creatine and the mitochondrial oxygen consumption rate of the viable left and right ventricles of the HF animal. The improvement of the cardiac output index and high-energy phosphate levels of the HF rat by the ACE inhibitors was associated with the recovery of the mitochondrial oxygen consumption rate. In sham-operated animals, treatment with the ACE inhibitors reduced mean arterial pressure and left ventricular systolic pressure, but not metabolic variables concerning myocardial energy metabolism. The present results provide evidence that ACE inhibitor therapy improves cardiac function and myocardial energy metabolism of experimental animals with chronic heart failure. The mechanism underlying the benefit of long-term treatment with ACE inhibitors is probably attributable to recovery or preservation of the mitochondrial function and reduction in preload.
J Mol Cell Cardiol 1995 Oct
PMID:Effects of long-term therapy with ACE inhibitors, captopril, enalapril and trandolapril, on myocardial energy metabolism in rats with heart failure following myocardial infarction. 857 37


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