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

Local vascular alterations may contribute to increased peripheral vasoconstriction in chronic heart failure. To test whether endothelial dysfunction might be involved, the effect of acetylcholine, nitroglycerin, and NG-monomethyl-L-arginine (L-NMMA) was investigated in a constant-flow perfused hindquarter of rats with and without chronic heart failure (CHF) due to myocardial infarction. Changes in perfusion pressure were measured as an index of changes in hindlimb vascular resistance. The endothelium-dependent vasodilator effect of acetylcholine was significantly reduced in rats with large infarcts (greater than 40% of the left ventricle). However, the endothelium-independent vasodilator effect of nitroglycerin and the vasoconstrictor effect of L-NMMA were similar for infarct and normal animals. The vasodilator response to acetylcholine was partially inhibited by pretreatment with L-NMMA. Thus the basal release of nitric oxide from hindquarter resistance vessels is preserved in CHF. However, the endothelium-mediated dilation in response to acetylcholine is attenuated, in part, due to a depressed stimulated release of nitric oxide. The latter mechanism might be involved in the impaired vasodilatory capacity in the peripheral circulation in CHF, e.g., during exercise.
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PMID:Endothelial dysfunction of hindquarter resistance vessels in experimental heart failure. 162 25

The recent discovery of endothelium-derived relaxation factor (EDRF) has altered the traditional classification of vasodilators used in angina pectoris and heart failure. If a vasodilator induces release of EDRF from the epithelium it is classified as endothelium-dependent, if not it is independent. Sodium nitroprusside and SIN-1 (active metabolite of molsidomine) are the main independent vasodilators since the endothelium relaxation factor appears to be principally a nitric oxide radical in these synthetic vasodilators. In contrast, calcium-channel blockers and a good number of endogenous chemical mediators (acetylcholine, bradykinin, serotonin, etc.) are endothelium-dependent. Furthermore, simple increase in blood flow through the large vessels can result in endothelium-dependent vasodilation (flow rate-dependence) the extent of which depends on the drug examined. The fact that the pharmacologic response of a vasodilator can be altered under certain pathologic conditions (atherosclerosis, hypertension, diabetes, etc.) further increases the importance of the role of the vascular endothelium in the action of vasodilators since endothelial modulation may then be completely diverted to secretion of endothelium-derived contracting factors (EDCFS).
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PMID:[Vasodilator agents and the vascular endothelium]. 262 13

Chronic heart failure is associated with neurohumoral activation and alterations of the peripheral circulation and skeletal muscle. Several mechanisms are involved in the impaired peripheral perfusion, including increased sympathetic tone and increased vascular stiffness. Recently, data suggest an important role of the endothelium for perfusion of skeletal muscle in heart failure. Endothelium-dependent dilation of resistance vessels is blunted in patients with severe chronic heart failure and may be involved in the impaired reactive hyperemia in these patients. In conductance vessels, flow-dependent dilation and the nitroglycerin-induced dilator response is attenuated in congestive heart failure as compared to normal subjects, indicating both endothelial dysfunction and a defect of smooth muscle relaxation. Recent data suggest that angiotensin-converting enzyme (ACE) inhibitors can improve endothelial function of resistance vessels, reduce serum level of the soluble endothelial (vascular cell) adhesion molecule (VCAM-1) and, in addition, improve peripheral vascular function by reducing or limiting the influence of cyclo-oxygenase-dependent vasoconstricting factor(s). It is conceivable that these beneficial effects of chronic ACE inhibition are due, in part, to blockade of bradykinin degradation by the ACE and the increased endothelial synthesis of prostaglandins and/or the release of nitric oxide by enhanced tissue levels of bradykinin.
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PMID:Effect of chronic angiotensin-converting enzyme inhibition on endothelial function in patients with chronic heart failure. 748 81

Systemic vasoconstriction due to stimulation of the sympathetic and renin-angiotensin-aldosterone systems is a hallmark of heart failure and this is accompanied by impaired endothelium-dependent relaxations at the level of large arteries. This study investigated, in a rat model of heart failure, whether such an endothelial dysfunction also exists at the level of the resistance artery, and whether this is associated with morphologic changes, as well as the effects of chronic treatment with the angiotensin-converting enzyme inhibitor perindopril (2 mg/kg/day). After 12 months, arterial pressure, left ventricular (LV) end diastolic pressure (LVEDP), and LV dP/dt were measured in anesthetized rats. Responses to acetylcholine and nitroprusside were determined in isolated and perfused mesenteric artery segments (diameter: 280 +/- 15 microns). After fixation, vessel diameter, media cross-sectional area, and media collagen and elastin densities were measured by image analysis. After 12 months, untreated rats showed signs of heart failure, i.e., reduced LV dP/dt, and increased LVEDP, heart weight/body weight, LV cavity circumference, and myocardial collagen density. In mesenteric vessels the endothelium-dependent vasodilator response to acetylcholine was impaired, whereas the response to the nitric oxide donor nitroprusside was unaffected. Heart failure did not affect vascular morphological parameters. Perindopril decreased blood pressure and LVEDP without any modification of LV dP/dt, and prevented cardiac remodeling. At the vascular level, perindopril improved the response to acetylcholine and reduced media cross-sectional area and collagen density without affecting internal vessel diameter or elastin density. Thus, heart failure decreases endothelium-dependent vasodilator response to acetylcholine without modification of vessel structure.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Vascular and myocardial protective effects of converting enzyme inhibition in experimental heart failure. 748 84

The mechanism of action of nitrates, compounds that have been used classically in the treatment of heart failure, appears to be the stimulation of guanylate cyclase in vascular smooth muscle, perhaps the same physiologic action as endothelium-derived relaxing factor, now thought to be synonymous with nitric oxide (NO). Drugs that release NO either inside cells or in plasma have been developed recently. One such compound, CAS 936, when taken orally, is converted to an active metabolite, 3754. The goal of our studies was to determine the effects of CAS 936 and 3754 on cardiovascular function in conscious dogs before and after the development of pacing-induced heart failure. CAS 936 (10 mg/kg, p.o.) increased large coronary artery diameter 9.1 +/- 1.2% and reduced left ventricular end diastolic pressure (LVEDP) 2.5 +/- 0.5 mm Hg, but had no significant effects on coronary blood flow or vascular resistance. The metabolite 3754 caused dose-related increases in coronary artery diameter, and large reductions in LVEDP. The effect of these compounds on large coronary artery diameter was significantly greater (p < 0.05) than that of nitroglycerin (25 micrograms/kg). After heart failure, both CAS 936 and 3754 caused significant increases in large coronary artery diameter (10%) and a reduction in preload, up to 10 mm Hg, which was even larger than in normal dogs. Thus, these NO-releasing agents are potent selective large-vessel dilators that also reduce preload and maintain this unique vasodilator profile even in the failing heart.
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PMID:Effects of an orally active NO-releasing agent, CAS 936, and its active metabolite, 3754, on cardiac and coronary dynamics in normal conscious dogs and after pacing-induced heart failure. 750 69

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

1. This study examines the cardiovascular effects of CAS 1609 (4-hydroxymethyl-furoxan-3-carboxamide) in vitro as well as in vivo in various animal models. 2. CAS 1609 relaxed guinea-pig pulmonary artery strips without endothelium with IC50-values of 0.9 microM (phenylephrine contracted) and 15 microM (KCl-depolarized). This effect was inhibited by oxyhaemoglobin. In these arteries CAS 1609 significantly increased (+192%) guanosine 3':5'-cyclic monophosphate levels, which indicates that the compound acts as a donor of nitric oxide (NO). 3. In the anaesthetized pig, CAS 1609 (0.3-1.0 mg kg-1, i.d.) significantly lowered blood pressure and left ventricular end-diastolic pressure. Left ventricular contractility was slightly reduced and heart rate remained almost unchanged. 4. In anaesthetized dogs, i.v. or i.d. administration of CAS 1609 (0.3-3.0 mg kg-1) decreased, in a dose-related fashion, preload and afterload of the heart, cardiac output, left ventricular work and myocardial oxygen consumption. This haemodynamic profile is similar to that of known NO-donors. 5. In anaesthetized dogs with acute heart failure due to intracoronary injection of microspheres, CAS 1609 (0.3 mg kg-1, i.v.) improved the haemodynamic condition and reduced mortality by 80%. 6. In conscious dogs, oral treatment with a dose of 0.5 mg kg-1 given twice daily at 07 h 00 min and 19 h 00 min (each dose had a duration of action > or = 12 h) for 5 days showed no signs of tolerance to the haemodynamic effects of the drug. 7. All these data indicate that CAS 1609 is a potent, long-lasting orally active donor of NO, devoid of tolerance development.
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PMID:Cardiovascular actions of the furoxan CAS 1609, a novel nitric oxide donor. 759 29

The vascular endothelium releases vasoactive substances that appear to play an important role in the normal regulation of peripheral vasomotor tone. Nitric oxide, endothelins, prostaglandins, and other endothelium-derived vasodilating and vasoconstricting factors are released by the vascular endothelium in response to a diverse array of hormonal, pharmacologic, chemical, and physical stimuli. Shear stress, produced by pulsatile blood flow at the endothelial cell luminal surface, alters endothelial production of several endothelium-derived vasoactive substances, which may contribute to regional regulation of skeletal muscle blood flow during exercise. Abnormal vascular endothelium function has been shown in both experimental and clinical heart failure. Preliminary data suggest that abnormalities of endothelial function may contribute to increased peripheral vasomotor tone during exercise in patients with congestive heart failure.
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PMID:The role of endothelium-derived vasoactive substances in the pathophysiology of exercise intolerance in patients with congestive heart failure. 763 Oct 19

The basal release of endothelium-derived nitric oxide (EDNO) is considered to play an important role in regulating the vascular tone in normal subjects; however, its role in the presence of acute heart failure is unknown. This study was designed to clarify the role of a basal release of EDNO in the presence of acute heart failure. Acute ischemic left ventricular (LV) dysfunction was produced in 22 dogs by coronary microembolization. After the embolization, only saline solution was intravenously infused for sixty minutes in 10 dogs. In another 12 dogs, NG-monomethyl-L-arginine (L-NMMA), which is known to inhibit the formation of EDNO in the vascular endothelium, was intravenously infused at a rate of 20 micrograms/kg/minute for sixty minutes. Infusion of saline solution did not produce any changes in hemodynamic variables. Infusion of L-NMMA caused increases in mean aortic pressure, systemic vascular resistance, and LV end-diastolic pressure without changes in the LV peak + and - dP/dt (time constant) of LV pressure fall, and these changes were associated with a giant "v" wave in the tracing of left atrial pressure and a decrease in cardiac output. The basal release of EDNO may play an important role in the prevention of afterload elevation, subsequent cardiac output reduction, and afterload mismatch in the presence of acute heart failure.
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PMID:Basal release of endothelium-derived nitric oxide plays an important role in the prevention of afterload mismatch in acute left ventricular dysfunction. 766 79


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