Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0018801 (heart failure)
 72,216 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cardiomyopathic hamsters (UM-X7.1) show clinical signs of congestive heart failure and an abnormal EKG pattern. The sarcolemmal fraction obtained from the failing hearts at advanced stages of myopathy exhibited no change in the basal adenylate cyclase activity; however, the activity of this enzyme in the presence of catecholamines or NaF was lower in the failing heart sarcolemma than that in the control. The activities of Ca2+-ATPase, Mg2+-ATPase, and Na+-K+-ATPase in the failing heart sarcolemma were also less than the control values. These results suggest an association of membrane defect with heart failure.
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PMID:Membrane alteration in failing hearts of cardiomyopathic hamsters. 12 77

Sarcolemmal Ca++-ATPase, Mg++-ATPase, and (Na+-K+)-ATPase activities were increased in late stages of heart failure in myopathic hamsters (BIO 14.6) without any changes in the adenylate cyclase activity. On the other hand, these hamsters at early and moderate stages of heart failure showed depressions in mitochondrial calcium binding and uptake and microsomal calcium binding. Sarcolemmal (Na+-K+)-ATPase was decreased in failing hearts because of substrate lack, oxygen lack, and perfusion with Ca++-free, Na+-free, or K+-free medium. Both Mg++-ATPase and Ca++-ATPase activities of sarcolemma did not change on perfusing the hearts with substrate-free, hypoxic, Na+-free, or K+-free medium. Adenylate cyclase activity decreased on substrate-free or Ca++-free perfusion. Intracellular calcium overload produced by perfusing the hearts with medium containing calcium after Ca++-free perfusion was associated with decrease in all the sarcolemmal-bound enzyme activities. All types of failing hearts employed in this study showed a dramatic shift in the electrolyte composition. Failure of the cardiac muscle to generate contractile force on treatment with trypsin was associated with defects in the functions of sarcolemma, mitochondria, and sarcoplasmic reticulum, whereas such an effect on treatment with phospholipase C was limited to alterations in the activities of sarcolemma. The data suggest that abnormality at the level of sarcolemma plays an important role in the pathogenesis of heart dysfunction; however, the degree and direction of alterations in the sarcolemmal functions seem to be dependent upon the type of heart failure.
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PMID:Role of sarcolemmal changes in cardiac pathophysiology. 13 Jun 63

We studied hearts from sham-operated and uninfected catheterized rabbits as well as from rabbits at early and late stages of cardiomyopathy and failure after 3 and 6 days of infection with Streptococcus viridans. No ultrastructural abnormalities or biochemical changes in membrane and myofibrillar activities were seen in 3-day uninfected hearts. In 6-day uninfected hearts there were decreased sarcolemmal M2+ ATPase, Na+-K+ ATPase, adenylate cyclase and calcium binding, microsomal calcium binding and uptake, and myofibrillar Ca2+-stimulated ATPase as well as increased mitochondrial calcium uptake. Slight ultrastructural changes also were apparent in 6-day uninfected hearts. At both early and late stages of infective cardiomyopathy and failure there were varying degrees of depression in sarcolemmal Mg2+ ATPase, Na+-K+ ATPase, adenylate cyclase and calcium binding, microsomal calcium binding, calcium uptake and basal ATPase, and myofibrillar Ca2+-stimulated ATPase activities. However, sarcolemmal Ca2+ ATPase and myofibrillar Mg2+ ATPase activities were decreased only after 6 days of infection. Mitochondrial calcium binding and uptake were increased in early stages but decreased in late stages of disease. Furthermore in infected hearts there were defects in mitrochondrial respiration and phosphorylation. Generalized severe myocardial cell damage involving myofibrils, mitochondria, and the sarcotubular system was seen only in late stages of infection. The results demonstrate impairment of different membrane and contractile protein functions as well as ultrastructural abnormalities in bacterial cardiomyopathic hearts which were absent or of lesser magnitude in hearts with only hypertrophy. The findings reported here suggest to use that there is an association between heart failure and changes in function of cellular components during bacterial infective cardiomyopathy.
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PMID:Abnormalities in heart membranes and myofibrils during bacterial infective cardiomyopathy in the rabbit. 13 11

1. The activities of some membrane-bound enzymes such as adenylate cyclase, Na+ + K+-stimulated adenosine triphosphatase (Na+ + K+-ATPase), Ca2+-stimulated ATPase and Mg2+-stimulated ATPase were examined in heart sarcolemmal fractions from control and cardiomyopathic hamsters at different stages of heart failure. 2. The basal adenylate cyclase activity in sarcolemma from cardiomyopathic animals with early, moderate and late stages of heart failure was not different from the control values whereas the sodium fluoride- and catecholamine-stimulated adenylate cyclase activities were depressed in cardiomyopathic sarcolemma at moderate and late stages. 3. The sarcolemmal Na+ + K+-ATPase activity was decreased and the non-specific phosphatase activity was increased at early, moderate and late stages of heart failure. 4. The sarcolemmal Ca2+-ATPase activity was decreased at moderate and late stages whereas the Mg2+-ATPase activity was decreased at the late stages of heart failure only. 5. A marked decrease was found in calcium binding by heart sarcolemma from cardiomyopathic hamsters at late stages of failure. 6. These results suggest that dramatic sarcolemmal changes are associated with heart failure, and support the view that membrane abnormalities play a crucial role in the development of myocardial dysfunction, cyclase, calcium binding, heart failure, heart membranes, sarcolemmal enzymes.
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PMID:Comparison of heart sarcolemmal enzyme activities in normal and cardiomyopathic (UM-X7.1) hamsters. 13 61

Sarcolemma consists of plasma and basement membranes and constitutes the real permeability barrier to the heart cell. It is considered to provide high electrical resistance and capacitance to heart cell and its properties are essentially similar to those of the other excitable membranes. Methods are now available for isolating heart sarcolemma with high specific activities of adenylate cyclase, (Na(+)-K(+) ATPase, Ca(++) ATPase, and Mg(++) APTase. These enzymes are considered to play an important role in heart function by regulating ion movements across sarcolemma as well as by providing signals for various metabolic processes. Sarcolemma possesses different hormone and drug receptors and any alteration in its composition could result in abnormal responses of the myocardium. We believe that heart failure is associated with sarcolemmal defects which can be detected by monitoring the activities of different membrane-bound enzymes and other related processes.
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PMID:Heart sarcolemma as a dynamic excitable membrane. 17 91

The present study investigated the effects of celiprolol a novel beta 1-antagonist with partial beta 2-agonist activity on the human failing heart. Experiments were performed on isolated electrically driven atrial and ventricular cardiac preparations and in membrane preparations from the left ventricles of nine patients (four with dilated cardiomyopathy; five with ischemic cardiomyopathy) undergoing cardiac transplantation for terminal heart failure. Celiprolol produced a negative inotropic effect in atrial and ventricular heart muscle. However, in the presence of forskolin--which activates the catalyst of the adenylate cyclase-or the cAMP phosphodiesterase inhibitor milrinone, celiprolol produced concentration-dependent positive inotropic effects and positive lusitropic effects. Experiments with the beta 1-and beta 2-selective antagonists CGP 207.12A and ICI 118.551, respectively, suggest that the positive inotropic response is mediated by beta 2-adrenoceptors. In radioligand binding experiments, a selectivity of 15.7 [-Gpp(NH)p] or 23.9 [+Gpp(NH)p] as judged from the Ki values--of binding to beta 2-adrenoceptors was measured in the failing human ventricular myocardium. Competition curves with celiprolol alone and in the presence of the guanine nucleotide Gpp(NH)p revealed no evidence for agonist activity at beta 1- or beta 2-adrenoceptors. It is concluded that amplification of the cAMP response is able to unmask partial agonist activity of celiprolol in the failing human heart at beta 2-adrenoceptors. The inotropic measurements are a more sensitive approach than radioligand binding studies. Whether the pharmacological profile of celiprolol will be useful in conditions like heart failure is questionable with respect to the potential downregulation of beta 2-adrenoceptors by its partial agonist activity.
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PMID:Positive inotropic effects due to partial agonistic activity of the beta-adrenoceptor antagonist celiprolol following amplification of cAMP formation in failing human myocardium. 127 96

The present study investigated whether reduced adenylate cyclase activity and an increase in inhibitory guanine nucleotide binding proteins (Gi alpha), which have been observed in the failing human heart, already occur in myocardial hypertrophy before the stage of heart failure. In membranes of hypertrophic hearts from rats with different forms of experimentally induced hypertension without heart failure (one-kidney, one clip rats, deoxycorticosterone-treated rats, and rats with reduced renal mass), basal as well as isoprenaline-, 5'-guanylylimidodiphosphate-, and forskolin-stimulated adenylate cyclase activity was reduced. The activity of the catalyst was depressed in deoxycorticosterone but unchanged in one-kidney, one clip and reduced renal mass compared with controls. The number of beta-adrenergic receptors was similar in all groups. Radioimmunological quantification of Gi alpha proteins revealed an increase by 73% in one-kidney, one clip, 67% in reduced renal mass, but only 20% in deoxycorticosterone compared with sham-operated, age-matched control rats. The increase of Gi alpha was accompanied by smaller changes of pertussis toxin-induced [32P]ADP-ribosylation of a 40-kd membrane protein. It is concluded that Gi alpha contributes to the reduced adenylate cyclase activity in cardiac hypertrophy in one-kidney, one clip and reduced renal mass and to a smaller extent in deoxycorticosterone. It is suggested that an enhanced expression of Gi alpha could occur not only in severe heart failure but also in cardiac hypertrophy and could, therefore, contribute to myocardial depression and progression of disease in heart failure. In addition, Gi alpha might represent an important regulatory mechanism for cardiac adenylate cyclase activity and thus, might play an important role in various cardiac diseases.
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PMID:Desensitization of adenylate cyclase and increase of Gi alpha in cardiac hypertrophy due to acquired hypertension. 131 58

Catecholamines acting through beta 1- and beta 2-adrenergic receptors cause positive inotropic and chronotropic effects in the human heart. However, recent evidence suggests that in the human heart other receptor systems can also affect heart rate and contractility. Positive inotropic effects can be mediated by receptor systems acting through accumulation of intracellular cyclic adenosine monophosphate (cAMP; Gs-protein-coupled receptors such as 5-hydroxytryptamine(5-HT)4-like, histamine H2, and vasoactive intestinal peptide) or by receptor systems acting independently of cAMP, possibly through the phospholipase C/diacylglycerol/inositol-1,4,5-trisphophate pathway (such as alpha 1-adrenergic, angiotensin II, and endothelin). In the nonfailing human heart, activation of all these receptor systems induces only submaximal positive inotropic effects compared with those caused by beta-adrenergic receptor stimulation, indicating that in humans the cardiac beta-adrenergic receptor/Gs-protein/adenylate cyclase pathway is the most powerful mechanism to increase heart rate and contractility. However, the human heart contains only a few spare receptors for beta-adrenergic receptor-mediated positive inotropic effects and nearly all beta-adrenergic receptors are needed to cause maximal inotropic effects. Thus any decrease in the number of beta-adrenergic receptors will automatically lead to a reduction in functional responsiveness of beta-adrenergic receptors. In chronic heart failure the number and responsiveness of cardiac beta-adrenergic receptors are reduced, presumably because of the enhanced sympathetic drive to the heart and hence endogenous down-regulation by an elevated release of (cardiac-derived) norepinephrine, and this loss in cardiac beta-adrenergic receptor function is strongly related to the severity of the disease. However, beta 1- and beta 2-adrenergic receptors are differentially changed in different forms of heart failure. In dilated cardiomyopathy and possibly in aortic valve disease the number of cardiac beta 1-adrenergic receptors is selectively reduced without alteration in the number of beta 2-adrenergic receptors (although beta 2-adrenergic receptors become somewhat uncoupled). In ischemic cardiomyopathy, mitral valve disease, and possibly tetralogy of Fallot, the number of both beta 1- and beta 2-adrenergic receptors is concomitantly decreased. Because of the lack of a substantial receptor reserve, such a decrease in the number of beta-adrenergic receptors is accompanied by reduced inotropic and chronotropic responses to beta-adrenergic receptor stimulation in vitro and in vivo.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Receptor systems affecting force of contraction in the human heart and their alterations in chronic heart failure. 135 62

Substantial evidence has accumulated that in the human heart both beta 1- and beta 2-adrenoceptors coexist. As a rule, the amount of beta 2-adrenoceptors is higher in the atria (about 30% of the total beta-adrenoceptor population) than in the ventricular myocardium (about 20%). Both beta 1- and beta 2-adrenoceptors couple to adenylate cyclase and mediate positive inotropic effects of isoprenaline and adrenaline on isolated, electrically driven cardiac preparations. In the atria, stimulation of both beta 1- and beta 2-adrenoceptors causes maximal increases in contractile force; in the ventricular myocardium, however, only beta 1-adrenoceptor stimulation maximally increases contractile force, whereas beta 2-adrenoceptor stimulation evokes only submaximal increases. On the other hand, noradrenaline induces its positive inotropic effect on atrial and ventricular preparations solely via beta 1-adrenoceptor stimulation. Because nordadrenaline is the main transmitter of the human sympathetic nervous system, this indicates that under normal physiological conditions, the heart rate and contractility are under the control of cardiac beta 1-adrenoceptors, whereas cardiac beta 2-adrenoceptors play only a minor role, if at all. However, in situations of stress, when large amounts of adrenaline (acting at both beta 1- and beta 2-adrenoceptors with the same affinity) are released from the adrenal medulla, activation of cardiac beta 2-adrenoceptors may contribute to an additional increase in heart rate and/or contractility. In chronic heart failure, cardiac beta-adrenoceptor function decreases (presumably due to endogenous "downregulation" by the elevated catecholamines) and this decrease is related to the severity of the disease (judged clinically by NYHA functional class).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[Importance of beta 2-adrenergic receptors in heart failure]. 136 62

The cardiovascular effects of NKH477 (6-(3-dimethylaminopropionyl)forskolin hydrochloride), a novel water-soluble forskolin derivative, were investigated in dogs. Intravenous (i.v.) injections of NKH477 (1-30 micrograms/kg) caused dose-related increases in left ventricular dP/dtmax (LVdP/dtmax), coronary and femoral artery blood flow (CBF, FBF), heart rate (HR), and myocardial oxygen consumption (MVO2) and a dose-related decrease in blood pressure (BP) in anesthetized dogs. The regression analysis between CBF and MVO2 showed that NKH477 did not influence substantially the balance of oxygen supply and demand. Infusions of NKH477 (0.15-0.6 microgram/kg/min i.v.) also increased LVdP/dtmax, cardiac output (CO), and HR and decreased BP, pulmonary arterial diastolic pressure, and total peripheral resistance (TPR) in a dose-dependent manner. In contrast to forskolin, NKH477 administered intraduodenally (0.05-0.2 mg/kg) and orally (0.15 and 0.3 mg/kg) clearly exhibited cardiovascular actions, as it did in i.v. administration, indicating that NKH477 is orally active. No arrhythmias were induced by NKH477 in any study. NKH477, like forskolin, showed adenylate cyclase stimulant activity in guinea pig ventricular membrane but did not inhibit Na+, K(+)-ATPase or phosphodiesterase (PDE) activity. Thus, NKH477 can be characterized as a potent, orally active, water-soluble forskolin derivative, which suggests that NKH477 is a useful inodilator for treatment of heart failure, especially in the severe stage with beta-adrenoceptor downregulation.
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PMID:Cardiovascular and adenylate cyclase stimulant properties of NKH477, a novel water-soluble forskolin derivative. 138 Jun 7


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