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 functional significance of the Frank-Starling mechanism under physiological and pathophysiological conditions is discussed, based mainly on animal experiment results (in the dog, pig and rat). The dependence of individual stroke volume on end-diastolic volume can be described adequately using Frank's diagram. This can be illustrated by varying filling pressure (respiratory cycle, vascular tone in the capacitance system, body position, circulating blood volume) and by alterations in the duration of the filling period (heart rate and rhythm, rate of relaxation) and in ventricular compliance (wall thickness, fibrosis; contracture, rigor). The functional importance of the Frank-Starling mechanism lies mainly in adapting left to right ventricular output. During upright physical exercise an increase in end-diastolic volume due to the action of the peripheral muscle pump and increased venous tone can assist in enhancing stroke volume. Reduced contractility leads to a shift of the operating point to the right in the pressure-volume diagram, thus tending to prevent a decrease in stroke volume. However, the consequences of increased circulating blood volume in chronic heart failure are, as a rule, mainly detrimental (congestive symptoms; myocardial component of coronary resistance; cardiac energetics). Reduced contractility results in a flattening of the relation between stroke volume (or stroke work) and end-diastolic volume. Furthermore, the Starling mechanism is prevented from becoming effective if the sarcomere-length reserve is exhausted, or in the presence of inadequate sarcomere extension due to impaired relaxation or reduced distensibility of the ventricular wall. The latter is illustrated using the example of a dilated fibrotic left ventricle from a rat with experimental supravalvular aortic stenosis.
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PMID:Functional significance of the Frank-Starling mechanism under physiological and pathophysiological conditions. 147 14

Adverse pulmonary reactions to some nitrofuran antibiotics are thought, in part, to involve production of reactive oxygen radicals. Furazolidone, a nitrofuran antibiotic, causes a dilated cardiomyopathy in domestic turkeys. The mechanism of this drug induced cardiomyopathy is unknown. We investigated the possible role of free radical injury in this heart failure model. Left ventricular lipid peroxidation capacity, assessed by two methods (the thiobarbituric acid reactive substances and lipid hydroperoxides assays respectively), was investigated in five 5-8 week old cardiomyopathic turkeys with severe cardiac dilatation, left ventricular dysfunction and systemic hypotension, and in five control birds. Superoxide dismutase activity, total and manganese, was also measured in the crude left ventricular homogenates. Both lipid peroxidation products were reduced in the myopathic hearts: thiobarbituric acid reactive substances (malondialdehyde) 70(SEM 4) v 86(3) nmol.100 mg protein-1 in controls, p less than 0.02; and lipid hydroperoxides 29(7) v 74(14) nmol.100 mg protein-1, p less than 0.02. Total superoxide dismutase activity was similar in cardiomyopathic and control hearts: 670(26) v 657(105) nitrite units.100 mg protein-1. Although total superoxide dismutase activity was unchanged, we found decreased manganese superoxide dismutase in the dilated hearts compared with controls (54% v 84% of total activity, p less than 0.02). In separate in vitro experiments furazolidone (2-10 mg.g wet weight-1) did not increase malondialdehyde production in turkey (or rat) left ventricular homogenates. These results indicate that cardiomyopathy induced by furazolidone is associated with decreased myocardial lipid peroxidation. Although as yet unexplained, the decrease may be due to a diminished amount of heart lipid susceptible to peroxidation accompanying the process of cardiac hypertrophy and dilatation.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Reduced lipid peroxidation in dilated hearts of cardiomyopathic turkeys. 325 24

The effects of low-dose oral spironolactone (SPIRO) in a rat model of hypertensive heart failure (spontaneously hypertensive heart failure rat) were compared with its effects when combined with captopril (CAP). Twenty-six spontaneously rats with hypertensive heart failure were treated with either placebo (CON), SPIRO (20 mg/kg/d by mouth), CAP (100 mg/kg/d by mouth), or both SPIRO and CAP for 12 weeks. This dose of oral SPIRO did not affect blood pressure, left ventricular end-diastolic diameter, left ventricular ejection fraction, plasma atrial natriuretic peptide concentration, or cardiac fibrosis; however, in combination with CAP, it exerted a significant depressor effect after 12 weeks of treatment that was accompanied by increased urine output and decreased urinary protein excretion. These effects were significantly greater than those with CAP treatment alone. A significant increase in plasma aldosterone level was observed only in CON (174 +/- 21%). These data suggest that the addition of low-dose SPIRO to angiotensin I-converting enzyme inhibitor treatment may prevent progression into end-stage congestive heart failure through synergistic effects on diuresis and renoprotection.
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PMID:Combined effects of low-dose oral spironolactone and captopril therapy in a rat model of spontaneous hypertension and heart failure. 1277 59

Today, dilated cardiomyopathy (DCM) represents the main cause of severe heart failure and disability in younger adults and thus is a challenge for public health. About 30% of DCM cases are genetic in origin; however, the large majority of cases are sporadic, and a viral or immune pathogenesis is suspected. Following the established postulates for pathogenesis of autoimmune diseases, here we provide direct evidence that an autoimmune attack directed against the cardiac beta(1)-adrenergic receptor may play a causal role in DCM. First, we immunized inbred rats against the second extracellular beta(1)-receptor loop (beta(1)-EC(II); 100% sequence identity between human and rat) every month. All these rats developed first, receptor-stimulating anti-beta(1)-EC(II) Ab's and then, after 9 months, progressive severe left ventricular dilatation and dysfunction. Second, we transferred sera from anti-beta(1)-EC(II)-positive and Ab-negative animals every month to healthy rats of the same strain. Strikingly, all anti-beta(1)-EC(II)-transferred rats also developed a similar cardiomyopathic phenotype within a similar time frame, underlining the pathogenic potential of these receptor Ab's. As a consequence, beta(1)-adrenergic receptor-targeted autoimmune DCM should now be categorized with other known receptor Ab-mediated autoimmune diseases, such as Graves disease or myasthenia gravis. Although carried out in an experimental animal model, our findings should further encourage the development of therapeutic strategies that combat harmful anti-beta(1)-EC(II) in receptor Ab-positive DCM patients.
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PMID:Direct evidence for a beta 1-adrenergic receptor-directed autoimmune attack as a cause of idiopathic dilated cardiomyopathy. 1514 32

Chronic stimulation of sympathetic nervous activity contributes to the development and maintenance of hypertension, leading to left ventricular hypertrophy (LVH), arrhythmias and cardiac death. Moxonidine, an imidazoline antihypertensive compound that preferentially activates imidazoline receptors in brainstem rostroventrolateral medulla, suppresses sympathetic activation and reverses LVH. We have identified imidazoline receptors in the heart atria and ventricles, and shown that atrial I1-receptors are up-regulated in spontaneously hypertensive rats (SHR), and ventricular I1-receptors are up-regulated in hamster and human heart failure. Furthermore, cardiac I1-receptor binding decreased after chronic in vivo exposure to moxonidine. These studies implied that cardiac I1-receptors are involved in cardiovascular regulation. The presence of I1-receptors in the heart, the primary site of production of natriuretic peptides, atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP), cardiac hormones implicated in blood pressure control and cardioprotection, led us to propose that ANP may be involved in the actions of moxonidine. In fact, acute iv administration of moxonidine (50 to 150 microg/rat) dose-dependently decreased blood pressure, stimulated diuresis and natriuresis and increased plasma ANP and its second messenger, cGMP. Chronic SHR treatment with moxonidine (0, 60 and 120 microg kg(-1) h(-1), sc for 4 weeks) dose-dependently decreased blood pressure, resulted in reversal of LVH and decreased ventricular interleukin 1beta concentration after 4 weeks of treatment. These effects were associated with a further increase in already elevated ANP and BNP synthesis and release (after 1 week), and normalization by 4 weeks. In conclusion, cardiac imidazoline receptors and natriuretic peptides may be involved in the acute and chronic effects of moxonidine.
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PMID:Imidazoline receptors in the heart: a novel target and a novel mechanism of action that involves atrial natriuretic peptides. 1527 26

Changes in proteolytic activity of the myocardium during the development of heart failure after left coronary artery ligation (CAL) of rats were examined. Hemodynamics of the rats at the eighth week (8w-CAL rat), but not at the second week (2w-CAL rat), after CAL showed the symptoms of chronic heart failure. Contents of mu-calpin and m-calpain, but not an intrinsic calpain inhibitor calpastatin, in the viable left ventricular muscle (viable LV) and the right ventricular muscle (RV) of the 2w-CAL and 8w-CAL rats were increased, which was associated with an elevation of intrinsic activities of leupeptin-sensitive, Ca(2+)-activated proteolysis in the cytosolic fractions of the viable LV and RV. Oral administration of 3 mg/kg/d trandolapril or 1 mg/kg/d candesartan from the second to eighth week after CAL improved the hemodynamics of 8w-CAL rats. The drug treatment attenuated the increases in mu-calpain and m-calpain contents and the elevation of the proteolytic activity of the viable LV and RV in the 8w-CAL rat. The drug treatment increased calpastatin content of the RV in the 8w-CAL rat. These results suggest that sustained activation of calpain is involved in the development of chronic heart failure and that trandolapril and candesartan prevent the activation of calpains after CAL.
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PMID:Possible involvement of calpain activation in pathogenesis of chronic heart failure after acute myocardial infarction. 1663 84

The metabolic syndrome is complicated by nephropathy in humans and rats, and males are more affected than females. We hypothesized that female rats had reduced expression of glomerular oxidized low-density lipoprotein (oxLDL) receptor 1 (LOX-1), attendant glomerular oxidant injury, and renal inflammation. Three groups, obese males (OM), obese females (OF), and lean males (LM) of first-generation (F(1)) hybrid rats derived from the Zucker fatty diabetic (ZDF) strain and the spontaneous hypertensive heart failure rat (SHHF/Gmi-fa) were studied from 6 to 41 weeks of age. OM had severe renal oxidant injury and renal failure. Their glomeruli expressed the LOX-1, and exhibited heavier accumulation of the lipid peroxide 4-hydroxynonenal (4-HNE). OM had compromised mitochondrial enzyme function, more renal fibrosis, and vascular leakage. Younger LM, OM, and OF ZS (ZDF/SHHF F(1) hybrid rat) rats, studied from 6 to 16 weeks of age, showed that unutilized renal lipids were comparable in OM and OF, although young OM had worse nephropathy and inflammation. In conclusion, glomerular LOX-1 expression is coupled to deposits of 4-HNE and glomerulosclerosis in OM. We presume that LOX-1 enhances glomerular uptake of oxidized lipids and renal inflammation, causing greater oxidant stress and severe glomerulosclerosis. In OF, renal protection from lipid oxidants appears to be conferred by blunted glomerular LOX-1 expression and renal inflammation.
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PMID:Renal injury: similarities and differences in male and female rats with the metabolic syndrome. 1668 21

The complexity of cardiovascular responses produced by 5-hydroxytryptamine (5-HT, serotonin), including bradycardia or tachycardia, hypotension or hypertension, and vasodilatation or vasoconstriction, has been explained by the capability of this monoamine to interact with different receptors in the central nervous system (CNS), on the autonomic ganglia and postganglionic nerve endings, on vascular smooth muscle and endothelium, and on the cardiac tissue. Depending, among other factors, on the species, the vascular bed under study, and the experimental conditions, these responses are mainly mediated by 5-HT(1), 5-HT(2), 5-HT(3), 5-HT(4), 5-ht(5A/5B), and 5-HT(7) receptors as well as by a tyramine-like action or unidentified mechanisms. It is noteworthy that 5-HT(6) receptors do not seem to be involved in the cardiovascular responses to 5-HT. Regarding heart rate, intravenous (i.v.) administration of 5-HT usually lowers this variable by eliciting a von Bezold-Jarisch-like reflex via 5-HT(3) receptors located on sensory vagal nerve endings in the heart. Other bradycardic mechanisms include cardiac sympatho-inhibition by prejunctional 5-HT(1B/1D) receptors and, in the case of the rat, an additional 5-ht(5A/5B) receptor component. Moreover, i.v. 5-HT can increase heart rate in different species (after vagotomy) by a variety of mechanisms/receptors including activation of: (1) myocardial 5-HT(2A) (rat), 5-HT(3) (dog), 5-HT(4) (pig, human), and 5-HT(7) (cat) receptors; (2) adrenomedullary 5-HT(2) (dog) and prejunctional sympatho-excitatory 5-HT(3) (rabbit) receptors associated with a release of catecholamines; (3) a tyramine-like action mechanism (guinea pig); and (4) unidentified mechanisms (certain lamellibranch and gastropod species). Furthermore, central administration of 5-HT can cause, in general, bradycardia and/or tachycardia mediated by activation of, respectively, 5-HT(1A) and 5-HT(2) receptors. On the other hand, the blood pressure response to i.v. administration of 5-HT is usually triphasic and consists of an initial short-lasting vasodepressor response due to a reflex bradycardia (mediated by 5-HT(3) receptors located on vagal afferents, via the von Bezold-Jarisch-like reflex), a middle vasopressor phase, and a late, longer-lasting, vasodepressor response. The vasopressor response is a consequence of vasoconstriction mainly mediated by 5-HT(2A) receptors; however, vasoconstriction in the canine saphenous vein and external carotid bed as well as in the porcine cephalic arteries and arteriovenous anastomoses is due to activation of 5-HT(1B) receptors. The late vasodepressor response may involve three different mechanisms: (1) direct vasorelaxation by activation of 5-HT(7) receptors located on vascular smooth muscle; (2) inhibition of the vasopressor sympathetic outflow by sympatho-inhibitory 5-HT(1A/1B/1D) receptors; and (3) release of endothelium-derived relaxing factor (nitric oxide) by 5-HT(2B) and/or 5-HT(1B/1D) receptors. Furthermore, central administration of 5-HT can cause both hypotension (mainly mediated by 5-HT(1A) receptors) and hypertension (mainly mediated by 5-HT(2) receptors). The increasing availability of new compounds with high affinity and selectivity for the different 5-HT receptor subtypes makes it possible to develop drugs with potential therapeutic usefulness in the treatment of some cardiovascular illnesses including hypertension, migraine, some peripheral vascular diseases, and heart failure.
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PMID:Cardiovascular responses produced by 5-hydroxytriptamine:a pharmacological update on the receptors/mechanisms involved and therapeutic implications. 1770 82

The positive inotropic effect produced by Na(+)/K(+)-ATPase inhibition has been used for the treatment of heart failure for over 200 years. Recently, administration of toxic doses of ouabain has been shown to induce cardiac myocyte apoptosis. However, whether prolonged administration of non-toxic doses of ouabain can also promote cardiac myocyte cell death has never been explored. The aim of this study was to assess whether non-toxic doses of ouabain can induce myocyte apoptosis and if so, to examine the underlying mechanisms. For this purpose, cardiac myocytes from rat and cat, two species with different sensitivity to digitalis, were cultured for 24h in the presence or absence of 2 microM (rat) and 25 nm-2 microM ouabain (cat). Cell viability and apoptosis assays showed that ouabain produced, in the rat, a 43+/-5% decrease in cell viability due to apoptosis (enhanced caspase-3 activity, increased Bax/Bcl-2 and TUNEL-positive nuclei) and necrosis (LDH release and trypan blue staining). Similar results were obtained with 25 nM ouabain in the cat. Ouabain-induced reduction in cell viability was prevented by the NCX inhibitor KB-R7943 and by the CaMKII inhibitors, KN93 and AIP. Furthermore, CaMKII overexpression exacerbated ouabain-induced cell mortality which in contrast was reduced in transgenic mice with chronic CaMKII inhibition. However, KN93 failed to affect ouabain-induced inotropy. In addition, whereas ERK(1/2) inhibition with PD-98059 had no effect on cell mortality, PI3K inhibition with wortmannin, exacerbated myocyte death. We conclude that ouabain triggers an apoptotic cascade that involves NCX and CaMKII as a downstream effector. Ouabain simultaneously activates an antiapoptotic cascade involving PI3K/AKT which is however, insufficient to completely repress apoptosis. The finding that KN93 prevents ouabain-induced apoptosis without affecting inotropy suggests the potential use of CaMKII inhibitors as an adjunct to digitalis treatment for cardiovascular disease.
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PMID:Na+/K+-ATPase inhibition by ouabain induces CaMKII-dependent apoptosis in adult rat cardiac myocytes. 2043 43

Exposure to Libby amphibole (LA) asbestos is associated with increased incidences of human autoimmune disease and mortality related to cardiovascular diseases. However, the systemic and vascular impacts are less well examined because of the dominance of pulmonary disease. It was postulated that regardless of the type of exposure scenario, LA exposure might produce systemic and vascular inflammogenic and thrombotic alterations in healthy and cardiovascular compromised rat models. Samples from three independent studies were examined. In the first study, male Wistar Kyoto (WKY), spontaneously hypertensive (SH), and SH heart failure (SHHF) rats were intratracheally instilled once with 0 (vehicle), 0.25, or 1 mg/rat of LA. In the second study, F344 rats were instilled with vehicle or LA at 0.5, 1.5, or 5 mg/rat. In the third study, F344 rats were instilled with the same mass concentrations of LA delivered by biweekly multiple instillations over 3 mo to simulate an episodic subchronic exposure. Complete blood count, platelet aggregation, serum cytokines, and biomarkers of systemic and aortic effects were examined. LA reduced adenosine diphosphate (ADP)-induced platelet aggregation and decreased circulating platelets in WKY (1 mg/rat) and F344 (5 mg/rat) at the 3-mo time point but did not do so in SH or SHHF rats. A decline in circulating lymphocytes with age appeared to be exacerbated by LA exposure in F344 rats but the differences were not significant. Aorta mRNA expression for biomarkers of oxidative stress (HO-1, LOX-1), inflammation (MIP-2), and thrombosis (tPA, PAI-1, vWf) were increased at baseline in SH and SHHF relative to WKY. LA exposure upregulated several of these biomarkers and also those involved in aortic contractility of WKY rats at 3 mo, suggesting thrombogenic, vasocontractile, and oxidative stress-mediated impairments. The aorta changes in F344 rats were less remarkable than changes noted in WKY following LA exposure. In conclusion, exposure to LA decreased circulating platelets and platelet coagulability while increasing the expression of oxidative stress, thrombosis, and vasoconstriction biomarkers in the aorta of healthy rats. These changes were similar to those noted at baseline in SH and SHHF rats, suggesting that LA-induced pulmonary injury might increase the risk of developing cardiovascular disease in healthy individuals.
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PMID:Vascular and thrombogenic effects of pulmonary exposure to Libby amphibole. 2235 30


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