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Query: UMLS:C0038454 (stroke)
 147,016 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We studied the acute haemodynamic dose response of nicorandil, a combined nitrate and potassium channel opener, in patients evaluated for chest pain. Single dose oral nicorandil (5, 10, 20, or 30 mg) or placebo was given to 42 right-heart catheterized patients using a randomized block design. Persistent, significant (P < 0.05) haemodynamic changes occurred primarily after 30 mg. Arterial systolic pressure fell significantly after all doses and remained reduced (maximum, 31 mmHg) up to 6 h after 30 mg; heart rate increased significantly up to 1 h. Individual haemodynamic sensitivity varied and three patients (1, 10 mg; 2, 30 mg) developed transient symptomatic hypotension associated with bradycardia. Pulmonary artery systolic pressure (diastolic was unchanged) declined significantly (maximum, 5 mmHg) up to 6 h after 30 mg whereas pulmonary capillary wedge (baseline normal) and mean right atrial pressures decreased transiently. Cardiac index (baseline normal) declined slightly (significantly after 30 mg); however, stroke volume index and stroke work index were significantly and persistently reduced after all doses. Total systemic vascular resistance declined slightly after 30 mg. Individual plasma nicorandil concentrations were variable and systemic bioavailability was reduced compared with values reported in healthy subjects. Nicorandil demonstrated cardiac unloading actions. Variable plasma concentrations, haemodynamic effects, and patient sensitivity warrant low initial doses with individual dose titration, especially if cardiac filling pressures are low.
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PMID:Dose-related haemodynamic effects and pharmacokinetics of oral nicorandil in patients evaluated for chest pain. 807 66

It is a common opinion that nitrate therapy may have a harmful effect on cardiac output in patients with congestive heart failure when left ventricular filling pressure is markedly reduced. In this study, we evaluated, using hemodynamic monitoring with Swan-Ganz catheterization, the effects on cardiac output and filling pressures of high-dose intravenous nitroglycerin in 8 patients with dilated cardiomyopathy and severe heart failure. At maximal doses of nitroglycerin utilized (350 +/- 220 micrograms/m, range 100-800), a significant reduction in right atrial pressure (from 4 +/- 3.5 to -1 +/- 4 mm Hg, p < 0.001) and pulmonary capillary wedge pressure (from 16 +/- 5 to 7 +/- 3 mm Hg, p < 0.001) was observed. Furthermore, we found neither a significant reduction in systemic vascular resistances (from 1,500 +/- 329 to 1,320 +/- 330 dynes/s/cm-5) nor changes in heart rate or blood pressure. Finally, stroke volume and cardiac index increased slightly although not significantly (from 62 +/- 18 to 70 +/- 16 ml and from 2.3 +/- 0.45 to 2.65 +/- 0.4 l/m/m2). The preservation of stroke volume despite a marked reduction in left ventricular filling pressure can be explained by a reduction in pericardial constraint and of mitral regurgitation induced by nitroglycerin. The clinical implications of these hemodynamic results are discussed with emphasis on the short- and long-term use of nitrates in congestive heart failure.
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PMID:[Nitrates in heart failure: the hemodynamic effects and clinical implications]. 808 25

The efficacy of nitrates versus that of angiotensin-converting enzyme (ACE) inhibitors in heart failure may be evaluated based on 3 treatment aims: hemodynamic improvement, symptom relief, and survival benefit. Nitrates used in conjunction with hydralazine produce a relatively large increase in stroke volume and a prominent reduction of left ventricular filling pressure, whereas ACE inhibitors produce a comparatively modest increase in stroke volume with a prominent reduction in filling pressure. The effect of these drugs on arterial compliance has been evaluated using a modified Windkessel model of the circulation to define their mechanism of action. Nitrates appear to affect the large arteries and arterial bed as well as the venous circulation. Intermediate-term response to therapy is often evaluated by changes in exercise tolerance. A review of multicenter trials reveals that, although both ACE inhibitors and hydralazine/nitrate have favorable hemodynamic actions, the effect of hydralazine/nitrate on exercise capacity appears to be slightly better. ACE inhibitors and nitrates both may reduce dysfunctional myocardial remodeling, as evaluated in a canine model of chronic left ventricular dysfunction. The increase in the ejection fraction by these drugs and the decrease of plasma norepinephrine levels by ACE inhibitors may contribute to improved long-term survival. It appears, therefore, that the long-term benefits of nitrates and ACE inhibitors in heart failure probably relate to their ability both to affect cardiac remodelling and to relax vascular smooth muscle.
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PMID:Nitrates versus angiotensin-converting enzyme inhibitors for congestive heart failure. 837 97

1. A reproducible model of the hyperdynamic circulatory sequelae of endotoxaemia in conscious, chronically-instrumented Long Evans rats, was achieved with a continuous infusion of lipopolysaccharide (LPS, 150 micro g kg(-1) h(-1)) for 32 h. Over the first 2 h of LPS infusion, there was a transient hypotension and tachycardia, accompanied by a marked increase in renal flow and vascular conductance, although there were reductions in cardiac and stroke index. Between 4-8 after the start of LPS infusion, there was slight hypotension and tachycardia, and a transient rise in mesenteric flow and conductance, but reductions in the hindquarters vascular bed; the hyperaemic vasodilatation in the renal vascular bed was maintained. At this stage, all cardiac haemodynamic variables were not different from baseline. At this stage, cardiac and stroke index were substantially elevated, in association with marked increases in peak aortic flow, dF/dtmax and total peripheral conductance; these changes were well-maintained over the following 8 h of LPS infusion. 2. By 2 h after the start of LPS infusion, only lung inducible nitric oxide synthase (iNOS) activity was increased, but at 6 h there were significant increases in iNOS activity in lung, liver, spleen, heart and aorta. (43.3 +/- 7.8, 28.8 +/- 3.3, 50.8 +/- 7.2, 3.04 +/- 0.29, 3.76 +/- 0.94 pmol min(-1) mg(-1) protein, respectively). However, by 24 h after the start of LPS infusion, iNOS activity was not elevated significantly in any tissue examined, and kidney iNOS activity did not change significantly during LPS infusion. Plasma nitrite/nitrate levels were increased after 2 h infusion of LPS (from 6.07 +/- 1.23 to 29.44 +/- 7.08 micromol l(-1)), and further by 6 h (228.10 +/- 29.20 micromol l(-1)), but were less 24 h after onset of LPS infusion (74.96 +/- 11.34 micromol l(-1)). Hence, the progressive hypotension, increasing cardiac function and developing hyperaemic vasodilatation in renal and hindquarters vascular beds between 8-24 h after the onset of LPS infusion, occurred when tissue iNOS activity and plasma nitrite/nitrate levels were falling. 3. Pretreatment with NG-monomethyl-L-arginine (L-NMMA, 30 mg kg(-1) bolus, 30 mg kg(-1) h(-1) infusion) 1 h before LPS infusion did not prevent the early hypotension, but abolished the initial renal vasodilatation and the later (6-8 h) fall in mean arterial pressure (MAP), and the additional renal vasodilatation.
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PMID:Cardiac and regional haemodynamics, inducible nitric oxide synthase (NOS) activity, and the effects of NOS inhibitors in conscious, endotoxaemic rats. 864 Mar 39

The effects of endoscopic variceal ligation (EVL) on systemic hemodynamics are unknown. This study was conducted to determine whether the obliteration of portal-systemic collaterals by EVL affects systemic hemodynamics and serum nitrate concentrations in patients with compensated cirrhosis. We measured systemic and hepatic hemodynamics, azygos vein blood flow (AzBF), and serum nitrate concentrations before and immediately following EVL. A prompt decrease in left ventricular end-diastolic volume (LVEDV), stroke volume, cardiac index (CI), and an increase in systemic vascular resistance index (SVRI) were observed following variceal ligation. The reduction in LVEDV was associated with a decline in CI with a rise in SVRI. There was also a prompt reduction in serum nitrate concentration following variceal ligation. AzBF also significantly decreased following variceal ligation. These findings indicate that EVL decreased cardiac output via a reduction in cardiac preload (central venous return). Blood flow through portal-systemic collaterals has an important role in the enhanced cardiac preload of cirrhotic patients. The sudden decrease in serum nitrate concentrations suggests that endogenous nitric oxide may be involved in the regulation of systemic hemodynamics in patients with compensated cirrhosis.
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PMID:Systemic hemodynamics and serum nitrate levels in patients undergoing endoscopic variceal ligation. 870 81

Medical records of 150 patients who had undergone microvascular free tissue transfer to the head and neck (85% for malignancy) were retrospectively assessed to identify predictors of postoperative outcomes and complications. 5% of flaps failed and 20% required re-exploration. Surgical and medical problems occurred in 23% and 67% patients respectively; mortality was 4.7%. 132 records were analysed by logistic regression. Mortality and stroke were commoner in patients with previous myocardial infarction or steroid medication. Chest infection was commoner in men and with increasing age. Hypoxaemia was associated with bronchodilator therapy. Thromboembolism was commoner in patients on diuretics. Nutritional problems were more frequent in patients on opioids, with low weight or hypertension. Donor site infection was related to haemoglobin concentration, cerebrovascular disease, hypertension, opioid consumption or previous radiotherapy. Recipient site infection was associated with hypertension. Flap failure was related to nitrate or bronchodilator treatment. Re-exploration was associated with opioid or bronchodilator therapy. It was concluded that several factors predicted complications and death following microvascular surgery to the head and neck.
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PMID:Prediction of outcomes in 150 patients having microvascular free tissue transfers to the head and neck. 877 39

Following CNS trauma or ischemia, peroxynitrite may be a toxic intermediate which forms in vivo when nitric oxide condenses with superoxide. Alone, peroxynitrite appears to directly react with aromatic and sulfhydryl nucleophiles. However, at physiological pH, peroxynitrite is protonated and, in that form, will rapidly (within seconds) decompose to species with hydroxyl radical and nitrogen dioxide characteristics. These reactive species are shown to initiate lipid peroxidation, hydroxylate aromatic residues, and nitrate aromatic residues. This reactivity may contribute to differential toxicity in vivo and in vitro. Tirilazad mesylate (TZ) is a lipid-soluble antioxidant shown to inhibit iron-dependent lipid peroxidation. It is an effective therapy in a variety of CNS injury and ischemia models and is currently undergoing human clinical evaluation in stroke, head injury, and spinal injury. This study was designed to investigate the cytoprotective properties of TZ in a cerebellar granule cell model of peroxynitrite toxicity. Cytoprotective efficacy of TZ was based on viability measurements, blockade of lipid hydroperoxide generation, and blockade of nitrotyrosine formation. Cell viability was determined by [3H]-aminoisobutyric acid (3H-AIB) uptake, and lipid hydroperoxide and nitrotyrosine content were determined by HPLC assays. Tirilazad mesylate was found to have similar cytoprotective effects (approximately 50% protection at 100 microM) when applied before or after exposure of cells to peroxynitrite. In contrast, post-treatment with superoxide dismutase (50 units/ml) or allopurinol (100 microM) failed to produce any cytoprotection. Furthermore, we discovered that TZ inhibited the peroxynitrite-induced increase of phosphatidylethanolamine hydroperoxide (PEOOH), but did not affect the peroxynitrite-induced formation of nitrotyrosine formation. This suggests that the ability of TZ to afford cytoprotection in this peroxynitrite toxicity model is due to the inhibition of membrane-localized lipid peroxidation, and not to the inhibition of nitration of tyrosine residues.
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PMID:Protective effects of tirilazad mesylate in a cellular model of peroxynitrite toxicity. 882 75

The coronary and systemic hemodynamic effects of the novel nitrate ester ITF 296 were investigated in conscious, resting dogs and compared with nitroglycerin and nicorandil. ITF 296 at 1-25 micrograms/kg i.v. elicited selective, long-lasting, and dose-dependent increases in large epicardial coronary artery diameter (CD) without affecting coronary blood flow (CBF) or coronary vascular resistance (CVR). Blood pressure (BP) and heart rate (HR) were also unaltered. At 125 micrograms/kg, ITF 296 further increased CD but simultaneously reduced CVR and mean aortic pressure and increased CBF and HR. Nitroglycerin 1-25 micrograms/kg induced a shorter and less selective dilatation of large coronary conductance arteries, as it was accompanied by a decrease in CVR at all doses used. Nicorandil produced a selective increase in left circumflex CD only at the lowest dose used (10 micrograms/kg), whereas higher doses were effective on both CD and CVR. ITF 296 significantly reduced left ventricular end-diastolic pressure and increased stroke volume (SV) and cardiac output (CO) at doses that did not alter HR or BP, indicating an increase in cardiac efficiency. In contrast, the increases in CO produced by nitroglycerin and nicorandil were dependent on the augmentation of HR, because SV was unchanged at all doses used. Nitroglycerin dose-dependently decreased BP, whereas ITF 296 reduced BP only at the highest dose used. In conclusion, ITF 296 induces a selective, flow-independent dilatation of large coronary conductance arteries without affecting the tone of small coronary resistance vessels or systemic hemodynamics over a broad range of doses. An equally selective effect was elicited by nicorandil only at the lower dose used, whereas no selective effect of nitroglycerin on the diameter of coronary conductance arteries was seen at the doses utilized in this study.
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PMID:Effect of the new nitrate ester ITF 296 on coronary and systemic hemodynamics in the conscious dog: comparison with nitroglycerin and nicorandil. 883 21

1. Delayed neuronal cell death elicited by excess excitatory amino acid concentrations has been strongly implicated in many neurological disorders including head trauma, stroke, motor neurone disease and Huntington's disease. We have used the neurotoxin, L-2-chloropropionic acid (L-CPA) to model cellular events in vivo leading to delayed neuronal cell loss which is confined to the cerebellar cortex and can be prevented by inhibitors of nitric oxide synthase such as NG-nitro-L-arginine methyl ester. 2. Experiments were performed to determine whether the constitutive nitric oxide synthase (NOS) or inducible form of NOS (iNOS) was responsible for the neuronal cell death. Activation of NOS was confirmed by a 39% increase in cerebellar total nitrate and nitrite concentrations in L-CPA-treated brains, as compared to controls (controls = 2.53 +/- 0.10; L-CPA treated = 3.51 +/- 0.31 nmol mg-1 protein, P < 0.01 Student's t tests, n = 6, mean +/- s.e.mean). Biochemical measurements of total NOS activity were made in homogenates of cerebellum 6 h and 48 h following L-CPA administration, times at which L-CPA concentrations are maximal in brain and a time when there is a high proportion of cerebellar granule cell death, respectively. NOS activity as measured by the amount of [3H]-arginine converted to [3H]-citrulline, did not reveal any difference between controls (rats dosed with water) and animals dosed with L-CPA at either 6 or 48 h following dosing. Furthermore the ability of three NOS inhibitors, NG-nitro-L-arginine, 7-bromo-3-nitroindazole and S-methylisothiourea to block the conversion of [3H]-citrulline to [3H]-arginine was identical at 6 and 48 h time points in control and L-CPA treated rats. 3. Quantitative autoradiography using [3H]-NG-nitro-L-arginine was used to measure the relative anatomical distribution and amount of NOS enzyme in the cerebellum of controls and L-CPA-treated rats 48 h following dosing. There was no significant alteration in the binding of [3H]-NG-nitro-L-arginine to granular and molecular layers of the cerebellum of control and L-CPA-treated rat brains. 4. Western blotting using antibodies against the inducible NOS enzyme failed to detect the protein in cerebellums of L-CPA-treated rats when measured 48 h after L-CPA dosing. 5. In conclusion, the increase in cerebellar nitrate/nitrite concentrations in L-CPA-treated rats provides further evidence for activation of NOS in the cerebellum following administration of L-CPA. The failure to demonstrate an increase in NOS activity at 6 or 48 h in L-CPA-treated rats as compared to controls suggests that the source of nitric oxide responsible for the granule cell death must originate from the constitutive NOS enzyme, probably the neuronal form which is highly enriched in the cerebellum. This hypothesis was further substantiated by Western blotting and quantitative autoradiography.
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PMID:Evidence for mediation of L-2-chloropropionic acid-induced delayed neuronal cell death by activation of a constitutive nitric oxide synthase. 888 23

Tumor necrosis factor-alpha (TNF) causes vasodilatation and a hyperdynamic state by activating nitric oxide (NO) synthesis. Tyrphostins, specific inhibitors of protein tyrosine kinase (PTK), block the signaling events induced by TNF and NO production. A hyperdynamic circulatory syndrome (HCS) is often observed in portal hypertension (PHT). TNF and NO seem to mediate these hemodynamic changes. The aim of this work was to study the effect of PTK inhibition on the systemic and portal hemodynamics, TNF and NO production, in cirrhotic rats with portal hypertension. Rats with liver cirrhosis induced by chronic inhalation of carbon tetrachloride were used. Animals were treated daily with tyrphostin AG 126 (alpha-cyano-(3-hydroxy-4-nitro) cinnamonitrile) or placebo for 5 d. Mean arterial pressure (MAP), heart rate (HR), and portal pressure (PP) were measured by indwelling catheters. Cardiac output (CI) and stroke volume (SV) were estimated by thermodilution, systemic vascular resistance (SVR) was calculated (MAP/CI), and portal systemic shunting (PSS) was quantitated using radioactive microspheres. Serum and mesenteric lymph node (MLN) TNF levels were measured using an immunoassay kit, and serum NOx was determined photometrically by its oxidation products. The AG 126-treated group showed a statistically significant increase in MAP and SVR, and decreases in CI, SV, MLN TNF, and serum NO oxidation products nitrite and nitrate (NOx) in comparison with the placebo-treated rats. No significant differences were noticed in HR, PP, PSS, or serum TNF. Significant correlations were observed between MAP and NOx, MAP and MLN TNF, PSS and NOx, and serum TNF and serum NOx. The HCS observed in PHT seems to be mediated, at least in part, by TNF and NO by the activation of PTKs and their signaling pathways. PTK activity inhibition ameliorates the hyperdynamic abnormalities that characterize animals with cirrhosis and PHT.
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PMID:Tyrosine kinase inhibition ameliorates the hyperdynamic state and decreases nitric oxide production in cirrhotic rats with portal hypertension and ascites. 923 14


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