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Query: UMLS:C0018801 (heart failure)
 72,216 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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

Prior physiological studies have suggested that parasympathetic control is altered in heart failure. The goal of our studies was to investigate the influence of heart failure on the muscarinic receptor, and its coupling to adenylate cyclase. Ligand binding studies using [3H]quinuclidinyl benzilate and enriched left ventricular (LV) sarcolemma, demonstrated that muscarinic receptor density in heart failure declined 36% from a control of 5.6 +/- 0.6 pmol/mg, with no change in antagonist affinity. However, agonist competition studies with both carbachol and oxotremorine showed that it was a loss of high affinity agonist binding sites in the sarcolemma from failing LV that accounted for this difference. The functional efficacy of the muscarinic receptor was also examined. When 1 microM methacholine was added to 0.1 mM GTP and 0.1 mM isoproterenol, adenylate cyclase stimulated activity was inhibited by 15% in normal LV but only 5% in LV sarcolemma from animals with heart failure even when the reduced adenylate cyclase in these heart failure animals was taken into account. Even at 100-fold greater concentrations of methacholine, significantly less inhibition of adenylate cyclase activity was observed in LV failure as compared with normal LV sarcolemma. Levels of the GTP-inhibitory protein known to couple the muscarinic receptor to adenylate cyclase, as measured with pertussis toxin labeling, were not depressed in LV failure. Thus, the inhibitory pathway regulating LV adenylate cyclase activity is defective in heart failure. The decrease in muscarinic receptor density, and in particular the specific loss of the high affinity agonist binding component of this receptor population, appears to be the major factor underlying this abnormality.
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PMID:Impaired cardiac muscarinic receptor function in dogs with heart failure. 329 Feb 56

The myocardial beta-receptor adenylate cyclase system was investigated in short-term streptozotocin-diabetic rats. Earlier reports of a decreased sensitivity of the myocardium to isoproterenol (ISO) in these animals were elucidated by measuring the in vivo production of cAMP after ISO. A substantial decrease was seen in diabetic animals compared with controls and starved animals, and thyroxine treatment, known to sensitize the myocardium to catecholamines, did not normalize the response. The desensitization was retained in a membrane fraction in such a way that ISO was unable to increase the cAMP production while stimulation via the nucleotide-binding protein (with NaF or GTP) leads to a normal cAMP response. As the beta-adrenergic receptor number and affinity turned out to be identical in control and diabetic animals, a functional uncoupling of the myocardial beta-receptor from productive adenylate cyclase activation seems thus to exist in experimental diabetes. It is unlikely that it has anything to do with the thyroid status of the animals, but the possibility of a catecholamine-induced densensitization cannot be excluded. The phenomenon is not universal as the beta-receptor-adenylate cyclase system is normal in isolated spleen lymphocytes. Whether the described phenomenon obtained in an animal study has any relevance for the increased incidence of heart failure in human diabetes mellitus is not known at present.
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PMID:The adrenergic beta-receptor adenylate cyclase system in heart and lymphocytes from streptozotocin-diabetic rats. In vivo and in vitro evidence for a desensitized myocardial beta-receptor. 631 97

With increasing age, cardiac beta-adrenoceptor function decreases. To study possible mechanisms underlying this process, we assessed in right atrial appendages from 52 patients of different ages (group A, < 20 years, mean age 3.7 +/- 1.0 years, n = 20; group B, 20-50 years, mean age, 37.9 +/- 2.3 years, n = 9; group C, > 50 years, mean age 66.1 +/- 1.5 years, n = 23) without apparent heart failure who were undergoing open heart surgery beta-adrenoceptor number and subtype distribution (by (-)-[125I]-iodocyanopindolol [ICYP] binding), adenylyl cyclase activity, and Gs- and Gi-protein alpha-subunits (by quantitative Western blotting). beta-Adrenoceptor number in the three groups was not significantly different; in contrast, basal, 10 microM GTP-, 100 microM isoprenaline (ISO), 10 mM NaF-, 100 microM forskolin-, and 10 mM Mn(2+)-stimulated adenylyl cyclase activity was significantly higher in group A than in group B and was further decreased in group C. Similarly, 100 microM terbutaline-, 100 microM histamine-, and 100 microM 5-HT-stimulated adenylyl cyclase activity significantly decreased from group A to group C. Moreover, all these adenylyl cyclase parameters were significantly negatively correlated with the age of the patients. Although Gs alpha was not altered, Gi alpha in group C was significantly higher than in group A; moreover, there was a weak but significant positive correlation between Gi alpha and the age of the patients. We conclude that an impairment of the activity of the catalytic unit of adenylyl cyclase is involved in the decrease in cardiac beta-adrenoceptor function with age; an increase in Gi alpha might contribute further to the reduced beta-adrenoceptor function.
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PMID:Age-dependent changes in the beta-adrenoceptor-G-protein(s)-adenylyl cyclase system in human right atrium. 756 60

Alterations in beta-adrenergic receptor-Gs-adenylyl cyclase coupling underlie the reduced catecholamine responsiveness that is a hallmark of human and animal models of heart failure. To study the effect of altered expression of Gs alpha, we overexpressed the short isoform of Gs alpha in the hearts of transgenic mice, using a rat alpha-myosin heavy chain promoter. Gs alpha mRNA levels were increased selectively in the hearts of transgenic mice, with a level 38 times the control. Despite this marked increase in mRNA, Western blotting identified only a 2.8-fold increase in the content of the Gs alpha short isoform, whereas Gs activity was increased by 88%. The discrepancy between Gs alpha mRNA and Gs alpha protein levels suggests that the membrane content of Gs alpha is posttranscriptionally regulated. The steady-state adenylyl cyclase catalytic activity was not altered under either basal or stimulated conditions (GTP + isoproterenol, GTP gamma S, NaF, or forskolin). However, progress curve studies did show a significant decrease in the lag period necessary for GppNHp to stimulate adenylyl cyclase activity. Furthermore, the relative number of beta-adrenergic receptors binding agonist with high affinity was significantly increased. Our data demonstrate that a relatively small increase in the amount of the coupling protein Gs alpha can modify the rate of catalyst activation and the formation of agonist high affinity receptors.
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PMID:Overexpression of Gs alpha protein in the hearts of transgenic mice. 770 76

L-type calcium currents were studied in ventricular myocytes isolated from non-failing hearts, i.e. donor hearts not suitable for transplantation, and from severely failing hearts, i.e. explanted hearts of organ recipients, in order to identify possible alterations of the currents in cardiomyopathy. Human atrial myocytes were investigated for comparative purposes. As deficient production of cyclic AMP might contribute to the development of cardiac failure, the responses to forskolin, a direct stimulator of adenylyl cyclase, were also studied. The patch-clamp technique was applied in the single electrode whole-cell mode. Calcium currents were similar in myocytes from non-failing and failing hearts: Maximum current-densities were 3.8 v 3.1 pA/pF, and 2.2 pA/pF in atrial cells. In human ventricular cells, threshold was at -33 mV, maximum at +6 mV and reversal potential at about +50 mV, potentials of half-maximum steady-state inactivation -24 mV and -18 mV. The slopes of steady-state inactivation curves were +4.1 mV in myopathic and +5.5 mV in non-failing cells. In all myocytes the current inactivated with two time constants, a fast one with weak and a slow one with pronounced potential dependency. Ventricular or atrial myocytes from patients pretreated with calcium antagonists and untreated did not differ in current density or steady-state inactivation. Forskolin (0.5 microM) increased calcium currents in myocytes from non-failing and failing hearts to the same extent (by 143 and 150%). While beta-adrenoceptor numbers are reported to decline in severely failing myocardium, our data do not suggest that alterations of the properties of calcium currents contribute to the pathophysiology of heart failure, though the number of investigated hearts is limited due to restricted access to non-failing cardiac tissue. No evidence for impairment of the signal transduction cascade beyond the level of GTP binding proteins was found.
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PMID:L-type calcium currents of human myocytes from ventricle of non-failing and failing hearts and from atrium. 786 91

The development of pacing-induced heart failure was studied in chronically instrumented, conscious dogs paced at a rate of 240 beats/min for 1 d (n = 6), 1 wk (n = 6), and 3-4 wk (n = 7). Left ventricular (LV) dP/dt was decreased (P < 0.0125) at 1 d, LV end-diastolic pressure and heart rate were increased (P < 0.0125) at 1 wk, but clinical signs of heart failure were only observed after 3-4 wk of pacing. Plasma norepinephrine rose (P < 0.0125) after 1 d of pacing, whereas LV norepinephrine was reduced (P < 0.0125) only after 3-4 wk of pacing. Both the fraction of beta-adrenergic receptors binding agonist with high affinity and adenylyl cyclase activity decreased (P < 0.0125) after 1 d of pacing. Total beta-adrenergic receptor density was not changed at any time point, but beta 1-adrenergic receptor density was decreased (P < 0.0125) after 1 wk. The functional activity of the guanine nucleotide binding protein, Gs, was not reduced, but the Gi alpha 2 isoform of the alpha subunit of the GTP-inhibitory protein rose after 3-4 wk of pacing. Thus, myocardial beta-adrenergic signal transduction undergoes change shortly (1d) after the initiation of pacing, before heart failure develops. The mechanism of beta-adrenergic receptor dysfunction in pacing-induced heart failure is characterized initially by elevated plasma levels of catecholamines, uncoupling of beta-adrenergic receptors, and a defect in the adenylyl cyclase catalytic unit. Selective down-regulation of beta 1-adrenergic receptors, increases in Gi alpha 2, and decreases in myocardial catecholamine levels occur as later events.
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PMID:Myocardial beta-adrenergic receptor function during the development of pacing-induced heart failure. 838 4

In end-stage heart failure the expression of different myocardial regulatory proteins involved in the beta-adrenergic cAMP signalling pathway is altered. The downregulation of beta 1-adrenoceptors and their uncoupling from the effector as well as an increased expression of the inhibitory GTP-binding protein seem to be the most important alterations. Since catecholamine levels are elevated in these patients and since some alterations can be 'restored' after treatment with beta-adrenoceptor antagonists it was hypothesized that excessive beta-adrenergic stimulation could be involved in these alterations. In this article the changes of beta-adrenergic receptors, GTP-binding proteins, sarcoplasmic reticulum Ca(2+)-ATPase and of phospholamban found in heart failure are addressed with its possible therapeutic implications.
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PMID:Adrenergic and muscarinic receptor regulation and therapeutic implications in heart failure. 873 55

Evidence from ventricular preparations of cat, sheep, rat and dog suggests that both beta 1-adrenoceptors (beta 1AR) and beta 2-adrenoceptors (beta 2AR) mediate positive inotropic effects but that only beta 1AR do it through activation of a cAMP pathway. On the other hand, our evidence has shown that both beta 1AR and beta 2AR hasten relaxation of isolated human myocardium consistent with a common cAMP pathway. We have now investigated in the isolated human right atrial appendage, a tissue whose beta-AR comprise around 2/3 of beta 1AR and 1/3 of beta 2AR, whether or not beta 2AR-mediated effects occur via activation of a cAMP pathway. We carried out experiments on atria obtained from patients without advanced heart failure undergoing open heart surgery. To activate beta 2AR, we used the beta 2AR-selective ligand zinterol. Experiments were carried out on paced atrial strips (1 Hz) and tissue homogenates and membrane particles. Zinterol caused positive inotropic and lusitropic (i.e. reduction of t1/2 of relaxation) effects with EC50 values of 3 and 2 nM, respectively. The zinterol-evoked effects were unaffected by the beta 1AR-selective antagonist CGP 20712A (300 nM) but blocked surmountably by the beta 2AR-selective antagonist ICI 118551 (50 nM) which reduced both EC50 values to 1 microM. Zinterol stimulated adenylyl cyclase activity with an EC50 of 30 nM and intrinsic activity of 0.75 with respect to (-)-isoprenaline (600 microM); the effects were resistant to blockade by CGP 20712A (300 nM) but antagonised surmountably by ICI 118551 (50 nM). Zinterol bound to membrane beta AR labelled with (-)-[125I] cyanopindolol with higher affinity for beta 2AR than for beta 1AR; the binding to beta 2AR but not to beta 1AR was reduced by GTP gamma S (10 microM). In the presence of CGP 20712A (300 nM) (-)-isoprenaline (400 microM) (to activate both beta 1AR and beta 2AR maximally) and zinterol (10 microM) increased contractile force 3.4-fold and 2.5-fold respectively and reduced relaxation t1/2 by 32% and 18% respectively. These effects of (-)-isoprenaline and zinterol were associated (5 min incubation) with phosphorylation (pmol P/mg supernatant protein) of troponin I and C-protein to values of 8.4 +/- 2.0 vs 12.4 +/- 2.3 and 10.1 +/- 2.5 vs 8.6 +/- 1.6 respectively. (-)-Isoprenaline and zinterol also caused phosphorylation of phospholamban (1.8 +/- 0.3 vs 0.4 +/- 0.1 pmol P/mg respectively) specifically at serine residues. We conclude that in human atrial myocardium activation of both beta 1AR and beta 2AR leads to cAMP-dependent phosphorylation of proteins involved in augmenting both contractility and relaxation.
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PMID:Beta 2-adrenoceptor activation by zinterol causes protein phosphorylation, contractile effects and relaxant effects through a cAMP pathway in human atrium. 897 46

Muscarinic receptor-linked G protein, Gi, can directly activate the specific K+ channel (IK(ACh)) in the atrium and in pacemaker tissues in the heart. Coupling of Gi to the K+ channel in the ventricle has not been well defined. G protein regulation of K+ channels in isolated human ventricular myocytes was examined using the patch-clamp technique. Bath application of 1 microM acetylcholine (ACh) reversibly shortened the action potential duration to 74.4 +/- 12.1% of control (at 90% repolarization, mean +/- SD, n = 8) and increased the whole-cell membrane current conductance without prior beta-adrenergic stimulation in human ventricular myocytes. The ACh effect was reversed by atropine (1 microM). In excised inside-out patch configurations, application of GTPgammaS (100 microM) to the bath solution (internal surface) caused activation of IK(ACh) and/or the background inwardly-rectifying K+ channel (IK1) in ventricular cell membranes. IK(ACh) exhibited rapid gating behavior with a slope conductance of 44 +/- 2 pS (n = 25) and a mean open lifetime of 1.8 +/- 0.3 msec (n = 21). Single channel activity of GTPgammaS-activated IK1 demonstrated long-lasting bursts with a slope conductance of 30 +/- 2 pS (n = 16) and a mean open lifetime of 36.4 +/- 4.1 msec (n = 12). Unlike IK(ACh), G protein-activated IK1 did not require GTP to maintain channel activity, suggesting that these two channels may be controlled by G proteins with different underlying mechanisms. The concentration of GTP at half-maximal channel activation was 0.22 microM in IK(ACh) and 1.2 microM in IK1. Myocytes pretreated with pertussis toxin (PTX) prevented GTP from activating these channels, indicating that muscarinic receptor-linked PTX-sensitive G protein, Gi, is essential for activation of both channels. G protein-activated channel characteristics from patients with terminal heart failure did not differ from those without heart failure or guinea pig. These results suggest that ACh can shorten the action potential by activating IK(ACh) and IK1 via muscarinic receptor-linked Gi proteins in human ventricular myocytes.
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PMID:Activation of inwardly rectifying potassium channels by muscarinic receptor-linked G protein in isolated human ventricular myocytes. 914 60


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