UMLS:C0018801 - FACTA Search

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

The response of cardiac SR Ca(2+)-loading to cAMP in failing rabbit and human myocardium was examined. Right ventricular (RV) trabeculae were isolated and mounted for isometric tension measurement. They were treated with saponin to permeabilise the sarcolemma but retain SR function, and bathed in a mock intracellular solution including adenosine triphosphate (ATP) and buffered calcium. Caffeine (10 mM) was used to release calcium from the SR. The amplitude of the caffeine-induced contracture was used as a quantitative gauge of the calcium content of the SR. Trabeculae were isolated from rabbits with coronary ligation-induced heart failure (LIG, n = 11), sham operated controls (SH, n = 10), isoprenaline-infused rabbits (ISO, 7 days mini-osmotic pump 100 micrograms/kg.h; n = 7) and saline-infused controls (SAL, n = 7). Failing human RV trabeculae were obtained at the time of cardiac transplantation. Failing rabbit trabeculae demonstrated increased baseline caffeine-induced contractures compared with controls, the response to cAMP was similar in the two groups (LIG 9.3 +/- 2.8 vs SH 10.6 +/- 3.2% Fmax; P = 0.55), There was no difference in the baseline SR Ca(2+)-loading in ISO trabeculae compared with SAL controls but there was a marked difference in the response to cAMP (11.1 +/- 5.4 vs 4.2 +/- 2.1% Fmax, P = 0.02). SR Ca(2+)-loading in failing human RV trabeculae was related to the severity of LV dysfunction (r = 0.59, P = 0.04) and demonstrated a marked cAMP-induced enhancement of caffeine-contracture (20.2 +/- 4.7% increase of Fmax) which was greater in patients with low compared with high ejection fraction. While beta-receptors are known to be down regulated in heart failure these results suggest that the scope for cAMP-mediated enhancement of SR Ca(2+)-loading is maintained.
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PMID:Effects of cyclic adenosine monophosphate (cAMP) on sarcoplasmic reticulum Ca(2+)-loading in failing rabbit and human cardiac trabeculae. 983 52

How different the effects of caffeine on cardiac mechanoenergetics in failing hearts are from those of normal hearts remains to be fully elucidated. First we successfully instituted a new experimental model of acute mild heart failure in the rat by 0.005 mM Ca2+ Tyrode perfusion. These failing hearts neither decreased left ventricular end-systolic pressure nor increased left ventricular end-diastolic pressure, indicating unchanged left ventricular mechanics. However, their myocardial mitochondrial respiratory function examined by respiratory control index (RCI) and oxygen consumption rate in state III (State III O2) was significantly depressed compared with normal hearts. From these results, we judged that this Ca2+ protocol could make mild Ca2+ overload acute failing hearts and that this model would be appropriate for comparing the effects of caffeine on cardiac mechanoenergetics between normal hearts and these failing hearts. We investigated the effects of caffeine on cardiac mechanoenergetics above a concentration of 0.05 mM that corresponds to the maximum blood concentration after a healthy human subject drinks a cup of coffee or tea. We obtained results indicating that caffeine depressed left ventricular systolic and diastolic functions and decreased a measure of total mechanical energy per beat in terms of systolic pressure-volume area (PVA) more severely in these failing hearts at concentrations (20-fold higher than the concentration in a cup of coffee) lower than those in normal hearts. This result implies that these acute failing hearts are Ca2+ overloaded.
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PMID:Effects of intracoronary caffeine on left ventricular mechanoenergetics in Ca2+ overload failing rat hearts. 985 46

Our objective was to determine the respective roles of the sarcoplasmic reticulum (SR) and the Na+/Ca2+ exchanger in the small, slowly decaying Ca2+ transients of failing human ventricular myocytes. Left ventricular myocytes were isolated from explanted hearts of patients with severe heart failure (n=18). Cytosolic Ca2+, contraction, and action potentials were measured by using indo-1, edge detection, and patch pipettes, respectively. Selective inhibitors of SR Ca2+ transport (thapsigargin) and reverse-mode Na+/Ca2+ exchange activity (No. 7943, Kanebo Ltd) were used to define the respective contribution of these processes to the Ca2+ transient. Ca2+ transients and contractions induced by action potentials (AP transients) at 0.5 Hz exhibited phasic and tonic components. The duration of the tonic component was determined by the action potential duration. Ca2+ transients induced by caffeine (Caf transients) exhibited only a phasic component with a rapid rate of decay that was dependent on extracellular Na+. The SR Ca2+-ATPase inhibitor thapsigargin abolished the phasic component of the AP Ca2+ transient and of the Caf transient but had no significant effect on the tonic component of the AP transient. The Na+/Ca2+ exchange inhibitor No. 7943 eliminated the tonic component of the AP transient and reduced the magnitude of the phasic component. In failing human myocytes, Ca2+ transients and contractions exhibit an SR-related, phasic component and a slow, reverse-mode Na+/Ca2+ exchange-related tonic component. These findings suggest that Ca2+ influx via reverse-mode Na+/Ca2+ exchange during the action potential may contribute to the slow decay of the Ca2+ transient in failing human myocytes.
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PMID:The sarcoplasmic reticulum and the Na+/Ca2+ exchanger both contribute to the Ca2+ transient of failing human ventricular myocytes. 1006 78

Our previous studies supported the hypothesis that prolonged administration of caffeine to animals with high-renin hypertension causes progressive deterioration of renal function. However, thus far this hypothesis has been tested with only a few animal models of hypertension. The aim of this study was to test this hypothesis further by investigating the effects of long-term caffeine consumption on renal function in adult spontaneously hypertensive heart failure (SHHF/Mcc-fa(cp)) rats, another model of high-renin hypertension. Lean, male, 9-month-old SHHF/Mcc-fa(cp) rats were randomized to receive either normal drinking water (control group) or drinking water containing 0.1% caffeine (caffeine group) for 20 weeks. No changes in body weight, food and fluid intake, urine volume, and sodium and potassium excretion were found in conscious SHHF/Mcc-fa(cp) rats after 10 or 20 weeks of caffeine treatment. However, caffeine treatment accelerated the time-related decline in renal function and augmented urinary protein excretion. Ten weeks into the protocol, creatinine clearance was 3.6+/-0.4 and 5.7+/-0.9 L/kg/day in the caffeine group and control group, respectively (p<0.02), whereas 20 weeks into the study, creatinine clearance was similarly diminished in both groups. Proteinuria was greater in the caffeine group compared with the control group at both 10 (928+/-131 vs. 439+/-21 mg/kg/day, respectively; p<0.02) and 20 weeks (1,202+/-196 vs. 603+/-30 mg/kg/day, respectively; p<0.01) into the protocol. After 20 weeks, all animals were anesthetized and instrumented. Caffeine treatment for 20 weeks had no effects on blood pressure, heart rate, or vascular resistance in four examined vascular beds (abdominal aorta and renal, carotid, and mesenteric arteries). No changes in renal hemodynamics and electrolyte excretion were found, whereas significantly lower glomerular filtration rate (GFR; inulin clearance) and creatinine clearance (p<0.05) were observed in caffeine-treated animals. These data support our hypothesis that prolonged consumption of caffeine has adverse effects on renal function, in high-renin hypertension.
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PMID:Effects of long-term caffeine consumption on renal function in spontaneously hypertensive heart failure prone rats. 1006 69

In a previous study, we showed that caffeine (CAFF) increases basal renin secretion by blocking intrarenal adenosine receptors and, when sympathetic activity is increased, augments renin release in part by blockade of brain adenosine receptors, leading to increased central sympathetic tone. The purpose of this study was to investigate the effects of CAFF treatment on neurohumoral status and heart performance in experimental heart failure. Two series of experiments were performed. First, the effects of CAFF (10 mg/kg +150 microg/min over 40 min) on heart performance (time-pressure variables) and neurohumoral status were studied in conscious, 9-month-old Wistar-Kyoto (WKY) rats, spontaneously hypertensive rats (SHRs), and spontaneously hypertensive heart failure (SHHF/Mcc-fa(cp) rats. Second, caffeine (0.1% in drinking water) was given for 10 days to 14-month-old SHHF/Mcc-fa(cp) rats, and cardiac performance, renal function, and neurohumoral status determined in vivo. CAFF infusion increased heart rate, left ventricular peak systolic pressure, and workload in hypertensive (SHRs and SHHF), but not in normotensive (WKY) animals and had no effects on cardiac contractility in all three strains. CAFF increased plasma renin activity (PRA), norepinephrine (NE), and epinephrine (E) levels in all three strains [treatment effect, p<0.001, 2F analysis of variance (ANOVA)], and these effects were greater in hypertensive (SHRs and SHHF) animals as compared with normotensive WKY rats (p<0.015). Ten-day CAFF treatment in 14-month-old SHHF did not change measured cardiac time-pressure variables, or hemodynamic or renal excretory function parameters that can affect renin secretion. However, CAFF treatment significantly increased renal renin secretion (71.1+/-19.2 vs. 9.5+/-5.8 ng Ang I/h/min/kg for caffeine and control group, respectively; p<0.01). In summary, acute administration of CAFF increases workload, but has no effects on cardiac contractility in conscious SHHF rats. The cardiac effects are accompanied by increased renin release and NE and E plasma levels. Moreover, this study provides the first evidence that short-term caffeine consumption increases renal renin secretion in heart failure, an effect most likely due to the blockade of intrarenal adenosine receptors. It is possible that long-term activation of neurohumoral mechanisms by CAFF could have adverse effects in heart failure.
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PMID:Caffeine increases renal renin secretion in a rat model of genetic heart failure. 1006 81

The elimination of caffeine was investigated in a 1860 g, 31 week gestation neonate, following the accidental administration of a 160 mg.kg-1 dose. The first serum concentration measured was 217.5 mg.l-1 at 36.5 h after dosing. Fitting of time-concentration data was performed using non-linear regression with MKMODEL. A first order elimination model was superior to a mixed order model. Parameter estimates were: clearance 0.01 l.h-1, volume of distribution 1.17 litres, elimination half-life 81 h. Toxic manifestations included hypertonia, sweating, tachycardia, cardiac failure, pulmonary oedema and metabolic disturbances (metabolic acidosis, hyperglycaemia and creatine kinase elevation). An unusual feature of this infant's illness course was gastric dilatation. These signs resolved by day 7 at a serum concentration of 60-70 mg.l-1. Caffeine clearance has traditionally been reported as either an absolute value or as directly proportional to body weight. The per kilogram model gives an erroneous impression that clearance is greatest in early childhood and then decreases with age until adult rates are reached in late adolescence. Age-related clearance values reported in the literature were reviewed using an allometric 3/4 power model. This size model demonstrates that clearance increases in infancy and reaches adult rates within the first three months of life.
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PMID:Caffeine overdose in a premature infant: clinical course and pharmacokinetics. 1038 69

We have tested the hypothesis that decreased functioning of creatine kinase (CK) at sites of energy production and utilization may contribute to alterations in energy fluxes and calcium homeostasis in congestive heart failure (CHF). Heart failure was induced by aortic banding in 3-week-old rats. Myofilaments, sarcoplasmic reticulum (SR), mitochondrial functions, and CK compartmentation were studied in situ using selective membrane permeabilization of left ventricular fibers with detergents (saponin for mitochondria and SR and Triton X-100 for myofibrils). Seven months after surgery, animals were in CHF. A decrease in total CK activity could be accounted for by a 4-fold decrease in activity and content (Western blots) of mitochondrial CK and a 30% decrease in M isoform of CK (MM-CK) activity. In myofibrils, maximal force, crossbridge kinetics, and alpha-myosin heavy-chain expression decreased, whereas calcium sensitivity of tension development remained unaltered. Myofibrillar CK efficacy was unchanged. Calcium uptake capacities of SR were estimated from the surface of caffeine-induced tension transient (SCa) after loading with different substrates. In CHF, SCa decreased by 23%, and phosphocreatine was 2 times less efficient in enhancing calcium uptake. Oxidative capacities of the failing myocardium measured as oxygen consumption per gram of fiber dry weight decreased by 28%. Moreover, the control of respiration by creatine, ADP, and AMP was severely impaired. Our observations provide evidence that alterations in CK compartmentation may contribute to alterations of energy fluxes and calcium homeostasis in CHF.
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PMID:Subcellular creatine kinase alterations. Implications in heart failure. 1040 Sep 12

Three-dimensional cardiac mapping in rabbits with nonischemic cardiomyopathy has shown that ventricular arrhythmias initiate by a nonreentrant mechanism that may be due to triggered activity from delayed afterdepolarizations. Delayed afterdepolarizations are thought to be due to spontaneous release of Ca(2+) from the sarcoplasmic reticulum (SR) and consequent activation of an inward Na(+)/Ca(2+) exchange (NaCaX) current. The goal of this study was to determine whether there is enhanced NaCaX gene expression and functional activity that may contribute to nonreentrant activation. Heart failure (HF) was induced in rabbits by combined aortic insufficiency and aortic constriction. HF rabbits had left ventricular enlargement (left ventricular end-diastolic dimension increased from 1.43+/-0.03 to 1.97+/-0.05 cm) and severely depressed function (fractional shortening reduced from 37% to 26%, P<0.02). Heart-to-body weight was increased by 79% in HF. Western blots showed a 93% increase in NaCaX protein in HF (P<0.04). NaCaX mRNA (7-kb transcript) was increased by 104% relative to the 18S rRNA in HF. A 14-kb NaCaX transcript was also seen in the HF rabbits, raising total NaCaX mRNA to 2.7-fold compared with controls. The amplitude of caffeine-induced contractures, used to assess SR Ca(2+) load, was not significantly different in HF. Relaxation and [Ca(2+)](i) decline during caffeine-induced contractures is attributable to Ca(2+) transport by NaCaX and was 61% and 45% faster in HF (P<0.05), respectively. NaCaX current measured under controlled voltage clamp conditions was also 2-fold higher in HF cells. SR Ca(2+)-ATPase mRNA and protein levels and Ca(2+) current density were not significantly altered in HF. Twitch amplitudes from HF myocytes were 26% smaller compared with control (P<0.02), but twitch relaxation and [Ca(2+)](i) decline (due largely to SR Ca(2+)-ATPase) were not altered. Thus myocytes and myocardium from HF rabbits exhibit enhanced NaCaX expression and function. The enhanced NaCaX activity may contribute to depressed contractions, increased transient inward current (for a given SR Ca(2+) release), delayed afterdepolarizations, and nonreentrant initiation of ventricular tachycardia in this arrhythmogenic model of HF.
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PMID:Upregulation of Na(+)/Ca(2+) exchanger expression and function in an arrhythmogenic rabbit model of heart failure. 1057 27

Overexpression of calsequestrin (CSQ) induces severe cardiac hypertrophy, whereas overexpression of Na(+)-Ca(2+) exchanger (NCX) does not affect cardiac weight. To investigate a possible beneficial effect of NCX in hypertrophy, we produced transgenic mice overexpressing both NCX and CSQ (NCX/CSQ). Surprisingly, these mice developed severe heart failure. The heart/body weight ratio was enhanced and the mRNA expression of ANF, as a marker of hypertrophy, was highest in double transgenic mice. In isolated muscle strips, the basal relaxation time was prolonged in CSQ and NCX/CSQ mice. Moreover, in the presence of caffeine, force of contraction was increased only in CSQ and NCX/CSQ and was accompanied by elevated diastolic tension. In some respects, however, additional overexpression of NCX altered the CSQ phenotype into the wild-type phenotype. The expression of sarcoplasmic reticulum (SR)-Ca(2+)-ATPase and phospholamban, proteins involved in the Ca(2+) uptake of the SR, were only increased in CSQ, indicating a possible influence of NCX in the regulation of SR-Ca(2+) uptake proteins. The Ca(2+) transients and the L-type Ca(2+) currents in the presence of caffeine were very large in CSQ, but smaller increases were noted in double transgenic mice. Therefore, the successful co-overexpression of CSQ and NCX in these mice provides a novel model in which to investigate the interaction of proteins tightly linked to maintain Ca(2+) homeostasis.
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PMID:Functional properties of transgenic mouse hearts overexpressing both calsequestrin and the Na(+)-Ca(2+) exchanger. 1090 Feb 44

We examined 1) contractile properties and the intracellular Ca(2+) concentration ([Ca(2+)](i)) transient in cardiac myocytes and 2) sarcoplasmic reticulum (SR) Ca(2+) uptake and release function in myocardium from patients with end-stage heart failure caused by ischemic (ICM) vs. idiopathic dilated cardiomyopathy (DCM). The amplitude of cell motion was decreased 43 +/- 6% in ICM and 68 +/- 7% in DCM compared with that in normal organ donors (DN). Time to peak of shortening was increased 43 +/- 15% in DCM, but not in ICM. Prolongation of the relaxation time was more predominant in ICM. In DCM the systolic [Ca(2+)](i) was decreased 27 +/- 9% and diastolic [Ca(2+)](i) was increased 36 +/- 11%. In ICM the diastolic [Ca(2+)](i) was increased 59 +/- 12% but the systolic [Ca(2+)](i) was unchanged. A significant decrease of the ATP-dependent SR Ca(2+) uptake rate associated with the reduction of the SR Ca(2+)-ATPase protein level was found in ICM. In contrast, the significant decrease in SR Ca(2+) release rate was distinct in DCM. The large amount of Ca(2+) retained in the SR associated with a significant decrease in the maximum reaction velocity and increase in the Michaelis-Menten constant in the caffeine concentration-response curve suggests a fundamental abnormality in the SR Ca(2+) release channel gating property in DCM. We conclude that potentially important differences exist in the intracellular Ca(2+) homeostasis and excitation-contraction coupling in ICM vs. DCM. The SR Ca(2+) release dysfunction may play an important pathogenetic role in the abnormal Ca(2+) homeostasis in DCM, and the SR Ca(2+) uptake dysfunction may be responsible for the contractile dysfunction in ICM.
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PMID:Differences in mechanisms of SR dysfunction in ischemic vs. idiopathic dilated cardiomyopathy. 1092 70

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