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)

Myocarditis is thought to be commonly caused by various viruses, and accumulating evidence links viral myocarditis with the eventual development of dilated cardiomyopathy. Recently, the importance of hepatitis C virus infection was noted in patients with dilated and hypertrophic cardiomyopathy. Cytokines are being increasingly recognized as an important factor in the pathogenesis and pathophysiology 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 negative inotropism and myocardial damage. This review discusses the etiology and pathogenesis of myocarditis and cardiomyopathy from this point of view.
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PMID:Molecular and immune mechanisms in the pathogenesis of cardiomyopathy--role of viruses, cytokines, and nitric oxide. 915 79

We have previously shown that nitric oxide (NO) release by the coronary circulation in the failing and nonfailing human heart is, in part, regulated by local kinin production in coronary microvessels. Angiotensin-converting enzyme (ACE) also known as kininase II, inactivates kinins. ACE inhibitors prevent kinin breakdown by ACE, thereby increasing the concentration of bradykinin (BK) and related kinins. The goal of this study was to determine if kinins contribute to the therapeutic action of ACE inhibitors. Six hearts from end-stage heart failure patients were harvested at the time of orthotopic cardiac transplantation. Microvessels were prepared as previously described, and nitrite production, a metabolic product of NO in vitro, was determined by the Griess reaction. Microvessels were incubated in the presence of kininogen and bradykinin, and with the ACE inhibitors ramiprilat, enalaprilat, or captopril. All caused dose-dependent increases in nitrite. For instance, ramiprilat increased nitrite from 76 +/- 5.6 to 155 +/- 15 pmol/min per mg wet weight. Nitrite production in response to ACE inhibition was blocked by N-nitro-L-arginine methyl ester (L-NAME), a NO synthase inhibitor, and icatibant (HOE 140), a B2-kinin receptor-specific antagonist. Furthermore, NO production was prevented by 3 different serine protease inhibitors, which block kallikrein, the enzyme responsible for conversion of kininogen to kinins. Our results indicate that ACE/kininase inhibitors increase NO production by the coronary microvasculature in the failing human heart, through increased available active kinins. The therapeutic action of ACE inhibition in the failing human heart may result in part from increased NO production by coronary microvessels.
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PMID:Angiotensin-converting enzyme inhibitors promote nitric oxide production in coronary microvessels from failing explanted human hearts. 929 67

Recent reports demonstrated the expression of inducible-type NO synthase in the heart of viral myocarditis. Since NO has multiple biological actions, a substantial amount of NO produced in the diseased heart may act either as a cytotoxic or as a cytoprotective molecule in the process of myocarditis. In the present study, we examined the effect of inhibition of NO synthesis on the mortality and the extent of myocardial injury in a murine model of coxsackievirus B3-induced myocarditis. We fed the infected mice drinking water containing a relatively low concentration (0.37 mmol/L) of N omega-nitro-L-arginine methyl ester (L-NAME) for 14 days after virus inoculation. This dose of L-NAME did not change virus titers in the heart. However, L-NAME-fed mice showed a significant reduction in mortality compared with those fed normal drinking water (nontreated mice). On the contrary, mice given a higher concentration of L-NAME (3.7 mmol/L) exhibited increased mortality. In addition, mice fed a low concentration of L-NAME showed reductions in the severity of heart failure and in the area of myocardial necrosis. Although systemic blood pressure was reduced in nontreated mice, in mice fed a low concentration of L-NAME, it was maintained at a level similar to that in uninfected control mice, L-NAME-treated mice also exhibited a reduction in the degree of inflammatory cell infiltration associated with decreased production of tissue prostaglandin E2 levels in the heart compared with nontreated mice. Therefore, NO is likely to be involved in the pathogenic mechanisms of myocardial injury and resultant cardiac dysfunction in a murine model of coxsackievirus B3-induced viral myocarditis.
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PMID:Low-dose N omega-nitro-L-arginine methyl ester treatment improves survival rate and decreases myocardial injury in a murine model of viral myocarditis induced by coxsackievirus B3. 931 31

Alterations in nitric oxide (NO) biosynthesis in the heart have been implicated in the pathophysiology of heart failure. We compared changes in cardiac nitric oxide synthase (NOS) activity and expression in genetically heart failure-prone (SHHF) rats at 6, 12, and 18 mo of age with those in age-matched spontaneously hypertensive (SHR) and Sprague-Dawley (SD) rats. Systolic blood pressure was significantly higher in SHHF and SHR rats compared with SD rats; however, it declined with age in SHHF rats only. Left ventricular mass increased with age in SHR and SHHF, but not in SD rats. Plasma nitrate and nitrite level was elevated in SHHF and SHR rats at 18 mo only. In left ventricular homogenates from SHHF rats, Ca(2+)-dependent NOS activity increased markedly with age and was accompanied by enhanced expression of endothelial NOS (eNOS). In contrast, SHR rats showed a much smaller increase in Ca(2+)-dependent NOS activity over time without changes in eNOS expression; neither parameter was altered with age in SD rats. Ca(2+)-independent NOS activity was not detected in any heart. This is the first report of a unique alteration in myocardial NOS activity in hypertensive rats genetically prone to heart failure.
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PMID:Age-dependent augmentation of cardiac endothelial NOS in a genetic rat model of heart failure. 932 10

The paraventricular nucleus (PVN) of the hypothalamus is known to be involved in the control of sympathetic outflow. The goal of the present study was to examine the role of nitric oxide within the PVN in the regulation of renal sympathetic nerve activity. Renal sympathetic nerve discharge (RSND), arterial blood pressure, and heart rate in response to the microinjection of nitric oxide synthase inhibitor NG-monomethyl-L-arginine (L-NMMA; 50, 100, and 200 pmol) into the PVN were measured in male Sprague-Dawley rats. Microinjection of L-NMMA elicited an increase in RSND, arterial blood pressure, and heart rate. Administration of NG-monomethyl-D-arginine (D-NMMA, 50-200 pmol) into the PVN did not change RSND, arterial pressure, or heart rate. Similarly, microinjection of another nitric oxide inhibitor NG-nitro-L-arginine methyl ester (L-NAME; 100 nmol) also elicited an increase in RSND, arterial blood pressure, and heart rate. L-Arginine (100 nmol) reversed the effects of L-NAME in the PVN. Furthermore, microinjection of sodium nitroprusside (SNP; 50, 100, and 200 nmol) into the PVN elicited a significant decrease in RSND, arterial blood pressure, and heart rate. These effects of L-NMMA, L-NAME, and SNP on RSND and arterial blood pressure were not mediated by their vasoactive action because microinjection of phenylephrine and hydralazine did not elicit similar respective changes. In conclusion, our data indicate that endogenous nitric oxide within the PVN regulates sympathetic outflow via some inhibitory mechanisms. Altered nitric oxide mechanisms within the PVN may contribute to elevated sympathetic nerve activity observed during various diseases states such as heart failure and hypertension.
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PMID:Nitric oxide within the paraventricular nucleus mediates changes in renal sympathetic nerve activity. 932 61

Heart failure is a common problem associated with considerable mortality and morbidity. The mechanisms underlying the heart failure syndrome, which remain poorly understood, may involve an inflammatory process. Nitric oxide (NO) and various cytokines could play an important role in this inflammatory process. Recent evidence has emerged in both animal models and humans suggesting that both of these mediators may play an important role in heart failure. NO is synthesized by the NO synthase family of enzymes. Two of these enzymes are constitutive, endothelial NO synthase and neuronal NO synthase. The third enzyme, inducible NO synthase, is capable of producing large amounts of NO once induced by mediators such as interleukin (IL)-1, IL-2, IL-6, tumour necrosis factor (TNF)-alpha, and interferon-gamma. Endothelial NO synthase is present in the heart in the endocardium, cardiac myocytes, and cardiac conduction tissue. Inducible NO synthase is present in cardiac myocytes, endocardium, vascular smooth muscle cells, and infiltrating inflammatory cells. Evidence from both animal models and patients suggests that NO exerts a negative inotropic effect. Increased inducible NO synthase, TNF-alpha, and IL-6 have been found in patients with heart failure in several studies. In other studies, decreased endothelial NO synthase was found in patients with heart failure. TNF-alpha and IL-6 may be produced in heart failure and may induce inducible NO synthase, resulting in NO production, which acts as a negative inotrope. Endothelial NO synthase may be decreased as a result of downregulation by TNF-alpha or inducible NO synthase. The possible role of these mediators in heart failure needs further evaluation because these findings could have novel therapeutic implications.
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PMID:The role of nitric oxide and cytokines in heart failure. 934 18

Hypertension is accompanied by architectural changes in the kidney, heart, and vessels that are often maladaptive and can eventually contribute to end-organ disease such as renal failure, heart failure, and coronary disease. Nitric oxide, an endogenous vasodilator and antithrombotic agent synthesized in the endothelium by a constitutive nitric oxide synthase, inhibits growth-related responses to injury in vascular cells. Specifically, in the presence of hypertension, nitric oxide may work in the kidney by inhibiting both mesangial cell hypertrophy and hyperplasia as well as synthesis of extracellular matrix and in the heart and systemic vessels by modulating smooth muscle cell hypertrophy and hyperplasia. The effects of nitric oxide are antagonistic of the effects of angiotensin II. Shear stress and cyclic strain, physical forces known to operate in hypertension, are accompanied by increases in endothelial nitric oxide synthase expression, nitric oxide synthase protein, and nitric oxide synthase activity in endothelial cells. Experimental studies using genetic models of hypertension show a variation in hypertension-modulated vascular nitric oxide synthase activity in different strains of rats. These studies suggest that upregulation of vascular nitric oxide synthase activity is a homeostatic adaptation to increased hemodynamic workload in hypertension and that this may help prevent end-organ damage. If these findings apply to humans, differences in end-organ disease seen in patients with similar degrees of hypertension may be due in part to genetic differences in vascular nitric oxide synthase activity in response to hypertension.
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PMID:Nitric oxide in hypertension: relationship with renal injury and left ventricular hypertrophy. 945 1

Cytokines are being increasingly recognized as important factors in the pathogenesis and pathophysiology of heart failure. 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. We have recently compared the effects on cytokine production of drugs for therapy of heart failure that have different effects on survival. Amrinone, pimobendan and vesnarinone, phosphodiesterase III inhibitors that have been shown to have short term haemodynamic benefits, inhibited TNF-alpha production. Differential modulation of the production of IL-1beta and IL-6 was observed; amrinone and pimobendan enhanced the production of IL-1beta, whereas vesnarinone did not. As inotropic agents differentially modulate cytokine production, these agents may interfere with induction of inducible nitric oxide (NO) synthase through an inhibition of cytokine formation. Although differential modulation of the production of NO by inotropic agents may explain their different effect in patients with heart failure, further study is necessary to reach this conclusion. We have shown that amlodipine increases the survival of mice with viral myocarditis and inhibits expression of inducible NO synthase and production of NO in vivo and in vitro. The therapeutic effect of amlodipine may in part result from inhibition of overproduction of NO. As we learn more about the pathophysiological and pathogenetic role of cytokines in heart failure, it should be possible to design better and more targeted pharmacological agents. Furthermore, the investigation of inotropic agents that are effective against the production of cytokines may help in the classification of these agents.
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PMID:The use of cytokine inhibitors. A new therapeutic insight into heart failure. 946 76

The therapeutic effects of calcium channel blockers on heart failure are controversial. However, a recent clinical trial demonstrated a favorable effect of amlodipine on survival rates in patients with heart failure resulting from nonischemic dilated cardiomyopathy. There are a number of studies showing that cytokines generated by activated immune cells cause an increase in nitric oxide (NO) via induction of NO synthase (NOS), which results in a direct negative inotropic effect and a modulation of inotropic responsiveness. Increases in inflammatory circulating cytokines have been detected in patients with heart failure and cardiomyopathy, elevated plasma levels of nitrite/nitrate in patients with heart failure have been reported, and inducible NOS (iNOS) has been found in ventricular tissue from patients with dilated cardiomyopathy. In our recent study, amlodipine improved histopathological lesions in the heart and survival rates in a murine model of nonischemic heart failure induced by encephalomyocarditis virus. Amlodipine inhibited NO production in vitro and decreased the number of iNOS positive cells in vivo. In this model, the therapeutic effect of amlodipine on myocardial injury is considered in part to result from inhibition of overproduction of NO. In this review, the possible roles of cytokines and NO in the pathophysiology of heart failure are discussed, along with the opportunities for therapeutic intervention.
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PMID:Calcium channel blocker-induced protection against cardiovascular damage. 948 94

It has been suggested that the myocardial production of nitric oxide, as a consequence of expression of the inducible isoform of nitric oxide synthase (NOS), plays an important role in the pathophysiology of heart failure. We determined the net cardiac production of nitrogen oxides (NOx), as a measure of NOS activity, by performing arterial and coronary sinus sampling in healthy control subjects (n=6) and patients with end-stage heart failure (n=10). The arterial plasma NOx concentration was significantly elevated in heart failure patients (58.4 +/- 7.0 vs 36.9 +/- 4.9 microM, p<0.05). However, we found net extraction of NOx across the heart, with no difference between the two groups. Therefore, the heart does not appear to be a source of NOx in heart failure, and this study does not support a pathophysiological role for NOx in this condition.
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PMID:The failing human heart does not release nitrogen oxides. 949 10


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