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)

In heart failure, the sympathetic nervous system is activated. The increased release of norepinephrine from the heart and the elevated levels of circulating catecholamines produce a downregulation of myocardial beta 1-adrenoceptors. In ischemic cardiomyopathy and mitral valve disease, a downregulation of beta 2-adrenoceptors has been observed also. The beta-adrenoceptor downregulation closely correlates to the reduced positive inotropic effects of beta-adrenoceptor agonists. In addition, an increase of the inhibitory guanine-nucleotide binding protein (Gi alpha) has been observed, while the levels of the stimulatory guanine-nucleotide binding protein (Gs alpha), the activity of the catalyst and the anti-adrenergic effects of A1-adenosine receptor- or m-cholinoceptor stimulation remain unchanged in the failing human heart. The increase of Gi alpha correlated closely to the reduced positive inotropic responses to the cAMP-phosphodiesterase inhibitor milrinone. In the failing human heart, the beta-adrenoceptor downregulation and the increased expression of Gi alpha represent pathobiochemical alterations which are involved in the reduced effects of cAMP-dependent positive inotropic agents. The therapeutic reversal of these pathobiochemical alterations is a future promise in the treatment of heart failure.
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PMID:[Adrenergic beta receptors and guanine nucleotide binding proteins (G-proteins) of the failing human heart]. 133 8

The functional integrity of the beta-adrenergic stimulatory pathway in a rabbit model of heart failure induced by long-term adriamycin treatment was investigated. Adriamycin-induced cardiomyopathy was produced in 46 rabbits by injecting 0.75 mg/kg of adriamycin, three times per week, for a period of 11 weeks. Biochemical studies performed on isolated membrane preparations revealed a 40 and 55% decrease in basal adenylyl cyclase activity in the left and right ventricles of the adriamycin treated rabbits, respectively. Furthermore, the Vmax of forskolin stimulation was significantly lower in both ventricles with no change in Kact. The Vmax of 5'-guanylylimidodiphosphate stimulation of the stimulatory guanylyl nucleotide binding protein Gs and beta-adrenergic receptor stimulation by isoproterenol were also significantly decreased (42%) in both ventricles of the adriamycin-treated rabbits with no change in Kact. Despite the decrease in receptor-mediated cyclic AMP production, no decrease in beta-adrenergic receptor population was found. Mechanical studies on the isolated right ventricular papillary muscle revealed a decrease in baseline total tension (3.1 +/- 0.4 g/mm2 to 1.8 +/- 0.2 g/mm2) and dT/dt (15.1 +/- 1.6 g/mm2 s to 7.9 +/- 0.8 g/mm2 s) in the adriamycin-treated rabbits. Furthermore, tension generation and dT/dt response to increasing concentrations of forskolin or isoproterenol were both significantly lower in the adriamycin-treated rabbits as compared to normal. We suggest that a decrease in the activity of the adenylyl cyclase component of the beta-adrenergic stimulatory pathway is largely responsible for the decrease in cyclic AMP generation in the adriamycin-treated rabbits. This defect may play an important role in the decrease of contractility in this model of heart failure.
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PMID:Adriamycin-induced changes to the myocardial beta-adrenergic system in the rabbit. 165 46

The purpose of the present study was to characterize the effects of xamoterol in the human myocardium. In the presence of forskolin or milrinone, xamoterol increased isometric force of contraction, contraction velocity, and relaxation velocity in isolated, electrically driven preparations from human myocardium, but had no effect alone. There was no difference in the effect of xamoterol between right atrial myocardium and left ventricular myocardium from nonfailing (NF), moderately failing (NYHA II-III), and severely failing (NYHA IV) human hearts. The positive inotropic and lusitropic effects of isoprenaline were reduced depending on the severity of heart failure in left ventricular myocardium (i.e., NF greater than NYHA II-III greater than NYHA IV). In the presence of norepinephrine, xamoterol produced negative inotropic effects similar to those of the beta-adrenoceptor antagonists pindolol and propranolol. Xamoterol alone had no effects on force of contraction, whereas pindolol and propranolol markedly reduced contractile force. In NYHA class IV, isoprenaline stimulated adenylate cyclase about twofold but xamoterol, like pindolol or propranolol, had no effect. Experiments with the beta 1- and beta 2-selective antagonists CGP 207.12A and ICI 118.551, respectively, showed that the positive inotropic and lusitropic effects of xamoterol were mediated by beta 1-adrenoceptors. Consistently, xamoterol had a selectivity of 13.8 at beta 1-adrenoceptors as measured in radioligand binding experiments. It is concluded that xamoterol acts as a beta 1-adrenoceptor antagonist with a selectivity of 13.8 in human ventricular myocardium. The compound has an intrinsic sympathomimetic activity, as it produces beta 1-adrenoceptor-mediated positive inotropic and lusitropic effects in the presence of forskolin. The beneficial effects of xamoterol in patients with heart failure could be due to prevention of the detrimental effects of norepinephrine such as beta 1-adrenoceptor downregulation of an increase of Gi (inhibitory guanine-nucleotide binding protein).
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PMID:Effects of xamoterol on inotropic and lusitropic properties of the human myocardium and on adenylate cyclase activity. 197 79

Alterations in the level and function of the stimulatory guanyl nucleotide binding protein (Gs) from the cardiac sarcolemma were examined in a canine model of heart failure. The present study is based on our previous investigations that demonstrated both a loss of beta-adrenergic agonist high-affinity binding sites and a decreased adenylate cyclase activity in sarcolemma from failing hearts. Using cholera toxin and [32P]NAD, we labeled the alpha subunit of Gs (Gs alpha) and found a 59% reduction in the level of this protein. Further, a 50% reduction in Gs activity was noted in a reconstitution assay utilizing membranes from the mouse S49 lymphoma cell line cyc-, which is deficient in Gs. These data suggest that, in this model of pressure-overload left ventricular failure, the acquired defect in the beta-adrenergic receptor/adenylate cyclase system involves a deficiency in the coupling protein Gs. Such an abnormality may explain the decreased adrenergic responsiveness of the failing left ventricle.
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PMID:Decreased stimulatory guanosine triphosphate binding protein in dogs with pressure-overload left ventricular failure. 312 20

Acute myocardial ischemia and subsequent reperfusion result in biochemical and ionic changes in cardiac myocytes which cause contracture of the muscle and a reduced contractile force. Whether changes observed in single myocytes isolated from ischaemic ventricles are a direct consequence of the acute insult, or develop more slowly due to subsequent alterations in load and neurohumoural environment, is controversial. Myocytes from ischemic hearts have a similar contraction amplitude to those from non-failing hearts at physiological or maximally activating levels of ca2+. This could be partly due to the method of cell selection, or could represent the detection of a population of myocytes that have recovered from the original insult. However, there are significant decreases in the velocities of contraction and, particularly, relaxation in myocytes from the ischaemic heart. These resemble alterations caused by anoxia/reperfusion, but similar changes have also been observed in non-ischaemic causes of heart failure. Responses of beta-adrenoceptor stimulation are reduced in single cells from the failing heart, and a post-receptor defect has also been detected. Treatment with pertussis toxin, which reduces the activity of the inhibitory guanine-nucleotide binding protein (Gi) was able to restore beta-adrenoceptor responses to normal. The hypothesis that alterations in the beta-adrenoceptor/Gi/cAMP pathway represent the response of the myocyte to continued exposure to noradrenaline, because of the high sympathetic drive in these patients, is supported by the strong parallels observed with catecholamine-treated animals, and by the fact that non-ischemic aetiologies exhibit similar desensitization. It is concluded that the surviving myocytes in an ischaemic heart are damaged by the neurohumoral alterations that represent the body's attempt to restore cardiac output.
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PMID:Abnormalities of the myocytes in ischaemic cardiomyopathy. 882 61