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)

Cardiac transplantation, effective therapy for end-stage heart failure, is frequently complicated by allograft rejection, the mechanisms of which remain incompletely understood. Nitric oxide (NO), a vasodilator which is cytotoxic and negatively inotropic, can be produced in large amounts by an inducible NO synthase (iNOS) in response to cytokines. To investigate whether iNOS is induced during cardiac allograft rejection, hearts from Lewis or Wistar-Furth rats were transplanted into Lewis recipients. At day 5, allogeneic grafts manifested reduced contractility and histologic evidence of rejection (inflammatory infiltrate, edema, necrosis of myocytes). The mRNA for iNOS and iNOS protein were detected in ventricular homogenates and in isolated cardiac myocytes from rejecting allogeneic grafts but not in tissue and myocytes from syngeneic control grafts. Immunocytochemistry showed increased iNOS staining in infiltrating macrophages and in microvascular endothelial cells and cardiac muscle fibers and also in isolated purified cardiac myocytes from the rejecting allografts. Using a myocardial cytosolic iNOS preparation, nitrite formation from L-arginine and [3H] citrulline formation from [3H]L-arginine were increased significantly in the rejecting allogeneic grafts (P < 0.01). Myocardial cyclic GMP was also increased significantly (P < 0.05). The data indicate myocardial iNOS mRNA, protein and enzyme activity are induced in infiltrating macrophages and cardiac myocytes of the rejecting allogeneic grafts. Synthesis of NO by iNOS may contribute to myocyte necrosis and ventricular failure during cardiac allograft rejection.
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PMID:Induction of myocardial nitric oxide synthase by cardiac allograft rejection. 751 42

A major determinant of survival in patients with advanced viral or bacterial infection, or following severe trauma or burns complicated by multiple organ failure, is the combination of clinical signs termed the systemic inflammatory response syndrome (SIRS). SIRS is characterized by hypotension, tachypnea, hypo- or hyperthermia and leukocytosis as well as other clinical signs and symptoms, including a depression in myocardial contractile function. Heart failure complicating systemic sepsis or other causes of SIRS is usually not accompanied by coronary artery ischemia due to hypotension, myocardial necrosis, or marked cardiac interstitial inflammatory infiltrates, and thus the cause of cardiac contractile dysfunction in this syndrome has remained unclear. However, recent evidence has implicated an endogenous nitric oxide (NO) signalling pathway within cardiac myocytes and other cellular constituents of cardiac muscle, including the microvascular endothelium, as a possible contributor to the pathogenesis of heart failure in this syndrome. Cardiac myocytes are now known to express both constitutive NO synthase (cNOS) and inducible NO synthase (iNOS) activities. Activation of cNOS appears to modulate cardiac myocyte responsiveness to muscarinic cholinergic and beta-adrenergic receptor stimulation. Induction of iNOS by soluble inflammatory mediators, including cytokines, causes a marked depression in myocyte contractile responsiveness to beta-adrenergic agonists. Thus, inappropriate activation of cNOS or excessive or prolonged induction of iNOS in the myocardium may contribute to cardiac dysfunction complicating SIRS.
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PMID:Myocardial contractile dysfunction in the systemic inflammatory response syndrome: role of a cytokine-inducible nitric oxide synthase in cardiac myocytes. 753 82

The effect of L-arginine, 250 mg/kg over 10 min, on hemodynamics and venous function was studied in nine splenectomized dogs under light pentobarbital anesthesia before and after 17 +/- 1 days of rapid right ventricular pacing (RRVP) at 250 beats/min. Chronic RRVP induced mild congestive heart failure with increased mean circulatory filling (Pmcf), right atrial (Pra) and pulmonary capillary wedge pressures (Ppcw), and reduced cardiac output (CO). During the development of heart failure, total vascular compliance assessed from Pmcf-blood volume relationships during circulatory arrest was unchanged, but total vascular capacitance was markedly reduced, with an increase in stressed and reduction in unstressed blood volumes. At baseline but not after RRVP, L-arginine increased CO and reduced pulmonary vascular resistance. There were no significant changes in Pra, Ppcw, or total peripheral resistance. L-Arginine failed to alter total vascular compliance and capacitance or central blood volume in the baseline or failure state. These results do not support the hypothesis that increased Pmcf and reduced total vascular capacitance in the early stages of pacing-induced heart failure are caused by reduced substrate availability for or an endogenous competitive antagonist of NO synthase in venous endothelial cells.
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PMID:Acute effect of L-arginine on hemodynamics and vascular capacitance in the canine pacing model of heart failure. 858 82

Endothelium-dependent responses are depressed in coronary and peripheral blood vessels after the onset of pacing-induced heart failure in dogs and heart failure of various etiologies in humans. The present study was designed to examine whether these responses were due to decreases in the expression of endothelial cell NO synthase (ecNOS) and cyclooxygenase-1 (COX-1). After 1 month of left ventricular pacing, 8 mongrel dogs were monitored for heart failure as defined by clinical signs and left ventricular end diastolic pressures > 25 mm Hg. Total RNA and protein were isolated from endothelial cells scraped from the thoracic aorta and analyzed by Northern and Western blotting, respectively. Blots probed with 32P-labeled cDNAs for ecNOS and COX-1 were quantified densitometrically, and results were normalized against GAPDH or von Willebrand factor (vWF). In arbitrary units, the ratios of ecNOS to GAPDH were 2.66 +/- 0.77 (mean +/- SEM, n = 17) and 1.12 +/- 0.37 (n = 6 and the ratios of COX-1 to GAPDH were 1.52 +/- 0.52 and 0.56 +/- 0.15 before and after heart failure, respectively. These represent 56% to 64% (P < .05) reductions in ecNOS and COX-1 gene expression. There was no change in the ratios of either COX-1 or ecNOS to vWF. There was also a marked reduction in ecNOS protein after heart failure, estimated at 70%. A marked reduction in nitrite production, a measure of enzyme activity, from thoracic aortas in response to stimulation by either acetylcholine or bradykinin also occurred. To determine whether ecNOS and COX-1 could be independently regulated, an orally active NO-releasing agent, CAS 936, was given to 7 normal dogs for 7 days, and aortic ecNOS and COX-1 mRNAs were analyzed. The ratio of ecNOS to GAPDH was depressed by 52% (P < .05) in aortas from these dogs, whereas the ratio of COX-1 to GAPDH was unchanged. Similar results were found when data were normalized to vWF. These results suggest that at least two endothelial vasodilator gene products are reduced in heart failure, as opposed to a selective defect in NO synthase gene expression.
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PMID:Reduced gene expression of vascular endothelial NO synthase and cyclooxygenase-1 in heart failure. 860 6

1. The role of nitric oxide (NO) in congestive heart failure was investigated by studying the acute haemodynamic, hormonal and renal effects of N(G)-monomethyl-L-arginine (L-NMMA(, a nitric oxide inhibitor, given as incremental bolus doses in six sheep before (normal) and after induction of heart failure (HF) by rapid left ventricular pacing (LVoff+). 2. 6-NMMA caused significant initial dose-dependent rises in left ventricular systolic pressure, mean arterial pressure (MAP), peripheral resistance (PR) and left atrial pressure and declines in cardiac output in both normal and HF states (maximum response in 2-6 min). These responses were all but abolished when L-arginine was given concurrently with L-NMMA. The dose-response curve for the L-NMMA-induced rise in MAP was shifted to the right following LVP (P < 0.05), which is consistent with previous observations of blunted NO synthase activity in HF. A subsequent decline in MAP and PR to below prebolus levels was observed 30-60 min after L-NMMA administration in the paced state. No significant hormonal or renal effects were observed. 3. In conclusion, the present study confirms the important haemodynamic role played by endogenous NO in the normal state and demonstrates a blunted pressor response to NO inhibition in this model of heart failure.
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PMID:Nitric oxide inhibition in an ovine model of heart failure. 871 79

There is now considerable evidence that nitric oxide (NO) production and action are abnormal in patients with heart failure. Spontaneous NO release from the vascular endothelium is preserved or enhanced in patients with heart failure and this may help to maintain tissue perfusion by blunting the vasoconstriction induced by various neurohumoral factors. On the other hand, endothelial NO release in response to various stimuli including exercise appears to be diminished and this may contribute to the impaired exercise capacity of patients with heart failure. It is now apparent that NO produced within the heart plays an important role in the modulation of cardiac contractility under physiological conditions. In patients with heart failure, however, increased myocardial NO production in response to cytokines such as tumour necrosis factor-alpha may contribute to reduced contractility and myocyte injury. Our understanding of the role of NO in the control of vascular tone has provided an explanation for the efficacy of nitrovasodilators in heart failure and has stimulated novel approaches to augmenting endogenous vascular NO production. There is also evidence that ACE inhibitors act to restore normal endothelial function in patients with heart failure. Increased NO production within the heart, particularly that produced via the pro-inflammatory inducible NO synthase, may be detrimental. It remains to be determined whether selective inhibition of inducible NO synthase can favourably modify the course of this lethal condition.
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PMID:The role of nitric oxide in heart failure. Potential for pharmacological intervention. 873 29

Myocarditis is thought to be 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 cardiomyopathy. Cytokines are increasingly recognized as an important factor in the pathogenesis and pathophysiology of myocarditis and cardiomyopathy. Elevated 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 recent studies showed that cytokines generated by activated immune cells cause an increase in NO (nitric oxide) 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:Cytokines in myocarditis and cardiomyopathies. 883 73

Nitric oxide (NO), the free radical that accounts for the biological activity of endothelium-derived relaxing factor, is synthesized from L-arginine by NO synthase (NOS). There is evidence that NO availability is reduced in the peripheral vasculature of patients with congestive heart failure (CHF). The aim of this study was to investigate the expression of NOS in the descending aorta and in the skeletal muscles of rats subjected to heart failure. The alkaloid, monocrotaline, was used to induce pulmonary hypertension and cardiac failure in rats. The expression of both the constitutive (ecNOS) and the inducible (iNOS) isoforms of the enzyme was assessed by Western blot analysis. In CHF animals, the ecNOS location in the aorta is altered: the endothelial protein expression is substantially reduced (from 0.083 +/- 0.012 to 0.003 +/- 0.004 OD/microgram total proteins, P < 0.001) whereas the expression of ecNOS in the smooth muscle is increased (from 0.024 +/- 0.004 to 0.059 +/- 0.009 OD/ microgram total proteins, P < 0.01). The total aortic ecNOS is diminished in CHF respect to control animals (0.062 +/- 0.009 v 0.107 +/- 0.013 OD/microgram total proteins, P < 0.01). On the contrary, no difference in ecNOS protein expression was observed in the extensor digitorum longus and soleus muscles. Furthermore, iNOS was not detected in any of the tissues considered. In conclusion, experimental CHF causes a re-setting of the ecNOS protein expression in the descending aorta but not in skeletal muscles. The reduced abundance of ecNOS in the aortic endothelium is consistent with the impairment of the vasodilating function reported in patients with CHF.
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PMID:Aorta and skeletal muscle NO synthase expression in experimental heart failure. 893 77

We have previously proposed that pro-inflammatory cytokines and nitric oxide (NO) contributed to reversible myocardial depression in patients with sepsis and congestive heart failure. Sepsis and heart failure are also associated with refractoriness to beta-adrenoceptor agonists. Therefore, the chronotropic effects of cytokines and the NO synthase inhibitor, NG-methyl-L-arginine (NMA), on beta-adrenoceptor stimulation of neonatal cardiac myocytes were studied. Tumor necrosis factor alpha, interleukin-1 beta and interleukin-6 but not interleukin-4 or interleukin-5 significantly enhanced spontaneous beating rates compared to untreated myocytes in serum-free media for 48 h (P < 0.01; n = 12 for each). NMA also significantly enhanced spontaneous beating rates (P < 0.01; n = 12 for each). Only interleukin-1 beta treatment resulted in significant nitrite production, immunohistochemical staining for inducible nitric oxide synthase and detection of inducible NO synthase messenger RNA by reverse transcriptase-polymerase chain reaction (RT-PCR). However, tumor necrosis factor alpha, interleukin-1 beta, interleukin-6, and NMA each completely blocked the positive chronotropic effects of the beta-adrenoceptor agonist, isoproterenol (P < 0.01; n = 12 for each). These findings are most consistent with an inducible NO synthase-independent effect of cytokines and NMA on the chronotropic responses of neonatal cardiac myocytes to beta-adrenoceptor stimulation. This effect of cytokines and NMA on adrenergic signaling may involve a myocardial constitutive NO synthase or an NO-independent mechanism.
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PMID:Cytokines and nitric oxide synthase inhibitor as mediators of adrenergic refractoriness in cardiac myocytes. 905 50

Norepinephrine and epinephrine stimulate alpha- and beta-adrenergic receptors which, in turn, modulate force of contraction in heart muscle cells. However, chronic stimulation may be associated with growth-promoting effects and modulation of the cardiac phenotype. Sympathetic tone is chronically enhanced in chronic heart failure and results in a selective down regulation of beta 1 adrenergic receptors, most likely due to local mechanisms. Beyond reduced beta 1 receptor density and increased levels of inhibitory Gi proteins, there is now evidence that NO can modulate the beta-adrenergic stimulation in the human myocardium. Increased NO activity generated by an inducible NO synthase is associated with a reduced positive inotropic response to beta-agonists, a mechanism which may play an important role in inflammatory states such as myocarditis or sepsis. Experimental data suggests that stimulation of alpha-adrenergic receptors of cardiomyocytes results in cardiac growth and changes in phenotype which, in turn, may affect the functional properties of the myocardium. For example, phenylephrine can upregulate the expression of the sodium/calcium exchanger, while the expression SR Ca2+ ATPase may be reduced. The latter is also affected by angiotensin II. Similar changes in the expression of these crucial proteins for the cardiac calcium homeostasis have been reported in the failing human heart, raising the possibility that the increased sympathetic tone and the activated renin-angiotensin system may be involved in these changes.
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PMID:[Sympathetic nervous system in heart failure: effect of catecholamines and nitric oxide]. 906 72


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