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)

We studied functional and intracellular calcium responses to treppe and extracellular calcium in spontaneously hypertensive rat (SHR) hearts during the transition from compensated pressure overload to failure. Intracellular calcium was measured using aequorin, a bioluminescent Ca2+ indicator. Experiments were performed with intact, isovolumically contracting, buffer-perfused hearts from three rat groups: (1) aging SHR with evidence of heart failure (SHR-F), (2) age-matched SHR with no evidence of heart failure (SHR-NF), and (3) age-matched normotensive Wistar-Kyoto (WKY) rats. In each experiment, left ventricular pressure and intracellular calcium transients were simultaneously recorded. Hearts were studied at 30 degrees C and paced at a rate of 1.6 Hz while being perfused with oxygenated Krebs-Henseleit solution (95% O2/5% CO2) at 100 mm Hg. At the baseline state, peak systolic pressure was greatest in the SHR-NF group and lowest in the SHR-F group. Peak and resting [Ca2+]i were not significantly different among groups; however, the calcium transient was prolonged in the SHR-NF and SHR-F groups. With increasing perfusate [Ca2+]o from 0.5 to 3.0 mmol/L, the relative increases in peak [Ca2+]i and peak systolic pressure were similar among groups. When stimulation rate was increased from 1.6 to 2.0, 2.4, 2.8, and 3.2 Hz, peak [Ca2+]i, peak systolic pressure, and +/- dP/dt fell in SHR-F hearts. Peak systolic pressure decreased in the SHR-NF group at rates above 2.4 Hz but did not decline in the WKY group. Peak [Ca2+]i increased in the WKY and SHR-NF groups with increasing heart rates. Peak systolic pressure did not fall significantly in the WKY group at any heart rate. Elevation of diastolic [Ca2+]i and/or calcium transient and pressure alternans were present in 8 of 13 SHR-F hearts at the highest stimulation rate, findings that were absent in both the WKY and SHR-NF hearts. We conclude the following: (1) Under baseline conditions, depressed contractile function of failing myocardium cannot be explained by decreased peak [Ca2+]i, (2) relative increases in [Ca2+]i and inotropy with increasing [Ca2+]o are proportional among groups; and (3) although peak systolic [Ca2+]i and inotropy are maintained with increasing stimulation rate in the WKY and SHR-NF groups, peak systolic [Ca2+]i and pressure decrease in parallel in the SHR-F heart with increasing stimulation rate, suggesting that impaired calcium cycling may contribute to compromised pump function in the SHR-F heart.
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PMID:Effects of treppe and calcium on intracellular calcium and function in the failing heart from the spontaneously hypertensive rat. 808 41

To determine if chronic heart failure (CHF) leads to functional or structural alterations of skeletal muscle, we compared intracellular Ca2+ signaling, contractility, and the rate of fatigue development, together with electron microscopy (EM), in skeletal muscle preparations from rats with myocardial infarction-induced CHF versus sham-operated control rats. Bundles of 100 to 200 cells were dissected from the extensor digitorum longus (EDL) muscle of control (n = 13) and CHF (n = 19) rats and were either loaded with aequorin or fixed for EM. Muscles from CHF rats exhibited depressed tension development compared with control muscles during twitches (1.4 +/- 0.2 versus 2.8 +/- 0.7 g/mm2, P < .05) and maximal tetani (5.3 +/- 1.4 versus 10.7 +/- 2.4 g/mm2, P < .05). Depressed tension in CHF was accompanied by reduced quantitative [Ca2+]i release during twitches (0.7 +/- 0.1 versus 0.4 +/- 0.1 microM, P < .05) and during maximal tetani (1.8 +/- 0.3 versus 0.9 +/- 0.2 microM, P < .05). Skeletal muscle from CHF rats also demonstrated prolonged intracellular Ca2+ transients during twitches and tetani and accelerated fatigue development. EM revealed a lack of cellular atrophy in the CHF rats. In conclusion, EDL skeletal muscle from rats with CHF had intrinsic abnormalities in excitation-contraction coupling unrelated to cellular atrophy. These findings indicate that CHF is a condition accompanied by EDL skeletal muscle dysfunction.
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PMID:Alterations in contractility and intracellular Ca2+ transients in isolated bundles of skeletal muscle fibers from rats with chronic heart failure. 833 Mar 83

1. The purpose of this study was to elucidate the cellular mechanism of the positive inotropic effect of hydralazine, a vasodilator widely used for afterload reduction in patients with heart failure that has also been reported to have positive inotropic effects on the heart. After isolation, right ventricular papillary muscles from the ferret were maintained in bicarbonate-buffered salt solution (30 degrees C). A concentration-response relationship was obtained for hydralazine (10(-6) to 10(-3) M). In order to mimic different levels of catecholamine release found in heart failure, we utilized two methods of stimulation: (a) threshold punctate pulses and (b) suprathreshold punctate stimulation with voltage approximately 10% above threshold. 2. In a first group of muscles (n = 16), a maximally effective concentration of hydralazine (10(-3) M) increased peak isometric tension by 39 +/- 9% (P < 0.05). Doses lower than 10(-5) M had no significant effect. The bioluminescent Ca2+ indicator, aequorin, was loaded into a subset of these muscles (n = 7). A significant increase in peak light (i.e., intracellular Ca2+) developed, concurrently with an increase in peak tension (38 +/- 5% to 66 +/- 8%). This inotropic response was associated with a decrease in time to peak tension (ms), 221 +/- 7 to 186 +/- 5 (P < 0.05), and time to peak light, 65 +/- 4 to 52 +/- 2 (P < 0.05). These effects were markedly attenuated by pretreatment with autonomic blocking agents. 3. In a second group of muscles (n = 12), histamine was used to stimulate cyclic AMP production in the presence of propranolol. Hydralazine (3 x 10-4 M) led to a shift in the pD2 (i.e. the negative log of the concentration of histamine producing 50% of the maximal response) from 6.1 +/- 0.1 to 5.9 +/- 0.1(P <0.05), thus increasing the sensitivity of the muscles to histamine. Hydralazine also increased maximum tension from 160 +/- 77% to 195 +/- 57% (P <0.05) above baseline. Thus, hydralazine altered the potency and efficacy of histamine despite the presence of beta-adrenoceptor blockade.4. A third group of muscles were chemically skinned to examine the effects of hydralazine on myofilament Ca2+ responsiveness. Pretreatment of ferret papillary muscles with hydralazine (10-3 M)before skinning did not shift the force-pCa curve after skinning (n = 16). However, hydralazine added to previously skinned fibres desensitized the myofilaments, as indicated by a rightward shift of the force-pCa curve (n = 12). Maximum tension development was not changed.5. The pharmacological effects of hydralazine are characteristic of inotropic drugs that act mainly via cyclic AMP; however, the increase in peak tension demonstrated with histamine in the presence of hydralazine also suggests an effect on cyclic AMP-independent second messenger pathways. These data are consistent with reports that large doses of hydralazine may increase cellular levels of cyclic AMP, as well as other second messengers, by direct cardiac and indirect neuronal mechanisms.
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PMID:Cellular mechanism of the positive inotropic effect of hydralazine in mammalian myocardium. 835 64

The treatment of congestive heart failure has seen considerable changes: while treatment with diuretics, digitalis glycosides and vasodilators has remained the mainstay of therapy, recently neurohumeral inhibition has been developed as an important principle: ACE-inhibitors have been shown to significantly improve quality of life and exercise performance and to substantially reduce mortality. Beta-blockers have been employed with increasing success mainly in congestive heart failure due to dilated idiopathic cardiomyopathy, in which a significant improvement in symptoms and life expectancy has been demonstrated. However, the precise mechanisms by which beta-blockade improves congestive heart failure remain to be elucidated. In addition to direct sympathoadrenal inhibition, reduction of heart rate may also play a major role in the therapeutic efficacy of beta-blockade in congestive heart failure. In the normal human heart increase in heart rate is accompanied by an increase in myocardial contractile performance (Bowditch-Treppe phenomenon). In chronic heart failure the myocardium undergoes a phenotype change which includes alterations of the activity of enzymes regulating calcium homoeostasis. The sarcoplasmic reticulum calcium ATPase (SERCA) is depressed both in function, as well as in expression. At the same time the sarcolemmal sodium-calcium exchanger is increased both in function and in expression. The result is a characteristic change in calcium homoeostasis with decreased diastolic uptake of calcium into the sarcoplasmic reticulum with subsequently reduced calcium release during the next systole, resulting in reduced contractile performance. At the same time increased capacity of the sodium-calcium exchanger extrudes intracellular calcium ions to the extra-cellular space, thereby rendering these ions unavailable for the contractile cycle. A result of these, seemingly specific, phenotype changes is an alteration of the force/frequency relationship. Instead of increasing force of contraction with increasing heart rates, in the chronically failing myocardium the contractile performance declines with increasing heart rates and only improves with decreasing rates. Optimal performance can be seen at heart rates as low as 30 beats.min. Studies employing photoluminescence markers of free cytosolic calcium, such as aequorin, have shown that there is a direct correlation between free cytosolic calcium and contractile performance at different levels of heart rate. It is likely, therefore, that the heart rate reduction with beta-blockade may provide the major explanation for the therapeutic benefits of beta-blockade in chronic congestive heart failure.
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PMID:Pathophysiological targets for beta-blocker therapy in congestive heart failure. 873 64

Inotropic responsiveness to beta-adrenergic stimulation is generally found to be impaired in left ventricular (LV) hypertrophy and failure. To investigate the mechanisms by which angiotensin-converting enzyme inhibitor therapy may modulate inotropic responsiveness with long-term pressure overload, we studied the effects of captopril treatment on cardiac gene expression, LV muscle mechanical contraction, and intracellular calcium (Ca(2+)) transients from spontaneously hypertensive rats (SHR). LV papillary muscles from untreated SHR, age-matched normotensive Wistar-Kyoto rats (WKY), and SHR treated with captopril (CAP(Rx) started at 12, 18, and 21 months of age) were studied. All animals were studied at 24 months of age or when heart failure developed. In untreated SHR, alpha-myosin heavy chain (MHC) gene expression and protein were decreased, the Ca(2+) transient (with the bioluminescent indicator aequorin) was prolonged, and abundance of Na(+)/Ca(2+) exchanger mRNA levels increased in comparison to WKY. Active stress development at L(max) and the maximum rate of stress development were depressed and contractile duration prolonged in SHR relative to WKY. Isoproterenol administration further decreased active stress in untreated SHR despite an increase in intracellular Ca(2+) levels. In CAP(Rx) SHR, alpha-MHC gene expression and protein levels were increased, the Ca(2+) transient was not prolonged, Na(+)/Ca(2+) exchanger expression was downregulated, and papillary muscle function demonstrated increased active stress and maximum rate of stress development in response to isoproterenol. The increased abundance of alpha-MHC mRNA in conjunction with an increase in V(1) myosin isozyme suggests that captopril affects transcriptional regulation of cardiac gene expression. Restored LV inotropic responsiveness to beta-adrenergic stimulation in CAP(Rx) SHR appears to be coupled to normalization of Na(+)/Ca(2+) exchanger mRNA expression, upregulation of V(1) myosin isozyme levels, and increased speed of contraction.
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PMID:Altered inotropic responsiveness and gene expression of hypertrophied myocardium with captopril. 1085 64

Global contractile heart failure was induced in turkey poults by furazolidone feeding (700 ppm). Abnormal calcium regulation appears to be a key factor in the pathophysiology of heart failure, but the cellular mechanisms contributing to changes in calcium fluxes have not been clearly defined. Isolated ventricular myocytes from non-failing and failing hearts were therefore used to determine whether the whole heart and ventricular muscle contractile dysfunctions were realized at the single cell level. Whole cell current- and voltage-clamp techniques were used to evaluate action potential configurations and L-type calcium currents, respectively. Intracellular calcium transients were evaluated in isolated myocytes with fura-2 and in isolated left ventricular muscles using aequorin. Action potential durations were prolonged in failing myocytes, which correspond to slowed cytosolic calcium clearing. Calcium current-voltage relationships were normal in failing myocytes; preliminary evidence suggests that depressed transient outward potassium currents contribute to prolonged action potential durations. The number of calcium channels (as measured by radioligand binding) were also similar in non-failing and failing hearts. Isolated ventricular muscles from failing hearts had enhanced inotropic responses, in a dose-dependent fashion, to a calcium channel agonist (Bay K 8644). These data suggest that changes in intracellular calcium mobilization kinetics and longer calcium-myofilament interaction may be able to compensate for contractile failure. We conclude that the relationship between calcium current density and sarcoplasmic reticulum calcium release is a dynamic process that may be altered in the setting of heart failure at higher contraction rates.
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PMID:Intracellular calcium and the relationship to contractility in an avian model of heart failure. 1093 20

Excitation-contraction coupling and intracellular Ca2+ homeostasis are altered in heart failure. We tested the hypothesis that these changes are related to disturbed Ca2+ handling of the sarcoplasmic reticulum (SR). Isolated, electrically stimulated trabeculae were obtained from end-stage failing (NYHA IV) and nonfailing human hearts. Isometric twitch tension, intracellular Ca2+ transients (aequorin method) and SR Ca2+ content (rapid cooling contractures) were assessed under basal conditions (1 Hz, 37 degrees C) as well as after stepwise increasing rest intervals from 2-240 s (post-rest contractions). Protein expression of SERCA2a and phospholamban (Western blot) was assessed in a subset of failing trabeculae. In addition, the effects of SERCA1 overexpression on contractile function of isolated myocytes was tested. On average, post-rest twitch tension continuously increased with increasing rest intervals in nonfailing, but declined with rest intervals longer than 15 s in failing myocardium. The rest-dependent contractile changes were accompanied by parallel changes in intracellular Ca2+ transients. Failing trabeculae (n = 40) were grouped (group A: post-rest potentiation (force of contraction > pre-rest twitch force) after 120 s rest interval; group B: post-rest decay (force of contraction < pre-rest twitch force) after 120 s rest interval), and post-rest contractile function was related to SERCA2a and PLB expression. While PLB protein expression was not different, SERCA2a protein expression as well as SERCA2a/PLB ratio was significantly higher in group A vs. group B. Transfection of SERCA1 increased shortening amplitude and enhanced relaxation kinetics in failing human myocytes. In conclusion, SR Ca2+ handling is severely altered in human heart failure. Reduced SR Ca2+ release is due to diminished SR Ca2+ content directly related to a depressed expression of SERCA2a protein. Enhancing SERCA function or expression may improve SR Ca2+ handling in failing human myocardium.
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PMID:Sarcoplasmic reticulum Ca2+ load in human heart failure. 1247 37

Myocardial generation of insulin-like growth factor-1 (IGF-1) is altered in hypertrophy and heart failure, but there are no reports on acute functional effects of IGF-1 in human cardiac muscle. We examined inotropic responses and signal transduction mechanisms of IGF-1 in human myocardium. Experiments were performed in isolated trabeculae or cardiomyocytes from 46 end-stage failing hearts. The effect of IGF-1 (0.001 to 0.2 micromol/L) on isometric twitch force (37 degrees C, 1 Hz), intracellular Ca2+ transients (aequorin method), sarcoplasmic reticulum (SR) Ca2+ content (rapid cooling contractures), L-type Ca2+ current (whole-cell voltage clamp), and cAMP concentrations was assessed. In addition, the effects of blocking IGF-1 receptors, phosphoinositide 3-kinase (PI3-kinase), protein kinase C (PKC), or transsarcolemmal Ca2+ entry were tested. IGF-1 exerted concentration-dependent positive inotropic effects (twitch force increased to maximally 133+/-4% of baseline values at 0.1 micromol/L; P<0.05). The IGF-1 receptor antibody alphaIR3 or the PI3-kinase inhibitor wortmannin prevented the functional effects. The inotropic response was paralleled by increases in Ca2+ transients and SR Ca2+ content. IGF-1 (0.1 micromol/L) increased L-type Ca2+ current amplitude by 24+/-7% (P<0.05). Blockade of SR function did not affect the inotropic response to IGF-1. In contrast, L-type Ca2+ channel blockade with diltiazem partially prevented ( approximately 50%) the inotropic response to IGF-1. Inhibition of PKC (GF109203X), Na+-H+ exchange (HOE642), or reverse-mode Na+-Ca2+ exchange (KB-R7943) reduced the response to IGF-1 by approximately 60% to 70%. IGF-1 exerts Ca2+-dependent positive inotropic effects through activation of IGF-1 receptors and a PI3-kinase-dependent pathway in failing human myocardium. The increased [Ca2+]i with IGF-1 originates from both enhanced L-type Ca2+ currents and enhanced Na+-H+ exchange-dependent reverse-mode Na+-Ca2+ exchange. These nongenomic functional effects of IGF-1 may be of clinical relevance.
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PMID:Insulin-like growth factor-1 exerts Ca2+-dependent positive inotropic effects in failing human myocardium. 1257 44

We have documented the effects of long-term endothelin receptor antagonism on intracellular Ca2+ regulation and Ca2+ regulatory protein expression in rat hearts with right ventricular hypertrophy without signs of heart failure. Rats were given either a single injection of monocrotaline (50 mg/kg, n=9) resulting in pulmonary hypertension-induced myocardial hypertrophy, or monocrotaline followed by daily administration of the endothelin subtype-A receptor antagonist 2-benzo(1,3)dioxol-5-yl-3-benzyl-4-(4-methoxy-phenyl-)-4-oxobut-2-enoate-Na (PD 155080, 50 mg/kg) over 9 weeks (n=8). Hearts from saline-injected rats served as controls (n=9). Monocrotaline-treated animals developed marked right-sided hypertrophy without fibrosis as evident from hydroxyproline measurements, systolic contractility was increased, fully compensating for the increased afterload, but diastolic function was impaired as evident from protracted relaxation and slowed diastolic intracellular Ca2+ handling (measured by aequorin bioluminescence). In hypertrophic hearts, quantitative immunoblotting analyses showed increased levels both of sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA) and phosphorylated phospholamban, along with decreased levels of total phospholamban, which is in line with strengthened right ventricular systolic function. PD 155080 reversed abnormalities in Ca2+ handling, although SERCA and phospholamban protein levels were not altered (P=not significant versus monocrotaline group). Thus, endothelin-A receptor antagonism attenuates right ventricular remodeling and improves myocardial Ca2+ handling, but has no discernable effect on elevated expression of SERCA and phospholamban observed in hypertrophic hearts. These data indicate that the hypotensive action of PD 155080 is independent of its effects, if any, on SERCA and its regulation.
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PMID:Effect of endothelin antagonism on contractility, intracellular calcium regulation and calcium regulatory protein expression in right ventricular hypertrophy of the rat. 1472 13

Adrenomedullin (ADM) is an endogenous peptide with favorable hemodynamic effects in vivo. In this study, we characterized the direct functional effects of ADM in isolated preparations from human atria and ventricles. In electrically stimulated human nonfailing right atrial trabeculae, ADM (0.0001-1 micromol/l) increased force of contraction in a concentration-dependent manner, with a maximal increase by 35 +/- 8% (at 1 micromol/l; P < 0.05). The positive inotropic effect was accompanied by a disproportionate increase in calcium transients assessed by aequorin light emission [by 76 +/- 20%; force/light ratio (DeltaF/DeltaL) 0.58 +/- 0.15]. In contrast, elevation of extracellular calcium (from 2.5 to 3.2 mmol/l) proportionally increased force and aequorin light emission (DeltaF/DeltaL 1.0 +/- 0.1; P < 0.05 vs. ADM). Consistent with a cAMP-dependent mechanism, ADM (1 micromol/l) increased atrial cAMP levels by 90 +/- 12%, and its inotropic effects could be blocked by the protein kinase A (PKA) inhibitor H-89. ADM also exerted positive inotropic effects in failing atrial myocardium and in nonfailing and failing ventricular myocardium. The inotropic response was significantly weaker in ventricular vs. atrial myocardium and in failing vs. nonfailing myocardium. In conclusion, ADM exerts Ca(2+)-dependent positive inotropic effects in human atrial and less-pronounced effects in ventricular myocardium. The inotropic effects are related to increased cAMP levels and stimulation of PKA. In heart failure, the responsiveness to ADM is reduced in atria and ventricles.
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PMID:Atrial myocardium is the predominant inotropic target of adrenomedullin in the human heart. 1776 67


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