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

Peripheral vasodilator responsiveness was examined in pacing-induced heart failure (HF) in 11 conscious dogs chronically instrumented for measurement of systemic (total peripheral resistance [TPR]) and local (iliac blood flow) vascular resistance. Dose responses to isoproterenol (ISO), acetylcholine (ACh), and nitroglycerin (NTG) were examined in the same dogs before pacing (control) and after 4 to 7 weeks of rapid ventricular pacing, which induced congestive HF, characterized by increased left ventricular end-diastolic pressure (6.7 +/- 0.4 [control] versus 28 +/- 1.5 [HF] mm Hg) and decreased cardiac output (-30 +/- 5%) and left ventricular dP/dt (-53 +/- 3%), as well as ascites and peripheral edema. In the control state, TPR fell by 57 +/- 2% in response to ISO (100 ng/kg), by 61 +/- 3% in response to ACh (3 micrograms/kg), and by 55 +/- 2% in response to NTG (10 micrograms/kg). In HF, smaller decreases (P < .05) in TPR were observed with the same doses of ISO (-50 +/- 2%) and ACh (-49 +/- 2%) but not with NTG (-58 +/- 3%). Depressed responses to systemic ISO and ACh, but not NTG, were observed in HF in the presence of ganglionic blockade and also after local administration of smaller doses of the drugs in the absence of ganglionic blockade, but where systemic effects were not elicited. Inhibition of nitric oxide synthase increased TPR to a greater degree before HF (+154 +/- 28% [control]) than after (+80 +/- 22% [HF]) and eliminated the depressed responses to ACh but not to ISO. beta-Adrenergic receptor density, as determined by 125I-cyanopindolol binding in membrane preparations from mesenteric vessels was significantly decreased after HF (130 +/- 3 [control] versus 100 +/- 8 [HF] fmol/mg, P < .05) without any change in affinity. Thus, peripheral vascular beta-adrenergic receptor downregulation occurs in HF, independent of altered endothelium-mediated peripheral vasodilation.
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PMID:Depressed beta-adrenergic receptor- and endothelium-mediated vasodilation in conscious dogs with heart failure. 769 60

Angiotensin converting enzyme inhibitors (ACEIs) are a cornerstone of treatment of hypertension and heart failure yet their mechanism of action is still debated. This study was designed to test whether the ACEI captopril increases skin microvascular blood flow by a bradykinin-dependent mechanism. Local changes in microvascular blood flow were measured in the skin of rabbits and of human volunteers using a laser Doppler flow probe. Captopril injected intradermally increased skin blood flow over the dose range of 10(-12)-10(-8) mol site in rabbits and humans. In both species the response was abolished by coinjecting either a nitric oxide synthase (NOS) inhibitor or a cyclooxygenase inhibitor. Intradermal bradykinin also increased rabbit skin microvascular blood flow; at 10(-11) mol site it increased mean +/- SE basal blood flow by 88 +/- 12%. The responses to bradykinin or captopril were abolished by coinjecting a bradykinin antagonist, a specific bradykinin B2 receptor antagonist, or inhibitors of NOS or cyclooxygenase. Injecting a specific angiotensin II receptor antagonist at a dose that antagonized the constrictor effects of exogenous angiotensin II did not cause a significant increase in rabbit skin blood flow. This suggests that endogenous angiotensin II does not influence microvascular blood flow in this model. The results indicate that captopril increases skin microvascular blood flow in rabbits and humans secondary to an increase in endogenous tissue bradykinin; this stimulates B2 receptors with subsequent release of prostaglandins and nitric oxide. ACEIs may increase microvascular perfusion by a bradykinin-dependent mechanism.
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PMID:Captopril increases skin microvascular blood flow secondary to bradykinin, nitric oxide, and prostaglandins. 789 12

The role of nitric oxide in heart failure is unknown. The high-capacity inducible isoform of nitric oxide synthase is present in the myocardium of patients with idiopathic dilated cardiomyopathy. Plasma nitrate, the stable end-product of nitric oxide production, was significantly increased in patients with heart failure compared with normal controls (means 51.3 and 24.6 mumol/L). Vasodilation caused by increased nitric oxide may compensate for the vasoconstrictor effect of neurohumoral adaptions to heart failure. Alternatively, excess production may be detrimental to the heart by a direct negative inotropic effect.
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PMID:Increased nitric oxide production in heart failure. 791 9

Patients with heart failure have reduced forearm vasodilator responses when endothelial cell nitric oxide production is stimulated by muscarinic agonists. The aim of this study was to determine if activity of the nitric oxide pathway was also abnormal under basal conditions. Forearm blood flow (FBF) was measured with strain-gauge plethysmography in response to the intraarterial infusion of a subsystemic dose range of L-N-monomethylarginine (L-NMMA), a competitive inhibitor of nitric oxide synthase. In 18 normal subjects, the baseline FBF of 3.6 +/- 1.4 was decreased by 0.3 +/- 0.5 (p < 0.01), 1.0 +/- 0.7 (p < 0.01), 1.4 +/- 0.9 (p < 0.01), and 1.3 +/- 1.3 (p < 0.01) ml/min/100 ml forearm volume during infusions of 1, 4, 8, and 16 mumol/min of L-NMMA, respectively. In 10 patients with heart failure, the baseline FBF of 2.6 +/- 0.9 was decreased by 0.4 +/- 0.5 (p < 0.05), 0.4 +/- 0.5 (p < 0.05), 0.9 +/- 0.8 (p < 0.01), and 0.9 +/- 0.7 (p < 0.01) ml/min/100 ml forearm volume with the 4 doses of L-NMMA, respectively. There was no difference in the L-NMMA response between the 2 groups in terms of absolute flow, percent change, or with analysis of covariance to adjust for different baselines. The stable end products of nitric oxide (nitrite and nitrate) were measured in the forearm venous effluent. Nitrite and nitrate levels at baseline were not reduced in patients with heart failure.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Lack of contribution of nitric oxide to basal vasomotor tone in heart failure. 797 73

An enhanced risk for myocardial infarction has been observed in humans with sustained activation of the local and/or systemic renin-angiotensin system, such as a high renin-sodium profile or a heritably enhanced expression of angiotensin converting enzyme. Chronic renin-angiotensin system blockade by angiotensin converting enzyme inhibition reduces the rate of myocardial reinfarction in patients with moderate heart failure. Preliminary experimental evidence suggests that these clinical observations may be partially explained by a proatherogenic effect of an activated renin-angiotensin system, which can downregulate the expression of the endothelial nitric oxide synthase III. Nitric oxide exerts many potentially antiatherogenic effects on endothelium, platelets and low density lipoproteins and indirectly on monocytes and leukocytes Hypertension-induced chronic distension of elastic arteries upregulates the local renin-angiotensin system in these arteries and thereby downregulates nitric oxide synthase. Enhanced local synthesis of the trophic factor angiotensin-II and reduced releasability of the antitrophic factor nitric oxide appear to cooperate in the trophic adaptation of the distended vessel wall to the enhanced load, but with the disadvantage of enhanced susceptibility for atheroma development due to reduced availability of nitric oxide. Chronic blockade of the renin-angiotensin system by angiotensin converting enzyme inhibitors or by angiotensin receptor type-1 antagonists normalizes a reduced endothelial nitric oxide availability in several models, partially by a bradykinin-dependent mechanism. This endothelial protection proved to attenuate the progression of atherosclerosis in experimental models. The antiatherogenic potential of renin-angiotensin system blockade in humans is presently under study.
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PMID:The endothelium and the renin-angiotensin system. 818 13

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

We hypothesized that in cardiac muscles, angiotensin II partially inhibits the contractile response to beta-agonists. We studied the contractile response of isolated rat left ventricular papillary muscles to isoproterenol and the effect of angiotensin II on this response. We also investigated whether the effect of angiotensin II is mediated by bradykinin, prostaglandins, nitric oxide, and/or cGMP. Contractility of isolated papillary muscles was recorded with a force transducer, and rest tension, maximal developed tension (DT), maximal rate of rise in developed tension [T(+)], and maximal velocity of relaxation [T(-)] were measured (1) under basal conditions, (2) after pretreatment with various drugs, and (3) after cumulative doses of isoproterenol. Pretreatment groups included (1) vehicle (controls); (2) angiotensin II; (3) angiotensin II and N(omega)-nitro-L-arginine, an inhibitor of nitric oxide release; (4) L-arginine, the substrate for nitric oxide synthase; (5) L-arginine and N(omega)-nitro-L-arginine; (6) 8-bromo-cGMP, analogous to the second messenger of nitric oxide; (7) angiotensin II and icatibant (Hoe 140), a bradykinin B2 antagonist; and (8) angiotensin II and indomethacin, a cyclooxygenase inhibitor. There were no differences in contractile parameters before and after any of the pretreatments. Isoproterenol increased DT, T(+), and T(-), and these effects were attenuated by angiotensin II, L-arginine, and 8-bromo-cGMP. The effects of angiotensin II and L-arginine were blocked by inhibition of nitric oxide release with N(omega)-nitro-L-arginine. Neither the bradykinin B2 antagonist nor the cyclooxygenase inhibitor altered the effects of angiotensin II. We concluded that angiotensin II partially inhibits the contractile response of cardiac papillary muscles to isoproterenol This effect is likely mediated by nitric oxide release, perhaps acting via cGMP. Kinins and prostaglandins do not appear to participate in the inhibitory effect of angiotensin II. Attenuation of the contractile effect of isoproterenol by angiotensin II may help explain why cardiac function improves in heart failure after blockade of the renin-angiotensin system.
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PMID:Myocardial contractility is modulated by angiotensin II via nitric oxide. 861 28


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