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)

Recently, we have demonstrated a decreased neuronal isoform of nitric oxide synthase (nNOS) message in the hypothalamus of rats with heart failure (HF). The purpose of this study was to determine the changes in NADPH-diaphorase (a commonly used marker for neuronal NOS activity) positive neurons in specific hypothalamic sites of rats with HF. After a standard histochemical protocol, NOS positive neurons were measured in paraventricular nucleus (PVN), supraoptic nucleus (SON), median preoptic area (MePO), subfornical organ (SFO), organum vasculosum of the lamina terminalis (OVLT) and lateral hypothalamus (LH) of rats with coronary artery ligation (HF group; n=8) and sham-operated control rats (n=9). A total of 4 months after coronary ligation, the rats in the HF group displayed infarcts greater than at least 35% of the left ventricular wall (n = 8). Sham-operated rats had no observable damage to the myocardium. Rats with HF had a significantly lower number of NOS positive cells in the PVN (36% less) compared to sham rats. The number of NOS positive cells remained unaltered in the SON, MePO and LH in rats with HF. Conversely there was an increased number of NOS positive cells in the SFO (42% greater) and OVLT (100% greater). These data support the conclusion that the NO system within the hypothalamus involved in controlling autonomic outflow is altered during HF and may contribute to the elevated levels of vasopressin and sympatho-excitation commonly observed in HF.
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PMID:Altered number of diaphorase (NOS) positive neurons in the hypothalamus of rats with heart failure. 955 24

An inducible isoform of nitric oxide synthase (type II, iNOS) is expressed in cardiac and vascular smooth muscle in response to inflammatory cytokines. The dog is an important large animal used for cardiovascular research including effects of exercise, heart failure, and allograft rejection. However, molecular probes for iNOS developed in other mammals have not been reliable for the study of iNOS induction in canine vascular smooth muscle. Experiments were designed to develop a molecular probe for canine iNOS. Smooth muscle cells were isolated from canine aortas. The cells (passages 3-10) were incubated for 1, 3, 6, 12, 24, 48, or 72 h in the absence and presence of Escherichia coli lipopolysaccharide (LPS) to induce iNOS. Total RNA was isolated from the cells using standard techniques. RT-PCR with primers against conserved regions of all known iNOS enzyme was used to clone the iNOS cDNA. RT-PCR showed a single band only from cells treated with LPS. Cloned cDNA from cultured canine aortic smooth muscle cells has 84% homology to human, 81% to rat, and 81% to mouse iNOS gene. Identification of the cDNA for canine iNOS will be useful in the study of differential, transcriptional regulation of inducible (type II) compared with constitutive endothelial (type III) NOS in canine studies of allograft rejection and cardiovascular disease.
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PMID:Induction and cDNA sequence of inducible nitric oxide synthase from canine aortic smooth muscle cells. 974 58

The effects of exogenous and endogenous. NO on myocardial functions such as contraction, relaxation and heart rate have recently gained considerable scientific interest. .NO stimulates myocardial soluble guanylate cyclase to produce cGMP, which activates two major target proteins. A small increase in cGMP levels predominantly inhibits phosphodiesterase III, while high cGMP levels activate cGMP-dependent protein kinase. Accordingly, submicromolar .NO concentrations improve myocardial contraction, while submillimolar .NO concentrations decrease contractility. The latter action includes direct inhibitory .NO effects on ATP synthesis and voltage-gated calcium channels. Overall, the inotropic effects of exogenous .NO are small and probably of minor importance for myocardial contractility. Cardiomyocytes are capable of expressing eNOS and iNOS. Endogenous .NO has effects on myocardial contraction, similar to that of exogenous .NO. Various NOS inhibitors can substantially reduce myocardial contractility in vitro and in vivo, suggesting that basal endogenous .NO production supports myocardial contractility. There is also evidence for a .NO-dependent cardiodepressive effect of cytokines that is mediated by expression of iNOS. This is consistent with the negative inotropic effects of .NO at high concentrations. Cardiodepressive actions of endogenous .NO production may play a role in certain forms of heart failure. Finally, .NO also has an effect on heart rate. Physiologic .NO concentrations can stimulate heart rate by activating the hyperpolarization-activated inward current (If) and this effect decreases at submillimolar .NO concentrations. In summary, physiological concentrations of .NO increase contractility and heart rate under basal conditions, while high .NO concentrations induce the opposite effects.
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PMID:Regulation of basal myocardial function by NO. 1061 6

We evaluated the role of SH-groups in improvement of endothelial dysfunction with ACE-inhibitors in experimental heart failure. To this end, we compared the vasoprotective effect of chronic treatment with zofenopril (plus SH-group) versus lisinopril (no SH-group), or N-acetylcysteine (only SH-group) in myocardial infarcted (MI) heart failure rats. After 11 weeks of treatment, aortas were obtained and studied as ring preparations for endothelium-dependent and -independent dilatation in continuous presence of indomethacin to avoid interference of vasoactive prostanoids, and the selective presence of the NOS-inhibitor L-NMMA to determine NO-contribution. Total dilatation after receptor-dependent stimulation with acetylcholine (ACh) was attenuated (-49%, P<0.05) in untreated MI (n=11), compared to control rats with no-MI (n=8). This was in part due to impaired NO-contribution in MI (-50%, P<0.05 versus no-MI). At the same time the capacity for generation of biologically active NO after receptor-independent stimulation with A23187 remained intact. Chronic treatment with n-acetylcysteine (n=8) selectively restored NO-contribution in total dilatation to ACh. In contrast, both ACE-inhibitors fully normalized total dilatation to ACh, including the part mediated by NO (no significant differences between zofenopril (n=10) and lisinopril (n=8)). Zofenopril, but not lisinopril, additionally potentiated the effect of endogenous NO after A23187-induced release from the endothelium (+100%) as well as that of exogenous NO provided by nitroglycerin (+22%) and sodium nitrite (+36%) (for all P<0.05 versus no-MI). We conclude that ACE-inhibition with a SH-group has a potential advantage in improvement of endothelial dysfunction through increased activity of NO after release from the endothelium into the vessel wall. Furthermore, this is the first study demonstrating the selective normalizing effect of N-actylcysteine on NO-contribution to ACh-induced dilatation in experimental heart failure.
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PMID:Comparison of zofenopril and lisinopril to study the role of the sulfhydryl-group in improvement of endothelial dysfunction with ACE-inhibitors in experimental heart failure. 1095 93

The aims of this study were to (a) determine whether inducible nitric oxide synthase (iNOS) is expressed in small mesenteric arteries from rats with chronic heart failure (CHF), (b) investigate the functional significance of this potential source of nitric oxide (NO) on vascular responsiveness and (c) investigate the role that superoxide plays in modulating vascular function in these arteries. CHF was induced in male Wistar rats by coronary artery ligation (CAL). In sham-operated rats the ligature was not tied but pulled under the artery. Six weeks after surgery CAL rats had left ventricular (LV) infarctions and elevated LV end-diastolic pressures. Immunoreactive iNOS was found in endothelial cells, vascular smooth muscle cells and in the adventitia of small mesenteric arteries from CAL rats but not those from sham-operated rats. Third order mesenteric arteries (300-350 microm) were mounted in a small vessel pressure myograph. Endothelium-intact arteries from CAL rats were more responsive to phenylephrine (PE) than arteries from sham-operated rats (pD(2) value, CAL, 6.2+/-0.1; sham-operated, 5.9+/-0.1, P<0.05). Both the selective iNOS inhibitor, N-(3-(Aminomethyl) benzyl) acetamidine dihydrochloride (1400W; 10(-6) M) and the superoxide dismutase mimetic, Mn [III] tetrakis [1-methyl-4-pyridyl] porphyrin, (MnTMPyP; 10(-4) M) reversed the hyperesponsiveness (pD(2) values, 1400W, 5.9+/-0.1; MnTMPyP, 5.81+/-0.1, P<0.05). The NOS substrate, L-arginine (10(-3) M), reduced responsiveness of endothelium-denuded small mesenteric arteries from CAL rats (P<0.01). None of these drugs altered responses to PE in arteries from sham-operated rats. In summary, this study demonstrates that iNOS is expressed in mesenteric arteries from rats with CHF. However, instead of generating large quantities of NO, iNOS appears to be generating superoxide, perhaps because of a deficiency in its substrate, L-arginine. Increased superoxide generation from iNOS contributes to the hyperesponsive nature of endothelium-intact small mesenteric arteries from rats with CHF.
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PMID:Inducible nitric oxide synthase-derived superoxide contributes to hypereactivity in small mesenteric arteries from a rat model of chronic heart failure. 1096 65

The production of nitric oxide is impaired in patients with clinical and instrumental signs of arteriosclerosis (chronic coronary heart disease, stable and unstable angina, myocardial infarction); the NO deficiency is assessed through the vascular response to the infusion of stimulating (acetycholine) or inhibiting (N-mono-methylarginine) substances upon NO synthesis. Also in hypertensive subjects a weak endothelium-dependent vascular relaxation was documented, but this phenomenon is not constant and is still to be confirmed. In hypercholesterolemic patients a hyporesponsive endothelium-dependent vasodilation has been well documented, lipid lowering agents (drugs, apheresis) improve endothelium function. In heart failure low NO levels are found proportionally to the severity of disease: the expression of No is depressed, but cytokine mediated i NOS expression is enhanced, causing exaggerated amounts of NO and producing myocyte damage or death. Interesting findings indicated NO inhalation as a useful tool for reducing pulmonary hypertension and congestive heart failure.
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PMID:Cardiovascular diseases and nitric oxide in humans. 1121 29

We examined the effects of TCV-116, an angiotensin II type 1 receptor antagonist, on endothelial-cell nitric oxide synthase (eNOS), inducible NOS (iNOS), and adrenomedullin (ADM) expression in the left ventricle (LV) and evaluated these relation to myocardial remodeling in failing heart of Dahl salt-sensitive hypertensive rats (DS) fed a high-salt diet. TCV-116 (DSHF-T, 5 mg/kg/day, subdepressor dose) or vehicle (DSHF-V) were given from left ventricular hypertrophy to heart failure stage for 7 weeks. Markedly increased left ventricular end-diastolic diameter and reduced fractional shortening in DSHF-V was significantly ameliorated in DSHF-T. The eNOS mRNA and protein in the LV was significantly suppressed in DSHF-V compared with control rats (DR-C), and significantly increased in DSHF-T compared with DSHF-V. The iNOS mRNA and protein, ADM mRNA and immunoreactive ADM contents, and type I collagen mRNA in the LV were significantly increased in DSHF-V compared with DR-C, and significantly decreased in DSHF-T compared with DSHF-V. DSHF-V showed a significant increase of the wall-to-lumen ratio, perivascular fibrosis, and myocardial fibrosis, with all these parameters being significantly improved by TCV-116. In conclusion, myocardial remodeling and heart failure in DS rats fed a high-salt diet were significantly ameliorated by a subdepressor dose of TCV-116, which may be due to a increased in eNOS and a decreased in iNOS mRNA and protein expression in the LV. Moreover, the ADM mRNA and immunoreactive ADM contents are upregulated in failing heart of DS rats fed a high-salt diet, and increased ADM expression may have a role in the defense mechanism against further cardiac dysfunction and impaired myocardial remodeling.
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PMID:Effects of TCV-116 on expression of NOS and adrenomedullin in failing heart of Dahl salt-sensitive rats. 1139 21

Nitric oxide (NO), a potent regulator of myocardial contractility, has been implicated in the development of heart failure; however, no study exists describing the relation between expression of inducible nitric oxide synthase (iNOS), formation of NO in vivo, and cardiac contractility. We have therefore generated transgenic (TG) mice overexpressing iNOS under the cardiospecific alpha-myosin heavy chain (alpha-MHC) promoter. In vitro, iNOS activity in hearts of two transgenic lines was 260- to 400-fold above controls (wild type [WT]), but TG mice were viable and appeared normal. Ventricular mass/body weight ratio did not differ; heart rate and cardiac output as well as mean arterial blood pressure were decreased by 10%. NO(x) levels of hearts and blood of TG mice were 2.5- and 2-fold above WT controls, respectively. In the isolated heart, release of the NO oxidation products nitrate and nitrite, an index of in vivo NOS activity, was 40-fold over WT. However, cardiac hemodynamics and levels of ATP and phosphocreatine were unaltered. The high iNOS activity was associated with reduced cardiac L-arginine in TG hearts to only 15% of the WT, indicating limited substrate availability, whereas L-citrulline was 20-fold elevated. Our findings demonstrate that the heart can tolerate high levels of iNOS activity without detrimental functional consequences. The concept that iNOS-derived NO is the triggering factor in the pathomechanism leading to heart failure therefore needs to be reevaluated.
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PMID:Cardiac-specific overexpression of inducible nitric oxide synthase does not result in severe cardiac dysfunction. 1452 22

Strong expression of the inducible form of nitric oxide synthase (NOS II) has been shown in the myocardium of patients with myocardial infarction (MI). We hypothesized that NOS II plays an important role in the development of MI and subsequent heart failure and that inhibition of NOS II may beneficially alter the course of the disease. Long-term administration (2 mo) of the selective NOS II inhibitor S-methylisothiourea (SMT) to rats with MI significantly improved cardiac function. A significant drop in mortality, lung water content, infarct size, and cardiomyocyte hypertrophy was also associated with the use of SMT. Plasma concentration of nitrite and nitrate was also reduced by SMT. Short-term administration of SMT (first 2 wk only) significantly reduced infarct size; however, it did not improve cardiac dysfunction measured 2 mo after MI. These findings demonstrate that induction of NOS II during MI exerts negative effects on cardiac function and structure. Long-term administration of a selective NOS II inhibitor may prove to be beneficial in the treatment of MI and congestive heart failure.
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PMID:Inhibition of NOS II prevents cardiac dysfunction in myocardial infarction and congestive heart failure. 1206 7

Endothelial dysfunction is a generalized phenomenon detectable at various levels in the vasculature, and is evident very early in the atherosclerotic process. These peculiarities have stimulated the introduction of new non-invasive techniques dedicated to evaluate the vasomotor response of arteries or districts in favourable position in the body (forearm, hand) that may reflect the response of inner arteries otherwise requiring invasive procedures (i.e. coronary arteries). Moreover, these techniques can be theoretically used to detect abnormalities of vasomotor response before a clinical adverse event may occur in subjects prone to vascular accidents with risk factors for atherosclerosis. Of physical stimuli inducing e-NOS activation and subsequent nitric oxide synthesis, the shear stress produced by pulsatile blood flow is the most important. This property is actually used in clinical practice to study the flow-mediated vasodilation (FMD) of the brachial artery. Any condition that reduces the ability of endothelial cells to produce nitric oxide causes endothelial dysfunction, which is directly reflected into a depressed FMD. There is evidence that brachial artery flow-mediated dilation is improved after local as well as systemic exercise, suggesting that the improvement in endothelial function is generalized and documentable in different arterial districts with similar results. Aerobic exercise induces e-NOS expression and improves the endothelial-dependent relaxation in normal as well as cardiac patients. The endothelium-independent vasorelaxation is generally unchanged after chronic conditioning, but this result is not evident in all studies. The improved endothelial vasoreactivity is correlated with enhanced functional capacity after moderate aerobic exercise, suggesting an important pathophysiological role of oxygen transport in exercise tolerance. These beneficial effects has been described in patients with stable heart failure in II and III NYHA functional class and in patients with coronary artery disease with programs different for frequency, duration and intensity. The evaluation of vasomotor reactivity gives promising results in explaining the effects of medications and exercise training. The demonstration that flow-mediated dilation may quantify endothelial dysfunction in subjects with a variety of conditions can be used in clinical practice not only to assess the effects of interventions, but also to provide a preliminary screening in apparently healthy subjects who have an underlying silent coronary artery disease. In cardiac rehabilitation, there are promising results from FMD evaluation in selecting patients who take major benefits in terms of functional capacity and endothelium-dependent vasodilation.
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PMID:Vasomotor reactivity evaluation in cardiac rehabilitation. 1241 19


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