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)

The sequence of atrial natriuretic factor (ANF) has been determined, as well as the complete structure of the rat and human complementary DNA and gene. ANF and ANF messenger RNA are present not only in atria but also in ventricles. The circulating form of ANF has been identified as the C-terminal of the molecule, ANF (Ser 99-Tyr 126). The isolated secretory granules of rat atrial cardiocytes contain only pro-ANF (Asn 1-Tyr 126). An enzyme (IRCM-SP1) has been isolated from heart atria and ventricles. This enzyme is highly specific in cleaving ANF (Asn 1-Tyr 126), to yield ANF (103-126), (102-126), and (99-126). In target cells, ANF produces a rise in cyclic guanosine 3',5'-monophosphate (cGMP) due to activation of particulate guanylate cyclase, and inhibition of adenylate cyclase leading in some cases to a decrease in cyclic adenosine 3',5'-monophosphate (cAMP). ANF produces relaxation of rabbit and rat aortic strips, inhibits steroidogenesis in both zona glomerulosa and zona fasciculata cells, and inhibits the release of arginine vasopressin from the isolated rat hypothalamohypophysial preparation in vitro but decreases AVP release in vivo only at pharmacological doses. In all forms of experimental hypertension, plasma levels of ANF are increased and, at some time periods, atrial levels are also decreased. The ventricular levels of immunoreactive ANF are also increased in renal hypertension. Infusion of ANF by minipumps decreases the blood pressure near control levels in several models of experimental hypertension. In cardiomyopathic hamsters with heart failure, the atrial levels of immunoreactive ANF are decreased while the plasma and ventricular levels are increased.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:The heart as an endocrine gland. 282 60

Human heart failure is associated with a diminished contractile response to beta-adrenergic agonists. We hypothesized that alterations in the activity of a guanine nucleotide-binding regulatory protein (G protein) might be partially responsible for this abnormality. We therefore measured the activity of G proteins in failing human myocardium utilizing bacterial toxin-catalyzed ADP ribosylation. The activity of a 40,000-mol wt pertussis toxin substrate (alpha G40) was increased by 36% in failing human hearts when compared with nonfailing controls. In contrast, there was no change in the level of the stimulatory regulatory subunit (Gs). The increased activity in alpha G40 was associated with a 30% decrease in basal as well as 5'-guanylyl imidodiphosphate-stimulated adenylate cyclase activity. These data suggest that increased alpha G40 activity is a new marker for failing myocardium and may account at least in part for the diminished responsiveness to beta 1-adrenergic agonists in the failing human heart.
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PMID:Increase of the 40,000-mol wt pertussis toxin substrate (G protein) in the failing human heart. 283 45

Exposure of cultured heart muscle cells to noradrenaline led to a decrease in the effects of isoproterenol and prostaglandin E1 on cAMP formation and contraction velocity. However, heterologous desensitization, as measured by prostaglandin E1 stimulation, only occurred at higher noradrenaline concentrations than homologous desensitization (isoproterenol stimulation). As the defects of the adenylate cyclase system in heart failure are attributed to noradrenaline-induced desensitization, it is concluded from the results that, in comparison to the subsensitivity to beta-adrenoceptor agonists in failing human hearts, a decrease in the responsiveness to other receptor-dependent adenylate cyclase stimulators should also occur but only at higher degrees of heart failure.
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PMID:Homologous vs. heterologous desensitization of the adenylate cyclase system in heart cells. 284 30

Much has been learned in the 25 years since a beta-blocking drug was first administered to humans. The beta-adrenergic receptor has been divided into two general subtypes, and these have been purified to homogeneity. The beta 2-receptor gene has been cloned, and the primary structure of the beta 2 receptor has been deduced. Additionally, important details of the receptor-adenylate cyclase complex have been elucidated. Another general category of information relates to the unique features of the myocardial beta-adrenergic receptor population. These include (1) a relatively high proportion of beta 2 receptors and coupling of these receptors to muscle contraction; (2) the apparent lack of spare receptors; (3) selective down-regulation of the beta 1-receptor population in heart failure, with preservation of the beta 2 and alpha 1 populations; and (4) mediation of the most powerful inotropic stimulus that can be delivered by a receptor-coupled pathway. In the next 25 years, investigations will emphasize the use of molecular biologic techniques to discover crucial information about the control of beta-receptor structure and function. From this research will come both new pharmacologic agents and new applications of currently available agents.
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PMID:The beta-adrenergic receptor. Configuration, regulation, mechanism of action. 289 59

beta-Adrenoceptor concentrations have been measured in ventricles of rabbits with adriamycin-induced cardiomyopathy. Despite considerable cardiac hypertrophy (1.6 +/- 0.7 mean +/- S.E.M. g ventricle/kg body wt, n = 6; to 2.2 +/- 0.1) no change in beta-adrenoceptor density was observed (33.8 +/- 2.0 fmol/mg protein in membranes from cardiomyopathic rabbits compared with 36.8 +/- 3.0 for controls). Furthermore, no alteration in the profiles of high affinity agonist binding was observed, and the receptor interaction with the adenylate cyclase stimulatory coupling factor was unimpaired. These results indicate that, despite the marked changes which occur during the development of this model of low-output heart failure, the cardiac beta-adrenoceptor systems are normal.
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PMID:Ventricular beta-adrenoceptors in adriamycin-induced cardiomyopathy in the rabbit. 290 8

We studied the alterations in myocardial beta-adrenergic receptor-adenylate cyclase activity and muscarinic receptor density in a canine model of left ventricular (LV) failure. LV failure was characterized by a doubling of LV weight/body weight ratio (3.3 +/- 0.1 to 6.9 +/- 0.4 g/kg) and an elevation of LV end-diastolic pressure, 32 +/- 4.5 mmHg, compared with 7.7 +/- 0.6 mmHg in normal dogs. Despite a 44% increase in receptor density as measured by antagonist binding studies with [3H]dihydroalprenolol, there was a twofold decrease in receptor affinity, i.e., an increase in the dissociation constant (Kd) (5.6 +/- 0.7 to 12 +/- 1.6 nM) in heart failure. Agonist displacement of [3H]dihydroalprenolol binding with isoproterenol in the presence and absence of 5'-guanylylimidodiphosphate [Gpp(NH)p] demonstrated a striking loss of high affinity binding sites in heart failure (51 +/- 16 to 11 +/- 5%). Beta-Adrenergic receptor-mediated stimulation of adenylate cyclase and maximal stimulation with Gpp(NH)p or sodium fluoride was reduced in heart failure. There was a concomitant marked, P less than 0.01, reduction in muscarinic receptor density (242 +/- 19 vs. 111 +/- 20 fmol/mg). Thus, while muscarinic receptor density fell, beta-adrenergic receptor density actually increased in LV failure. However, a larger portion of the beta-adrenergic receptors are not functionally coupled to the GTP-stimulatory protein (Ns), as evidenced by a decrease in the fraction of receptors that bind agonist with high affinity.
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PMID:Loss of high affinity cardiac beta adrenergic receptors in dogs with heart failure. 300 Nov 47

Angiotensin converting enzyme (ACE) inhibitors are not known to have a direct effect on the myocardium. However, there is some evidence to suggest that they can play an important role in protecting the heart during the evolution of hypertensive and coronary arterial disease, both acutely and on a long term basis. Reduction of afterload by balanced arterial and venular dilatation has led to a sustained improvement of cardiac performance both in hypertension and heart failure. Reversal of cardiac hypertrophy has been shown to restore inotropic responsiveness to stimulators of the adenylate cyclase system. Following myocardial infarction, captopril has prevented undue ventricular dilatation and normalized left ventricular chamber stiffness; this prevented deterioration of cardiac function and improved long term survival after infarction. Control of secondary aldosteronism and prevention of hypokalaemia can play an important role in the prevention of cardiac arrhythmias. The lack of reflex sympathetic stimulation during long term captopril therapy can also play a favourable role in that respect. Although highly speculative, evidence is accumulating that ACE inhibition could have a cardioprotective effect in acute myocardial ischaemia. It is based on the demonstration that renin can be produced by myocardial cells, that angiotensin is liberated by the ischemic myocardium and that angiotensin in high renin conditions plays an active constrictor role in regulating the coronary circulation.
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PMID:Prospectives for angiotensin converting enzyme inhibition in heart diseases. 300 6

Hydralazine is a potent arteriolar dilator, which increases cardiac output in patients with heart failure. Previous studies suggested that these beneficial effects might be due in part to a positive inotropic effect. The present study further investigated the effect of hydralazine on myocardial contractility and adenyl cyclase activity. In isolated cat papillary muscles, bath concentrations of hydralazine up to 10(-4) mol X litre-1 did not alter force development, whereas 10(-3) mol X litre-1 hydralazine increased isometric force by 31%. This effect was blocked by 10(-6) mol X litre-1 propranolol and was absent after catecholamine depletion produced by previous reserpine treatment. In canine ventricular myocardium hydralazine in all concentrations used (10(-7) to 10(-3) mol X litre-1) increased control adenyl cyclase activity. This increase was statistically significant in 10(-6) to 10(-3) mol X litre-1 concentrations, reaching a maximum of 69.5% at 10(-4) mol X litre-1. In cat ventricular myocardium 10(-6) to 10(-3) mol X litre-1 hydralazine increased the cyclic AMP production, although to a lesser magnitude than that in canine tissue. Hydralazine 10(-5) mol X litre-1 produced a 37.8% increase, and the maximum effect of 45.2% occurred at 10(-3) mol X litre-1. The positive effects of hydralazine were completely abolished by the addition of propranolol in dogs as well as in cats. Thus the adenyl cyclase stimulation induced by hydralazine is mediated through the beta receptor.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Correlation between effects of hydralazine on force and on the adenyl cyclase system of ventricular myocardium in dogs and cats. 301 Dec 68

A large number of chemical substances increase contractility of isolated animal myocardial preparations. Their augmentation is the result of a number of mechanisms which ultimately increase the available calcium for contractile protein coupling. Although there is some research with drugs which activate calcium channels, present clinical research is mainly confined to agents whose major action on contraction is mediated by an increase in myocyte cyclic AMP. Species and age variations in the inotropic effect are common. These agents have additional cardiac effects (e.g. chronotropic, lusitropic) and non-cardiac actions. They are potent vasodilators. In isolated human myocardium obtained from patients without heart failure, they increase contractility at high concentrations. Generally this effect is attenuated in isolated myocardium obtained from patients and animals with chronic cardiac failure. In myocardium from patients with the most severe heart failure, even very high concentrations fail to increase contractility. Part of this attenuation may be due to reduced receptor number (or sensitivity) when the drug's effect is due to receptor-coupled adenylate cyclase activation. However, a reduced ability to produce and/or respond to cyclic AMP itself is suggested by impaired responses to phosphodiesterase inhibitors. In vivo, these agents have frankly harmful effects in patients with near normal cardiac function. Despite increasing contractility indices, they lower blood pressure, raise heart rate and impair myocardial lactate metabolism without increasing cardiac output. In patients with severe heart failure they produce beneficial resting haemodynamic changes; increased cardiac output and reduced filling pressures with only small changes in blood pressure and heart rate.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:New positive inotropic substances--true inotropy or peripheral effects? 306 33

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


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