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 phenomenon of postexcitatory depression (PED) of baroreceptors is related to augmentation of Na(+)- K(+) -adenosinetriphosphatase (ATPase) activity. To provide additional evidence to support the hypothesis that dogs with chronic heart failure have augmented Na(+) -K(+) -ATPase activity in baroreceptor endings, the present study was undertaken to compare the duration of the PED of carotid sinus baroreceptors from normal and heart failure dogs. The effect of perfusion of the carotid sinus with a cardiac glycoside was also investigated. Eight normal and six dogs with experimental heart failure induced by ventricular pacing (250 beats/min for approximately 5 wk) were used in this study. Dogs were anesthetized, and the carotid sinus was isolated and perfused. Single baroreceptor units from the carotid sinus nerve were recorded, and the duration of the PED was measured. The relationship between the magnitude of the pressure steps and the duration of PED was determined. Duration of PED was significantly prolonged in the heart failure group at each pressure step (range from 2.7 to 9.0 s compared with 0.5 to 2.9 s in normal dogs). For the relationship between the duration of the pressure step and duration of PED, the heart failure dogs exhibited a markedly longer duration of PED than the normal dogs (range from 2.3 to 12.4 s compared with 0.5 to 5.3 s in normal dogs). Perfusion of the carotid sinus with very low doses of ouabain decreased the duration of PED in the heart failure dogs; however, there was no such effect in the normal dogs. These data are consistent with the view that baroreceptor membranes have increased Na(+) -K(+) -ATPase activity in heart failure(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Postexcitatory depression of baroreceptors in dogs with experimental heart failure. 184 69

Modifications to cell relaxation and handling of intracellular Ca have been demonstrated in animals with cardiac cell hypertrophy leading to decompensated heart failure. A previously described model of renal hypertension leading to cardiac cell hypertrophy in the guinea pig, produced using the Goldblatt 2-kidney, 1-clip technique, was used to investigate which of the main mechanisms causing cell relaxation (the sarcoplasmic reticulum Ca-adenosinetriphosphatase and Na/Ca exchanger) are altered in hypertrophy. Relaxation upon rewarming from a rapid cooling contracture was slowed in hypertrophied (H) compared with control (C) cells. Relaxation was further slowed in H compared with C cells when Na/Ca exchange was inhibited by rewarming in a Na-free, Ca-free solution and slowed most markedly in H cells in the presence of 10 mM caffeine. Hypertrophy led to greater modification of cell length relaxation in comparison with the decline in the indo-1 transient, but the force-pCa relationship in skinned muscles showed that myofilament sensitivity was unchanged. Such results indicate that cell relaxation and Ca handling are affected in hypertrophy, possibly involving modifications of Na/Ca exchange activity.
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PMID:Effect of hypertrophy on mechanisms of relaxation in isolated cardiac myocytes from guinea pig. 797 15

To study the changes in myocardial digitalis binding sites in heart failure, we measured myocardial ouabain binding sites, Na-K-adenosinetriphosphatase (ATPase) activity, and ventricular muscle mechanical responses to acetylstrophanthidin in dogs with right-heart failure (RHF) produced by tricuspid avulsion and pulmonary artery constriction. Sham-operated dogs were studied as the control. RHF produced a significant decrease in ouabain binding sites in the right and left ventricular myocardium, which was accompanied by a proportional decrease in Na-K-ATPase activity. However, RHF and sham-operated dogs did not differ in systemic hemodynamic or right ventricular trabeculate muscle isometric contractile responses to acetylstrophanthidin. To determine whether chronic beta-adrenergic stimulation contributed to the development of Na-K-ATPase downregulation, we administered nadolol (40 mg/day) to a separate group of dogs during an early stage of RHF development. Nadolol effectively prevented the reduction of myocardial ouabain binding sites that occurred in RHF. Thus we conclude that myocardial ouabain binding sites and Na-K-ATPase activity are reduced in dogs with experimental heart failure and that these changes probably occur as a result of the attendant heightened sympathetic activity.
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PMID:Reductions of myocardial Na-K-ATPase activity and ouabain binding sites in heart failure: prevention by nadolol. 828 48

In an attempt to elucidate the effects of two major risk factors of heart failure in humans, high blood pressure and coronary artery disease, renal hypertension and coronary artery constriction were induced singularly and in combination in rats, and the functional, structural, and biochemical alterations of the myocardium were examined 12-13 wk later. Renal hypertension (RH), coronary narrowing (CN), and their association (NH) resulted in left ventricular failure demonstrated by a significant increase in left ventricular end-diastolic pressure, a decrease in +dP/dt and -dP/dt, and a reduction in stroke volume and cardiac output. Measurements of ventricular loading documented that RH was characterized by elevations in systolic and diastolic wall stress of 42 and 160%, respectively. Corresponding changes with NH were 80 and 315%. CN was accompanied by an augmentation of diastolic wall stress only (280%). The abnormalities in mural stress were coupled with reductions in systolic and diastolic wall thickness-to-chamber radius ratios of 39 and 29% after CN. These anatomic parameters were preserved with RH, whereas the systolic wall thickness-to-chamber radius ratio was reduced 31% with NH. Structurally, multiple foci of replacement fibrosis were found with each intervention. The sites of tissue injury and their volume percent in the myocardium were comparable with CN and RH but were significantly more numerous and occupied a larger fraction of the ventricular wall in the presence of NH. Biochemically, the calcium dose-response curve of myofibrillar Mg2+ adenosinetriphosphatase (ATPase) activity did not vary with CN, RH, and NH. In contrast, a marked decrease in Ca2+ myosin ATPase activity was found in NH rats in association with a shift in myosin isoenzymes from V1 to V3. In conclusion, multiple physiological, morphological, and biochemical factors may participate in the generation of the abnormalities in ventricular loading with hypertension and/or coronary artery stenosis.
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PMID:Effects of hypertension and coronary constriction on cardiac function, morphology, and contractile proteins in rats. 836 72

The proportion of slow-twitch, fatigue-resistant type 1 skeletal muscle (SM) fibers is often reduced in heart failure (HF), while the proportion of fatigue-sensitive type-II fibers increases. This maladaptation may be partially responsible for the exercise intolerance that characterize HF. In this study, we examined the effects of early monotherapy with the angiotensin-converting enzyme inhibor, enalapril, and the beta-blocker, metoprolol, on SM fiber type composition in 18 dogs with moderate HF produced by intracoronary microembolizations. HF dogs were randomized to 3 mo therapy with enalapril (10 mg twice daily), metoprolol (25 mg twice daily), or no treatment. Triceps muscle biopsies were obtained at baseline, before randomization, and at the end of 30 mo of therapy. Type I and type II SM fibers were differentiated by myofibrillar adenosinetriphosphatase (pH 9.4). In untreated dogs, the proportion of type I fibers was 27 +/- 1% before randomization and decreased to 23 +/- 1% (P < 0.05) at the end of 3 mo of follow up. In dogs treated with enalapril or metoprolol, the proportion of type I fibers was 30 +/- 4 and 28 +/- 2% before randomization and 33 +/- 4 and 33 +/- 1%, respectively, after 3 mo of therapy. In conclusion, in dogs with moderate HF, early therapy with enalapril or metoprolol prevents the progressive decline in the proportion of type I SM fibers.
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PMID:Effects of ACE inhibition and beta-blockade on skeletal muscle fiber types in dogs with moderate heart failure. 876 41

To determine whether reduced sarcoplasmic reticulum (SR) Ca(2+)-adenosinetriphosphatase (ATPase) (SERCA2) activity contributes to delayed myocardial relaxation during chronic left ventricular hypertrophy (LVH) progression, LVH was produced in rats by abdominal aortic coarctation. Systolic and diastolic functions were assessed in vivo 8 and 16 wk after surgery, and compositional alterations in LV myocardium [SERCA2 concentration, myosin heavy chain (MHC) isoenzymes, and tissue collagen] were correlated with the development of prolonged isovolumic relaxation and impaired cardiac performance over time. Myocardial relaxation was prolonged in 8-wk banded rats, despite normal isovolumic systolic function and LV end-diastolic pressure (LVEDP). No significant alterations in SERCA2 protein, beta-MHC, or fibrillar collagen levels were observed at this early time point. In contrast, LV SERCA2, beta-MHC, and fibrillar collagen concentrations were all significantly altered in 16-wk banded rats. These late compositional changes were associated with reduced cardiac performance, as manifested by a significant elevation in LVEDP (14 +/- 2 mmHg). The 34% decrease in SERCA2 protein was associated with reduced SR Ca2+ uptake and an even greater reduction (76%) in SERCA2 mRNA. SERCA2 mRNA levels were also significantly reduced to 43 +/- 10% of sham-operated rats 8 wk after banding, despite unchanged SERCA2 protein levels and normal SR Ca2+ uptake. These results argue against a significant contribution of SERCA2 downregulation to the subtle alterations in myocardial relaxation observed in compensated LVH. However, the early reduction in SERCA2 mRNA levels may serve as a molecular marker for impaired cardiac performance during the transition from compensated LVH to heart failure.
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PMID:Downregulation of sarcoplasmic reticulum Ca(2+)-ATPase during progression of left ventricular hypertrophy. 917 13

Abnormalities intrinsic to skeletal muscle are thought to contribute to decrements in exercise capacity found in individuals with chronic heart failure (CHF). Na+-K+-adenosinetriphosphatase (the Na+ pump) is essential for maintaining muscle excitability and contractility. Therefore, we investigated the possibility that the number and affinity of Na+ pumps in locomotor muscles of rats with CHF are decreased. Myocardial infarction (MI) was induced in 8 rats, and a sham operation was performed in 12 rats. The degree of CHF was assessed approximately 180 days after surgery. Soleus and plantaris muscles were harvested, and Na+ pumps were quantified by using a [3H]ouabain binding assay. At the time of muscle harvest, MI and sham-operated rats were similar in age (458 +/- 54 vs. 447 +/- 34 days old, respectively). Compared with their sham-operated counterparts, MI rats had a significant amount of heart failure, right ventricular-to-body weight ratio was greater (48%), and the presence of pulmonary congestion was suggested by an elevated lung-to-body weight ratio (29%). Left ventricular end-diastolic pressure was significantly increased in the MI rats (11 +/- 1 mmHg) compared with the sham-operated controls (1 +/- 1 mmHg). In addition, mean arterial blood pressure was lower in the MI rats compared with their control counterparts. [3H]ouabain binding sites were reduced 18% in soleus muscle (136 +/- 12 vs. 175 +/- 13 pmol/g wet wt, MI vs. sham, respectively) and 22% in plantaris muscle (119 +/- 12 vs. 147 +/- 8 pmol/g wet wt, MI vs. sham, respectively). The affinity of these [3H]ouabain binding sites was similar for the two groups. The relationship between the reduction in Na+ pump number and the reduced exercise capacity in individuals with CHF remains to be determined.
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PMID:Decreased [3H]ouabain binding sites in skeletal muscle of rats with chronic heart failure. 921 79

Conventional positive inotropy with beta-adrenergic agonists or phosphodiesterase inhibitors increases the amplitude of the calcium transient and is associated with increases in myocardial oxygen consumption that may not be desirable when used in heart failure. Alternatively, agents that increase the sensitivity of the contractile apparatus without increasing the amplitude of the calcium transient have been shown to increase contractility without increasing energy consumption. Also, agents that result in negative inotropy while maintaining the amplitude of the calcium transient result in more energy-inefficient negative inotropy in comparison with agents that cause negative inotropy though a decrease in the amplitude of the calcium transient. These experiments suggest that calcium handling is responsible for a large proportion of the total energy expenditure associated with changes in inotropy. Problems that remain with the use of calcium-sensitizing agents include uncertainty regarding the site of action, adverse effects on systemic and coronary vasculature and diastolic function, and concomitant phosphodiesterase-inhibiting activity. One alternative is to use genetically engineered mouse models in which specific mutations selective to the myocyte can be produced. Potential molecular targets include the protein kinase A and C phosphorylation sites on troponin I, which, when phosphorylated, mediate a reduction in calcium sensitivity and a reduction in maximal actomyosin adenosinetriphosphatase activity, respectively. Mutations at these sites, by altering the relationship between force and calcium, may provide significant insights into the molecular mechanisms controlling the energetics of positive inotropy.
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PMID:Inotropic and energetic effects of altering the force-calcium relationship: mechanisms, experimental results, and potential molecular targets. 1090 89