UMLS:C0018801 - FACTA Search

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 paraventricular nucleus (PVN) of the hypothalamus is known to be involved in the control of sympathetic outflow. Nitric oxide (NO) has been shown to have a sympathoinhibitory effect in the PVN. The goal of the present study was to examine the influence of overexpression of neuronal NO synthase (nNOS) within the PVN on renal sympathetic nerve discharge (RSND). Adenovirus vectors encoding either nNOS (Ad.nNOS) or beta-galactosidase (Ad.beta-Gal) were transfected into the PVN in vivo. Initially, the dose of adenovirus needed for infection was determined from in vitro infection of cultured fibroblasts. In Ad.nNOS-treated rats, the local expression of nNOS within the PVN was confirmed by histochemistry for NADPH-diaphorase-positive neurons. There was a robust increase in staining of NADPH-diaphorase-positive cells in the PVN on the side injected with Ad.nNOS. The staining peaked at 3 days after injection of the virus. In alpha-chloralose- and urethane-anesthetized rats, microinjection of N(G)-monomethyl-L-arginine (L-NMMA), a NO antagonist, into the PVN produced a dose-dependent increase in RSND, blood pressure, and heart rate. There was a potentiation of the increase in RSND, blood pressure, and heart rate due to L-NMMA in Ad.nNOS-injected rats compared with Ad.beta-Gal-injected rats. These results suggest that the endogenous NO-mediated effect in the PVN of Ad.nNOS-treated rats is more effective in suppressing RSND compared with Ad.beta-Gal-treated rats. These observations support the contention that an overexpression of nNOS within the PVN may be responsible for increased suppression of sympathetic outflow. This technique may be useful in pathological conditions know to have increased sympathetic outflow, such as hypertension or heart failure.
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PMID:Effect of in vivo gene transfer of nNOS in the PVN on renal nerve discharge in rats. 1178 7

Growth hormone (GH) application is a new strategy in the treatment of heart failure. However, clinical and experimental investigations have shown contradictory effects of GH on cardiac performance. We tested the hypothesis that GH could improve cardiac and renal function in volume overload-induced heart failure. The effect of 4 weeks of GH treatment (2 mg/kg daily) was investigated in Wistar rats with aortocaval shunt. GH application did not influence left ventricular contractility and end-diastolic pressure in rats with aortocaval shunt. In contrast, GH treatment normalized impaired diuresis (vehicle 10.8+/-0.6 mL/d, GH 15.8+/-0.7 mL/d; P<0.05) and sodium excretion (vehicle 1.5+/-0.1 mmol/d, GH 2.2+/-0.1 mmol/d; P<0.001) in shunt-operated rats, with a similar increase of fractional sodium excretion. The urinary excretion of cGMP, the second messenger of atrial natriuretic peptide and NO, was higher in animals with shunts than in sham-operated animals and was further increased by GH (vehicle 293+/-38 nmol/d, GH 463+/-57 nmol/d; P<0.01). Although the atrial natriuretic peptide plasma levels were unchanged after GH, the excretion of NO metabolites (nitrate/nitrite) was elevated (vehicle 2020+/-264 nmol/d, GH 2993+/-375 nmol/d; P<0.05) in parallel with increased renal mRNA levels of inducible NO synthase 2. The changes of renal function after GH and the increased excretion of NO metabolites and cGMP were abolished by simultaneous treatment with the NO synthase inhibitor N(G)-nitro-L-arginine methyl ester. GH treatment did not influence cardiac function in rats with aortocaval shunts. However, GH improved renal function by increasing diuresis and sodium excretion. The responsible mechanism might be the enhanced activity of the renal NO system.
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PMID:Cardiac and renal effects of growth hormone in volume overload-induced heart failure: role of NO. 1179 79

Endothelium-dependent vasodilation is impaired in patients with chronic heart failure (CHF). However, the mechanisms responsible for this effect are not fully understood. The vasodilator response to acetylcholine (ACh) has been used to examine the endothelium-dependent vasodilation in humans and is known to be mediated by nitric oxide (NO). The impaired production of NO or an increase in its degradation is thought to be responsible for the endothelial dysfunction in CHF. The aim of this study was to determine whether the decrease in availability of tetrahydrobiopterin (BH(4)), an essential cofactor of NO synthase, contributes to the impairment of endothelium-dependent vasodilation in patients with CHF. Fourteen patients with CHF (New York Heart Association functional class II-IV, age: 59 +/- 4 years, ejection fraction: 28 +/- 3%) and seven age-matched control subjects were examined. Forearm blood flow (FBF) was measured by plethysmography during an intra-arterial infusion of a graded dose of ACh (4, 8, and 16 microg/min) and sodium nitroprusside (SNP) (0.8, 1.6, and 3.2 microg/min). These procedures were repeated during a co-infusion of BH(4) (400 microg/min). The forearm vasodilator response to ACh was significantly enhanced during co-infusion of BH(4) in patients with CHF, whereas no effect was observed in healthy subjects. In contrast, the response to SNP was not affected by BH(4) in either group. The administration of BH(4) did not alter the baseline FBF in either group. These results suggest that an acute administration of BH(4 ) improves endothelium-dependent forearm vasodilation in patients with CHF.
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PMID:Tetrahydrobiopterin improves impaired endothelium-dependent forearm vasodilation in patients with heart failure. 1186 15

The beneficial effects of ACE inhibitors (ACEi) or angiotensin II type 1 receptor antagonists (AT(1)-ant) are reportedly mediated by NO in heart failure (HF). We hypothesized that in the absence of endothelial NO synthase (eNOS), (1) left ventricular (LV) dysfunction and myocardial remodeling would be more severe after myocardial infarction (MI), and (2) the cardioprotective effect of ACEi and AT(1)-ant would be diminished or absent in mice with HF after MI. eNOS knockout mice (eNOS-/-) and wild-type C57BL/6J (C57) mice (+/+) were subjected to MI by ligating the left coronary artery. One month after MI, each strain was treated with vehicle, ACEi (enalapril, 20 mg/kg per day), or AT(1)-ant (valsartan, 50 mg/kg per day) for 5 months. Echocardiography was performed, and systolic blood pressure was measured before MI and monthly thereafter. Interstitial collagen fraction and myocyte cross-sectional area were examined histologically. We found that (1) compared with C57 mice, eNOS-/- mice that underwent sham surgery had significantly increased systolic blood pressure (P<0.05) and increased LV mass both initially and at 1 to 3 months, although cardiac function and histological findings did not differ between strains; (2) the development of HF and myocardial remodeling were similar after MI in both strains; and (3) ACEi improved cardiac function and remodeling in C57 mice, as evidenced by increased LV ejection fraction (LVEF) and LV shortening fraction (LVSF) and decreased diastolic LV dimension, mass, myocyte cross-sectional area, and interstitial collagen fraction, but these benefits were absent or diminished in eNOS-/- mice (for C57 versus eNOS-/-: increase in LVEF after ACEi, 14.2 +/- 2% versus -4.9 +/- 2.5%, respectively [P<0.001]; increase in LVSF, 8.6 +/- 2.1% versus -7.2 +/- 2.8%, respectively [P<0.01]; and decrease in LV mass, -16.6 +/- 15 versus 73 +/- 23 mm(3), respectively [P<0.01]). AT(1)-ant had benefits similar to those of ACEi, which were also absent or diminished in eNOS-/- mice (for C57 versus eNOS-/-: increase in LVEF after AT(1)-ant, 13.5 +/- 1.8% versus -9.8 +/- 3%, respectively [P<0.001]; increase in LVSF, 6.1 +/- 1.6% versus -3.8 +/- 3.1%, respectively [P<0.01]). Our data suggest that the absence of NO does not alter the development of HF after MI; however, it significantly decreases the cardioprotective effects of ACEi or AT(1)-ant.
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PMID:Effect of ACE inhibitors and angiotensin II type 1 receptor antagonists on endothelial NO synthase knockout mice with heart failure. 1188 76

Myocarditis is thought to be commonly caused by various viruses, and accumulating evidence links viral myocarditis with the eventual development of dilated cardiomyopathy. Heart disease is the most prevalent cause of morbidity and mortality in developed countries. Cytokines are being increasingly recognized as an important factor in the pathogenesis of myocarditis and cardiomyopathy. Elevated levels of circulating cytokines have been reported in patients with heart failure, and various cytokines have been shown to depress myocardial contractility in vitro and in vivo. A number of reports have shown that cytokines generated by activated immune cells cause an increase in nitric oxide (NO) via induction of NO synthase. Increased generation of NO may induce myocardial damage. It has been suggested that NO can be either beneficial or harmful to the host, NO can protect the myocardium against damage from CVB3 infection by inhibiting viral replication. A better molecular understanding of the direct effect of viral infection on cardiac myocytes and the balance of beneficial and detrimental effects of the immune response will ultimately provide insight into the mechanisms by which viral infections cause cardiomyopathy in humans.
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PMID:[Involvement of immune system in the pathogenesis of viral myocarditis]. 1200 27

1. This study examined whether NO is involved in the in-vivo coronary vasodilator effects of amlodipine (a calcium channel blocker) and whether heart failure (HF) alters the coronary responses to amlodipine. 2. Nine conscious dogs were chronically instrumented to measure circumflex coronary blood flow (CBF) and coronary diameter (CD). Drugs were administered directly into the circumflex artery through an indwelling catheter to avoid systemic changes. HF was induced by right ventricular pacing (240 b.p.m., 3 weeks). 3. Compared with control (C), in HF, coronary responses to acetylcholine (1 - 10 ng kg(-1)) were reduced while responses to nitroglycerin (0.1 - 0.5 microg kg(-1)) were unchanged. In C, amlodipine (30 - 150 microg kg(-1)), increased dose-dependently CBF and CD. After LNA (a NO synthase inhibitor, 2 mg kg(-1)), amlodipine produced less increases in CBF and CD (+121+/-26 ml min(-1) and +76+/-35 microm versus +196+/-40 ml min(-1) and +153+/-39 microm respectively for 150 microg kg(-1) amlodipine alone, both P<0.05). In HF, the coronary responses to amlodipine were reduced (150 microg kg(-1) of amlodipine increased CBF and CD +121+/-23 ml min(-1) and +77+/-21 microm respectively, both P<0.05). After LNA, the CBF responses to amlodipine tended to be reduced (+94+/-19 ml min(-1) at 150 microg kg(-1)) but CD responses were significantly reduced (+41+/-16 microm, P<0.05). The supplementation with L-arginine did not enhance the coronary responses to amlodipine. 4. These results indicate that, in conscious dogs, NO participates in the coronary responses to amlodipine and in HF, the coronary responses to amlodipine are reduced, which is related to a reduced NO production.
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PMID:Reduced coronary vasodilator responses to amlodipine in pacing-induced heart failure in conscious dogs: role of nitric oxide. 1201 Jul 75

Both systolic and diastolic cardiac dysfunction coexist in various degrees in the majority of patients with heart failure. Although ACE inhibitors are useful in the treatment of heart failure, the roles of bradykinin in the systolic and diastolic properties of left ventricular function under long-term treatment of ACE inhibitor have not been fully elucidated. We therefore evaluated the changes in left ventricular function, histomorphometry, and the expression of several failing heart related genes, by use of an orally active specific bradykinin type 2 receptor antagonist, FR173657 (0.3 mg/kg per day), with an ACE inhibitor, enalapril (1 mg/kg per day), in dogs with tachycardia-induced heart failure (270 ppm, 22 days) and compared the effects to enalapril alone. Although there were no differences observed in blood pressure, left ventricular dimension, and percentage of fractional shortening, FR173657 significantly increased left ventricular filling pressure (P<0.01), prolonged the time constant of relaxation (P<0.05), and suppressed the expression of endothelial NO synthase and sarcoplasmic reticulum Ca(2+)-ATPase mRNA (P<0.05). FR173657 also upregulated collagen type I and III mRNA (P<0.05) and increased the total amount of cardiac collagen deposits (P<0.05) in left ventricle compared with that in the enalapril-treated group. In conclusion, endogenous bradykinin contributes to the cardioprotective effect of ACE inhibitor, improving left ventricular diastolic dysfunction rather than systolic dysfunction, via modification of NO release and Ca(2+) handling and suppression of collagen accumulation.
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PMID:Bradykinin improves left ventricular diastolic function under long-term angiotensin-converting enzyme inhibition in heart failure. 1201 75

Endothelial dysfunction (ED) has been documented in patients with both coronary artery disease (CAD) and chronic heart failure (CHF)-being responsible for exercise-induced myocardial ischemia in the former and increased afterload in the latter. In the last two decades exercise training has assumed a major role in both cardiovascular disorders. In CAD exercise training has established positive effects on myocardial perfusion. Recently, exercise training has been shown to attenuate paradoxical vasoconstriction in CAD. The improved ED after training explains the improvement of myocardial perfusion in the absence of changes in baseline coronary artery diameter. Since ED has been identified as a predictor of coronary events exercise may contribute to long-term reductions of cardiovascular mortality. In CHF the increased peripheral vascular resistance - especially during exercise - is more important. ED contributes to the peripheral vasoconstriction. Training programs have shown to improve ED in CHF. A long-term study of hemodynamic effects of training in CHF revealed a significant reduction of total peripheral resistance (TPR) that after 6 months with a concomitant increase in stroke volume. In a subgroup analysis a significant correlation between changes in TPR and changes in peripheral ED was observed. Cell culture and animal experiments suggest that shear stress increases the endothelial L-arginine uptake, enhances NO synthase activity and expression, and upregulates the production of extracellular superoxide dismutase, which prevents premature NO breakdown. All these molecular effects converge on a reduction of myocardial ischemic events in CAD and a decrease of afterload in CHF.
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PMID:Exercise training and endothelial dysfunction in coronary artery disease and chronic heart failure. From molecular biology to clinical benefits. 1203 63

Cardiac hypertrophy occurs in pathological conditions associated with chronic increases in hemodynamic load. Although hypertrophy can initially be viewed as a salutary response, ultimately, it often enters a phase of pathological remodeling that may lead to heart failure and premature death. A prevailing concept predicts that changes in gene expression in hypertrophied cardiac myocytes and cardiac myocyte loss by apoptosis contribute to the transition from hypertrophy to failure. In recent years, nitric oxide (NO) has emerged as an important regulator of cardiac remodeling. Specifically, NO has been recognized as a potent antihypertrophic and proapoptotic mediator in cultured cardiac myocytes. Studies in genetically engineered mice have extended these findings to the in vivo situation. It appears that low levels and transient release of NO by endothelial NO synthase exert beneficial effects on the remodeling process by reducing cardiac myocyte hypertrophy, cavity dilation and mortality. By contrast, high levels and sustained production of NO by inducible NO synthase seem to be maladaptive by reducing ventricular contractile function, and increasing cardiac myocyte apoptosis, and mortality. In the future, these novel insights into the role of NO in cardiac remodeling should allow the development of novel therapeutic strategies to treat cardiac remodeling and failure.
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PMID:Regulation of cardiac remodeling by nitric oxide: focus on cardiac myocyte hypertrophy and apoptosis. 1237 17

In many types of cardiovascular pathophysiology such as hypercholesterolemia and atherosclerosis, diabetes, cigarette smoking, or hypertension (with its sequelae stroke and heart failure) the expression of endothelial NO synthase (eNOS) is altered. Both up- and downregulation of eNOS have been observed, depending on the underlying disease. When eNOS is upregulated, the upregulation is often futile and goes along with a reduction in bioactive NO. This is due to an increased production of superoxide generated by NAD(P)H oxidase and by an uncoupled eNOS. A number of drugs with favorable effects on cardiovascular disease upregulate eNOS expression. The resulting increase in vascular NO production may contribute to their beneficial effects. These compounds include statins, angiotensin-converting enzyme inhibitors, AT1 receptor antagonists, calcium channel blockers, and some antioxidants. Other drugs such as glucocorticoids, whose administration is associated with cardiovascular side effects, downregulate eNOS expression. Stills others such as the immunosuppressants cyclosporine A and FK506/tacrolimus or erythropoietin have inconsistent effects on eNOS. Thus regulation of eNOS expression and activity contributes to the overall action of several classes of drugs, and the development of compounds that specifically upregulate this protective enzyme appears as a desirable target for drug development.
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PMID:Regulation of endothelial-type NO synthase expression in pathophysiology and in response to drugs. 1238 13

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