UMLS:C0018801 - FACTA Search

Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Target Concepts:

Query: UMLS:C0018801 (heart failure)
72,216 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Nitric oxide (NO) plays a role in controlling vascular tone and regulates the contractile properties of cardiac myocytes. Patients with heart failure exhibit high plasma levels of nitrite/nitrate (NOx), a stable metabolite of NO, and of cytokines such as tumor necrosis factor-alpha, a potent inducer of NO synthase. An increase in inducible NO synthase activity has been found in cardiac tissue from patients with dilated cardiomyopathy. These findings raise the possibility that local or systemic overproduction of NO induced by cytokines exerts a chronic negative inotropic effect on the myocardium and may have detrimental effects on systemic hemodynamics in patients with heart failure. Plasma levels of NG,NG-dimethylarginine (asymmetric dimethylarginine; ADMA), a circulating endogenous NO synthase inhibitor, were measured in control subjects and patients with valvular, hypertensive, or ischemic heart diseases or idiopathic cardiomyopathy. The plasma levels of NOx and ADMA were assessed by high performance liquid chromatography. The plasma levels of NOx and ADMA were significantly elevated in patients with heart failure. Both NOx and ADMA were positively correlated with New York Heart Association functional class. There was a significant inverse correlation between plasma NOx and ejection fraction, as estimated by echocardiography. A significant relationship between plasma NOx and ADMA was found only in patients with moderate to severe heart failure (r=0.41, p=0.01). Findings suggest a compensatory role of a circulating endogenous NO synthase inhibitor against induced NO synthase activity in patients with heart failure.
...
PMID:Increased endogenous nitric oxide synthase inhibitor in patients with congestive heart failure. 965 Nov 9

The aim of the present study was to determine whether cardiac nitric oxide (NO) production changes during the progression of pacing-induced heart failure and whether this occurs in association with alterations in myocardial metabolism. Dogs (n=8) were instrumented and the heart paced until left ventricular end-diastolic pressure reached 25 mm Hg and clinical signs of severe failure were evident. Every week, hemodynamic measurements were recorded and blood samples were withdrawn from the aorta and the coronary sinus for measurement of NO metabolites, O2 content, free fatty acids (FFAs), and lactate and glucose concentrations. Cardiac production of NO metabolites or consumption of O2 or utilization of substrates was calculated as coronary sinus-arterial difference times coronary flow. In end-stage failure, occurring at 29+/-1.6 days, left ventricular end-diastolic pressure was 25+/-1 mm Hg, left ventricular systolic pressure was 92+/-3 mm Hg, mean arterial pressure was 75+/-2.5 mm Hg, and dP/dtmax was 1219+/-73 mm Hg/s (all P<0.05). These changes in hemodynamics were associated with a fall of cardiac NO metabolite production from 0.37+/-0.16 to -0.28+/-0.13 nmol/beat (P<0.05). O2 consumption and lactate uptake did not change significantly from control, while FFA uptake decreased from 0.16+/-0.03 to 0.05+/-0.01 microEq/beat and glucose uptake increased from -2.3+/-7.0 to 41+/-10 microgram/beat (P<0.05). The cardiac respiratory quotient also increased significantly by 28%. In 14 normal dogs the same measurements were performed at control and 1 hour after we injected 30 mg/kg of nitro-L-arginine, a competitive inhibitor of NO synthase .O2 consumption increased from 0.05+/-0.002 mL/beat at control to 0.071+/-0.003 mL/beat after nitro-L-arginine, while FFA uptake decreased from 0.1+/-0.01 to 0.06+/-0.01 microEq/beat, lactate uptake increased from 0.15+/-0.04 to 0.31+/-0.03 micromol/beat, glucose uptake increased from 8.2+/-5.0 to 35.4+/-9.5 microgram/beat, and RQ increased by 23% (all P<0.05). Our results indicate that basal cardiac production of NO falls below normal levels during cardiac decompensation and that there are shifts in substrate utilization. This switch in myocardial substrate utilization also occurs after acute pharmacological blockade of NO production in normal dogs.
...
PMID:Reduced nitric oxide production and altered myocardial metabolism during the decompensation of pacing-induced heart failure in the conscious dog. 981 54

The adaptive changes that accompany hypertension and involve the kidney, heart, and vessels, namely, muscle hypertrophy/hyperplasia, endothelial dysfunction and extracellular matrix increase can, in fact, be maladaptive and eventually lead to end-organ disease, such as renal failure, heart failure, and coronary disease. However, these changes vary markedly between individuals with similar levels of hypertension. Nitric oxide (NO), an endogenous vasodilator and inhibitor of vascular smooth muscle and mesangial cell growth, is synthesized in the endothelium by a constitutive NO synthase (NOS). NO antagonizes the effects of angiotensin II on vascular tone and growth and also down-regulates the synthesis of angiotensin converting enzyme (ACE) and angiotensin II type 1 (AT-1) receptors. In hypertension, the physiologic response to the increased shear stress and cyclic strain is to upregulate NOS activity in endothelial cells. Upregulation of vascular NOS activity is a homeostatic adaptation to the increased hemodynamic workload that may help in preventing end-organ damage. Indeed, hypertension-prone salt-sensitive rats manifest a decrease (instead of an increase) in vascular NOS activity when hypertensive; these rats develop severe vascular hypertrophy, left ventricular hypertrophy, and renal injury. Studies in hypertensive humans suggest that, independent of the effects of salt on blood pressure, salt sensitivity may be a marker for susceptibility to the development of endothelial dysfunction as well as cardiovascular and renal injury. We hypothesize that in hypertension, recognition of markers of cardiovascular susceptibility to injury and the understanding of the pathophysiological mechanisms involved may open new opportunities for therapeutic intervention. In this context, only those antihypertensive agents that lower blood pressure and concomitantly restore the homeostatic balance of vasoactive agents such as angiotensin II and NO within the vessel wall would be effective in preventing or arresting end-organ disease.
...
PMID:Angiotensin II, nitric oxide, and end-organ damage in hypertension. 983 77

Patients with chronic heart failure (CHF) are hemodynamically characterized by increased vasoconstriction and a reduced vasodilator response to exercise. In addition to various compensatory neurohumoral mechanisms, there is evidence that the endothelium plays an important role in the abnormal vasodilator response. This evidence comes from studies investigating the microvascular response to regional, intra-arterial administration of the endothelium-dependent vasodilator acetylcholine, which found that the vasodilator response and therefore the bioavailability of nitric oxide (NO) was impaired in the microcirculation of the leg, forearm, and myocardium of patients with CHF. The mechanisms underlying this abnormal response are not entirely clear but may reflect a muscarinic receptor abnormality. Because conduit artery vasodilatation during hyperemic blood flow is also impaired and because this response is not dependent on muscarinic receptor activation, this possibility appears to be unlikely. However, impaired smooth muscle responsiveness to NO stimulation, impaired L-arginine availability or utilization, endothelial release of vasoconstricting prostanoids, increased NO degradation and reduced NO synthase activity have all been implicated in this impaired response. In addition, the vasoconstrictor activity of endothelin (ET)-1 appears to play an important role in the regulation of tone in CHF, although the importance of different ET receptors is not yet clear.
...
PMID:Endothelial control of vascular tone in chronic heart failure. 988 51

We performed experiments to test the hypothesis that experimental heart failure (HF) is associated with altered nitric oxide (NO)-dependent influences on the renal microvasculature, including diminished modulation of constrictor responses to ANG II. Eight to ten weeks after inducing HF in rats by coronary artery ligation, we administered enalaprilat to suppress ANG II synthesis and studied renal arteriolar function using the in vitro blood-perfused juxtamedullary nephron technique. In kidneys from sham-operated rats, NO synthase inhibition [100 microM Nomega-nitro-L-arginine (L-NNA)] reduced afferent arteriolar diameter by 4.1 +/- 0.6 microm and enhanced ANG II responsiveness (10 nM ANG II decreased afferent diameter by 10.1 +/- 1.4 micrometer before and 12.8 +/- 1.6 micrometer during L-NNA treatment; P < 0.05). In kidneys from HF rats, L-NNA did not alter afferent arteriolar baseline diameter or ANG II responsiveness (10 nM ANG II decreased diameter by 12.5 +/- 1.5 micrometer before and 12.5 +/- 2.3 micrometer during L-NNA). The effects of L-NNA on efferent arteriolar function were also abated in HF rats. In renal cortex of HF rats, NO synthase activity was decreased by 63% and superoxide dismutase activity was diminished by 39% relative to tissue from sham-operated rats. Urinary nitrate/nitrite excretion was also reduced in HF rats. Thus both diminished synthesis and augmented degradation are likely to contribute to a decreased renal microvascular impact of endogenous NO during chronic HF, the consequences of which include loss of NO-dependent modulation of ANG II-induced vasoconstriction.
...
PMID:Suppressed impact of nitric oxide on renal arteriolar function in rats with chronic heart failure. 988 83

An enhanced peripheral chemoreflex has been documented in patients with chronic heart failure (CHF). This study aimed to examine the characteristics of carotid body (CB) chemoreceptors in response to isocapnic hypoxia in a rabbit model of pacing-induced CHF and to evaluate the possible role that nitric oxide (NO) plays in the altered characteristics. The chemosensitive characteristics of the CB were evaluated by recording single-unit activity from the carotid sinus nerve in both an intact and a vascularly isolated preparation. It was found that the baseline discharge under normoxia (intact preparation: arterial PO2 90-95 Torr; isolated preparation: PO2 100-110 Torr) and the chemosensitivity in response to graded hypoxia (PO2 40-70 Torr) were enhanced in CHF vs. sham rabbits. These alterations were independent of the CB preparations (intact vs. isolated). NO synthase inhibition by Nomega-nitro-L-arginine increased the baseline discharge and the chemosensitivity in the intact preparation, whereas L-arginine (10(-5) M) inhibited the baseline discharge and the chemosensitivity in the isolated preparation in sham but not in CHF rabbits. S-nitroso-N-acetylpenicillamine, an NO donor, inhibited the baseline discharge and the chemosensitivity in both CB preparations in CHF rabbits but only in the isolated preparation in sham rabbits. The amount of NO produced in vitro by the CB under normoxia was less in CHF rabbits than in sham rabbits (P < 0.05). NO synthase-positive varicosities of nerve fibers within the CB were less in CHF rabbits than in sham rabbits (P < 0.05). These data indicate that an enhanced input from CB occurs in the rabbit model of pacing-induced CHF and that an impairment of NO production may contribute to this alteration.
...
PMID:Enhanced activity of carotid body chemoreceptors in rabbits with heart failure: role of nitric oxide. 1019 13

Endothelial-derived nitric oxide (NO) is an important mediator of vascular function. Clinical studies indicate that HMG-CoA reductase inhibitors (statins) improve endothelial function and reduce the incidence of stroke and myocardial infarction. Treatment of human endothelial cells with statins increased the expression of endothelial NO synthase (eNOS) protein and mRNA expression. Statins increased eNOS mRNA half-life but did not change eNOS gene transcription. Inhibition of mevalonate synthesis by statins not only blocks the formation of cholesterol but also of isoprenoids. The upregulation of eNOS expression by statins was independent of cholesterol but mediated via the inhibition of the isoprenoid geranylgeraniol, whereas farnesiol had no effect on eNOS. Immunoblot analyses, (35S)-GTP gamma S-binding assays and transfection studies revealed that statins upregulate eNOS expression by blocking the geranylgeranylation of the GTPase Rho which is necessary for its membrane-associated activity. Studies with mice showed, that statin treatment upregulates eNOS expression and function independent of serum cholesterol levels. Prophylactic treatment with statins augmented cerebral blood flow and reduced cerebral infarcts in normocholesterolemic mice. These effects of statins were completely absent in eNOS-deficient mice indicating that enhanced eNOS activity by statins is the predominant mechanism by which these agents protect against cerebral injury. Our results suggest that statins provide a novel prophylactic treatment strategy for increasing blood flow and reducing brain injury during cerebral ischemia. Upregulation of eNOS by inhibiting Rho may provide a new pharmacologic target for the treatment of arteriosclerosis, pulmonary hypertension, and heart failure.
...
PMID:[Regulation of endothelial NO production by Rho GTPase]. 1037 57

We hypothesized that nitric oxide (NO) opposes ANG II-induced increases in arterial pressure and reductions in renal, splanchnic, and skeletal muscle vascular conductance during dynamic exercise in normal and heart failure rats. Regional blood flow and vascular conductance were measured during treadmill running before (unblocked exercise) and after 1) ANG II AT(1)-receptor blockade (losartan, 20 mg/kg ia), 2) NO synthase (NOS) inhibition [N(G)-nitro-L-arginine methyl ester (L-NAME); 10 mg/kg ia], or 3) ANG II AT(1)-receptor blockade + NOS inhibition (combined blockade). Renal conductance during unblocked exercise (4.79 +/- 0.31 ml x 100 g(-1) x min(-1) x mmHg(-1)) was increased after ANG II AT(1)-receptor blockade (6.53 +/- 0.51 ml x 100 g(-1) x min(-1) x mmHg(-1)) and decreased by NOS inhibition (2.12 +/- 0.20 ml x 100 g(-1) x min(-1) x mmHg(-1)) and combined inhibition (3.96 +/- 0.57 ml x 100 g(-1) x min(-1) x mmHg(-1); all P < 0.05 vs. unblocked). In heart failure rats, renal conductance during unblocked exercise (5.50 +/- 0.66 ml x 100 g(-1) x min(-1) x mmHg(-1)) was increased by ANG II AT(1)-receptor blockade (8.48 +/- 0.83 ml x 100 g(-1) x min(-1) x mmHg(-1)) and decreased by NOS inhibition (2.68 +/- 0.22 ml x 100 g(-1) x min(-1) x mmHg(-1); both P < 0.05 vs. unblocked), but it was unaltered during combined inhibition (4.65 +/- 0.51 ml x 100 g(-1) x min(-1) x mmHg(-1)). Because our findings during combined blockade could be predicted from the independent actions of NO and ANG II, no interaction was apparent between these two substances in control or heart failure animals. In skeletal muscle, L-NAME-induced reductions in conductance, compared with unblocked exercise (P < 0.05), were abolished during combined inhibition in heart failure but not in control rats. These observations suggest that ANG II causes vasoconstriction in skeletal muscle that is masked by NO-evoked dilation in animals with heart failure. Because reductions in vascular conductance between unblocked exercise and combined inhibition were less than would be predicted from the independent actions of NO and ANG II, an interaction exists between these two substances in heart failure rats. L-NAME-induced increases in arterial pressure during treadmill running were attenuated (P < 0.05) similarly in both groups by combined inhibition. These findings indicate that NO opposes ANG II-induced increases in arterial pressure and in renal and skeletal muscle resistance during dynamic exercise.
...
PMID:Interactions between angiotensin II and nitric oxide during exercise in normal and heart failure rats. 1044 15

Myocardial NO signaling appears elevated in heart failure (HF). Whether this results from increased NO production, induction of the high-output NO synthase (NOS)2 isoform, or changes in NOS regulatory pathways (such as caveolae) remains controversial. We tested the hypothesis that increased abundance of caveolin-3 and/or sarcolemmal caveolae contribute to increased NO signaling in pacing-induced HF. Abundance of caveolin-3 (0.59+/-0.08 versus 0.29+/-0.08 arbitrary units, P = 0.01) but not caveolin-1 was increased in HF compared with control conditions, assessed by Western blot. Additionally, transmission electron microscopy revealed increased caveolae (2. 7+/-0.4 versus 1.3+/-0.3 per micrometer myocyte membrane, P<0.005). The association between caveolin-3 and NOS3 at the sarcolemma and T tubules was unchanged in HF compared with control myocytes. The impact of NOS inhibition with L-N(G)-methylarginine hydrochloride (L-NMMA) on beta-adrenergic inotropy was assessed in conscious dogs before and after HF. In control dogs, dobutamine (5 microg. kg(-1) x min(-1)) increased +dP/dt by 36+/-7%, and this was augmented to 66+/-24% by 20 mg/kg L-NMMA (P = 0.04 versus without L-NMMA, n = 8) but not affected by 10 mg/kg L-NMMA (34+/-10%, P = NS; n = 8). In HF, dobutamine +dP/dt response was depressed (P<0.001 versus control), and increased concentrations were required to match control inotropic responses (10 to 15 microg. kg(-1) x min(-1), 48+/-7%). L-NMMA enhanced +dP/dt responses similarly at 10 mg/kg (61+/-17%, P = 0.02; n = 4) and 20 mg/kg (54+/-7%, P = 0.04; n = 7). Caveolin-3 abundance positively correlated with L-NMMA augmentation of dobutamine inotropic responses in HF (r = 0.9, P = 0.03; n = 4). Thus, in canine pacing-induced HF, expression of caveolin-3 and of sarcolemmal caveolae is increased. This increase is associated with augmented agonist-stimulated NO signaling, likely via a compartmentation effect.
...
PMID:Contribution of caveolin protein abundance to augmented nitric oxide signaling in conscious dogs with pacing-induced heart failure. 1082 39

Endothelium-derived NO is considered to be primarily an important determinant of vascular tone and platelet activity; however, the modulation of myocardial metabolism by NO may be one of its most important roles. This modulation may be critical for the regulation of tissue metabolism. Several physiological processes act in concert to make endothelial NO synthase-derived NO potentially important in the regulation of mitochondrial respiration in cardiac tissue, including (1) the nature of the capillary network in the myocardium, (2) the diffusion distance for NO, (3) the low toxicity of NO at physiological (nanomolar) concentrations, (4) the fact that low PO(2) in tissue facilitates the action of NO on cytochrome oxidase, and (5) the formation of oxygen free radicals. A decrease in NO production is involved in the pathophysiological modifications that occur in heart failure and diabetes, disease states associated with altered cardiac metabolism that contributes to the evolution of the disease process. In contrast, several drugs (eg, angiotensin-converting enzyme inhibitors, amlodipine, and statins) can restore or maintain endogenous production of NO by endothelial cells, and this mechanism may explain part of their therapeutic efficiency. Thus, the purpose of this review is to critically evaluate the role of NO in the control of mitochondrial respiration, with special emphasis on its effect on cardiac metabolism.
...
PMID:Role of endothelium-derived nitric oxide in the regulation of cardiac oxygen metabolism: implications in health and disease. 1111 Jul 67

<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>