Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0038454 (stroke)
 147,016 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Clinical states associated with nitric oxide deficiency are often accompanied by vasoconstriction. We studied the effects of prolonged infusion of the nitric oxide synthase inhibitor NG-monomethyl-L-arginine (L-NMMA) on systemic and renal hemodynamics in humans and the reversibility of the established vasoconstriction by calcium channel blockade with nifedipine. Seven healthy men underwent three 7-hour clearance studies. During one study, L-NMMA (3 mg/kg priming dose plus 3 mg.kg-1.h-1) was infused during hours 2 through 5, and during another study, nifedipine (0.015 mg/kg priming dose plus 0.015 mg.kg-1.h-1) was coinfused during hours 4 and 5. A third study served as time control. L-NMMA elicited reproducible systemic and renal vasoconstriction that was stable during the 4 hours of infusion. Systemic vascular resistance index, calculated from bioimpedance-derived cardiac index, increased from 22 +/- 1 to 29 +/- 2 mm Hg.min.m2.L-1 (P < .05). Mean arterial pressure rose by 4 +/- 1 mm Hg (P < .05), and heart rate, stroke index, and cardiac index decreased. Renal blood flow, calculated from renal plasma flow, decreased from 1182 +/- 101 to 785 +/- 53 mL/min, and renal vascular resistance increased from 73 +/- 5 to 115 +/- 6 mm Hg.min.L-1 (P < .05). Glomerular filtration rate decreased from 114 +/- 6 to 104 +/- 6 mL/min (P < .05), and filtration fraction increased. Sodium excretion fell from 89 +/- 9 to 32 +/- 7 mumol/min (P < .05). Nifedipine completely reversed systemic vasoconstriction. Nifedipine caused partial restoration of renal vascular resistance and complete normalization of glomerular filtration rate and sodium excretion but left the elevated filtration fraction unaltered. We conclude that sustained nitric oxide deficiency in humans is accompanied by strong systemic and renal vasoconstriction, decreased glomerular filtration rate, and sodium retention. Nifedipine can reverse most of these effects, suggesting a role for calcium channel blockade in pathological states of impaired nitric oxide activity.
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PMID:Nifedipine attenuates systemic and renal vasoconstriction during nitric oxide inhibition in humans. 914 86

Cerebral ischemia induces a massive efflux of glutamate causing delayed neuronal death in stroke-prone spontaneously hypertensive rats (SHRSP) but not in Wistar Kyoto rats (WKY). It is obvious that L-N-nitroarginine (L-NNA; NO synthase (NOS) inhibitor), benzamide (poly(ADP-ribose) synthetase inhibitor), and growth factors are involved in reducing neuronal cell death due to toxic conditions, especially phosphatidylinositol 3 (PI3)-kinase activity; however, no studies have clarified whether genetic vulnerability to neurotoxic states is present in cortical neurons isolated from SHRSP. For this purpose, we prepared cortical neurons from WKY and SHRSP (15 weeks of gestation) to test the genetic vulnerability involved in the pathogenesis of stroke as well as apoptosis of cortical neurons isolated from SHRSP. We also examined the mechanisms necessary to reduce apoptosis under neurotoxic states using ultrastructural and biochemical techniques. Cortical neurons from SHRSP were in fact found to be more vulnerable than neurons from WKY and resulted in apoptosis when treated with nitric oxide (NO)- and N-methyl-D-aspartate (NMDA)-mediated neurotoxic agents. Growth factors, especially insulin-like growth factor (IGF), rescued neurons from NO- and NMDA-mediated neurotoxicity, particularly those from SHRSP. Conversely, benzamide and L-NNA reduced NMDA-mediated neurotoxicity but not NO-mediated toxicity. The ability to protect neurons from neurotoxicity was as follows: IGF-->nerve growth factor epidermal growth factor-->L-NNA-->benzamide. In addition, it was demonstrated that wortmannin, a PI3-kinase inhibitor, lessened the protective effects of these growth factors against NO-mediated toxicity. The data thus indicate that genetic factors related to neuronal vulnerability to apoptosis are involved in the pathogenesis of stroke lesions in SHRSP. PI3-kinase activity, which is stimulated by growth factors, is closely related to protective effects against NO- and NMDA-mediated toxicity in cortical neurons, especially those isolated from SHRSP. Moreover, the genetic vulnerability observed in SHRSP neurons is possibly linked to the inadequate activation of signaling pathways in the downstream of protein tyrosine kinases.
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PMID:Insulin-like growth factors prevent apoptosis in cortical neurons isolated from stroke-prone spontaneously hypertensive rats. 916 79

Cerebral ischemia followed by reperfusion induced apoptosis in stroke-prone spontaneously hypertensive rats (SHRSP) but not in Wistar Kyoto rats (WKY). Our in vitro studies revealed that IGF-1 prevented apoptosis caused by nitric oxide- and N-methyl-D-aspartate-mediated toxic agents in cortical neurons isolated from SHRSP. In addition, it was reported that IGF-1 given 1 hour before ischemia significantly attenuated the incidence of myocyte apoptosis after myocardial ischemia and reperfusion. IGF-1 (20 micrograms/rat) was administered ip 1 hour before the clipping of both common carotid arteries in WKY and SHRSP. Rats underwent cerebral ischemia for 20 minutes and reperfusion for 6 days before they were killed. We cut the brain coronally, removed sections from the hippocampal CA1 region, and examined the neurons in these samples using an electron microscope. We tried to clarify whether pretreatment using IGF-1 decreases the number of apoptotic neurons in SHRSP with cerebral ischemia followed by reperfusion. SHRSP with normal cerebral circulation had 30.4 +/- 8.0 apoptotic neurons per 1000 neurons. Cerebral ischemia followed by reperfusion significantly (p < 0.01) increased the number of apoptotic neurons (235.2 +/- 25.2/1000 neurons) in SHRSP. In contrast, pretreatment with IGF-1 reduced the number of apoptotic neurons in SHRSP (82.8 +/- 11.2/1000 neurons; p < 0.01) under otherwise identical conditions. We concluded that the genetic vulnerability to apoptosis in SHRSP neurons was involved in the pathogenesis of stroke lesions and that this vulnerability was attenuated by the IGF-1 pretreatment.
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PMID:Insulin-like growth factor-1 attenuates apoptosis in hippocampal neurons caused by cerebral ischemia and reperfusion in stroke-prone spontaneously hypertensive rats. 916 80

It is believed that the hypertensive effect of diaspirin crosslinked hemoglobin, a viable blood substitute, can be resolved by polymerization, which reduces the diffusion of this derivative into the interstitial space between nitric oxide-producing endothelium and the target vascular smooth muscle. We studied the systemic and renal responses to infusion of three cell-free human hemoglobins in anesthetized isovolemic rats: unmodified (HbA0), crosslinked (alpha-DBBF), and polymerized crosslinked (poly alpha-DBBF). HbA0 produced a significant increase in mean arterial blood pressure (MAP) throughout the 60-minute infusion. alpha-DBBF, on the other hand, produced a more marked and prolonged increase in MAP over 120 minutes. Only a moderate increase in MAP was observed in rats after a 30-minute infusion with poly alpha-DBBF. The extent of renal insufficiency produced by these proteins, as determined by the glomerular filtration rate, was in the following order: HbA0 > poly alpha-DBBF > alpha-DBBF. Infusion of poly alpha-DBBF, under hypovolemic but not isovolemic conditions in rats, produced an increase in heart rate, cardiac output, and stroke volume and a decrease in total peripheral resistance after 60 minutes. Chemical polymerization to increase the size of alpha-DBBF does not appear to improve its hemodynamic properties in rats, especially under partial exchange transfusion, a more clinically relevant indication for a hemoglobin-based blood substitute.
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PMID:Effects of polymerization on the hypertensive action of diaspirin cross-linked hemoglobin in rats. 917 23

The etiology of stroke in sickle cell disease is unclear, but may involve abnormal red blood cell (RBC) adhesion to the vascular endothelium and altered vasomotor tone regulation. Therefore, we examined both the adhesion of sickle (SS)-RBCs to cerebral microvessels and the effect of SS-RBCs on cerebral blood flow when the nitric oxide (NO) pathway was inhibited. The effect of SS-RBCs was studied in the rat cerebral microcirculation using either a cranial window for direct visualization of infused RBCs or laser Doppler flowmetry (LDF) to measure RBC flow. When fluorescently labeled human RBCs were infused into rats, SS-RBCs had increased adhesion to rat cerebral microvessels compared with control AA-RBCs (P = .01). Next, washed SS-RBCs or AA-RBCs were infused into rats prepared with LDF probes after pretreatment (40 mg/kg intravenously) with the NO synthase inhibitor, N-omega-nitro-L-arginine methyl ester (L-NAME), or the control isomer, D-NAME. In 9 rats treated with systemic L-NAME and SS-RBCs, 5 of 9 experienced a significant decrease in LDF and died within 30 minutes after the RBC infusion (P = .0012). In contrast, all control groups completed the experiment with stable LDF and hemodynamics. Four rats received a localized superfusion of L-NAME (1 mmol/L) through the cranial window followed by infusion of SS-RBCs. Total cessation of flow in all observed cerebral microvessels occurred in 3 of 4 rats within 15 minutes after infusion of SS-RBCs. We conclude that the NO pathway is critical in maintaining cerebral blood flow in the presence of SS-RBCs in this rat model. In addition, the enhanced adhesion of SS-RBCs to rat brain microvessels may contribute to cerebral vaso-occlusion either directly, by disrupting blood flow, or indirectly, by disturbing the vascular endothelium.
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PMID:Mechanisms of stroke in sickle cell disease: sickle erythrocytes decrease cerebral blood flow in rats after nitric oxide synthase inhibition. 919 84

Although nitric oxide (NO) has been shown to play an important role in the pathophysiology of cerebral ischemia, its contribution to the pathogenesis of experimentally induced thromboembolic stroke is unknown. In this study, we pharmacologically manipulated NO levels in the acute post-thrombotic stage and determined the effects on behavior and histopathology. The following drugs were used: nitro-L-arginine-methyl ester (L-NAME), a non-specific endothelial and neuronal nitric oxide synthase (eNOS and nNOS) inhibitor, 3-bromo-7-nitroindazole (7-NI), a specific inhibitor for nNOS, the NO precursor, exogenous L-arginine and the NO-donor, 3-morpholino-sydnonimine (SIN-1). Male Wistar rats (n = 76) were randomly assigned to receive vehicle or drug immediately after common carotid artery thrombosis (CCAT). Regional measurements of cortical NOS activity using the [3H]L-arginine to [3H]L-citrulline conversion assay were decreased 1 h after treatment with L-NAME and 7-NI by 50 and 65%, respectively; hippocampal NOS activity was reduced with L-NAME by 35% and with 7-NI by 65%. L-NAME significantly worsened forelimb placing as compared to other groups. 7-NI accelerated sensorimotor recovery. Water maze retention deficits were noted 48 h after CCAT and these were exacerbated by L-NAME treatment. Histopathological protection was conferred in the hippocampus by 7-NI and SIN-1; conversely, L-NAME increased neuronal injury in the contralateral cortex. L-arginine had no effect on these outcomes. In conclusion, both structural and functional consequences of CCAT can be aggravated by limiting endothelial NO production in the acutely post-thrombotic brain. In contrast, inhibition of nNOS and infusion of an NO donor has a beneficial effect on pathology.
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PMID:The role of nitric oxide in the pathophysiology of thromboembolic stroke in the rat. 921 60

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

1. Isolated basilar arteries from spontaneously hypertensive stroke-prone rats (SHRSP) are more sensitive to the contractile effect of 5-hydroxytryptamine (5-HT) than those from normotensive Wistar Kyoto rats (WKY). This has been attributed to a different proportion of 5-HT receptor subtypes mediating these responses. In the present study we have examined if differences in nitric oxide release could also contribute to this difference in sensitivity to 5-HT. 2. At rest, the normalized internal diameter was significantly smaller in SHRSP (297.4 +/- 3.5 microm, n = 88) than in WKY (375.1 +/- 4.0 microm, n = 62, P<0.01) arteries. The contractile response to 100 mM KCl was higher in WKY (3.57 +/- 0.15 mN mm(-1), n = 22) than in SHRSP arteries (2.32 +/- 0.20 mN mm(-1), n = 28, P<0.01). 3. When added on the plateau of contraction to 5-HT (1 microM), acetylcholine (ACh, 3 microM) evoked significant relaxation in all preparations from WKY (n = 20), but only in 15 out of 26 preparations from SHRSP. The mean relaxations were 55.4 +/- 5.2% in WKY and 20.6 +/- 4.6% in SHRSP (as % of the contractile tone evoked by 5-HT: P<0.01). 4. The NO synthase inhibitor N(omega)-nitro-L-arginine (L-NOARG, 0.1 mM) produced a similar increase in tone in both WKY and SHRSP. This tone was equal (in % of the contractile response to 100 mM KCl) to 70.8 +/- 4.4% in WKY (n = 20) and 67.6 +/- 5.9% in SHRSP (n=26) and was reversed by L-arginine (1 mM) and by 1,4-dihydropyridine calcium channel blockers (10 nM nisoldipine, 10 nM lacidipine, 100 nM nifedipine). The L-NOARG-induced tone was absent when the arteries were bathed in phosphate-free Krebs (pH 7.4). 5. EC50 values of 5-HT were about four fold smaller in SHRSP than in WKY arteries (P<0.01). The maximal response to 5-HT (Emax) was higher than 100 mM KCl-contraction in SHRSP but not in WKY arteries. Removal of endothelium produced a shift to the left of the 5-HT curve in WKY, but not in SHRSP arteries. 6. When evoked in phosphate-free Krebs, the contractile responses to 5-HT showed tachyphylaxis, but the responses were reproducible by adding the agonist at 30 min intervals. In such conditions, EC50 values of 5-HT were about two fold smaller in SHRSP than in WKY arteries (P<0.01). In phosphate-free Krebs, the blockade of NO synthase did not change the contractile response to 100 mM KCl; it reduced EC50 and increased Emax of 5-HT in WKY, but not in SHRSP. 7. These results confirm that the sensitivity to 5-HT is higher in basilar artery isolated from SHRSP than in those from WKY. They show that endothelium-dependent vasorelaxation to ACh is impaired in SHRSP. The finding that removal of endothelium or blockade of NO synthase augmented the contractile response to 5-HT in WKY, but not in SHRSP basilar arteries indicates that the difference in responsiveness to 5-HT observed between WKY and SHRSP basilar arteries might be, at least in part, related to dissimilarities in NO release. Furthermore, the L-NOARG-induced contraction sensitive to calcium channel blockers indicates that, in basilar arteries, NO production might lower L-type calcium channel opening and thereby control the tone of the vessels.
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PMID:Role of nitric oxide in the contractile response to 5-hydroxytryptamine of the basilar artery from Wistar Kyoto and stroke-prone rats. 924 38

Randomized trials of thrombolytic therapy in stroke have reported an improvement in neurologic outcome; however, the addition of aspirin has resulted in a significant increase in mortality and antagonism of clot lysis in clinical and animal studies, respectively. This finding is in contradistinction to the known synergy in mortality reduction for aspirin and thrombolytics in myocardial infarction. It is hypothesized that aspirin antagonism of clot lysis is related to inhibition of nitric oxide (NO) and may be reversed by providing a source of NO. Twenty rabbits were treated with aspirin (20 mg/kg, i.v.) prior to internal carotid clot embolization. One-half hour following embolization, rabbits were randomized to receive vehicle (n = 5), the NO precursor L-arginine (300 mg/kg, i.v. bolus at 0.5 and 2.5 h postembolus; n = 5), or a nitric oxide donor (nitroprusside, 1 mg/kg/h, i.a., or nitroglycerin, 10 microg/kg/min, i.v., n = 5 each agent). Tissue plasminogen activator (t-PA) (6.3 mg/kg) was administered from 1 to 3 h after embolization. Lysis of the tin-tagged clot was followed with serial X rays and gross examination. No rabbit in the control group experienced complete clot lysis. However, 2 of 5 rabbits in the L-arginine group and 6 of 10 rabbits in the nitric oxide donor (nitroprusside and nitroglycerin) groups noted complete clot lysis (P < 0.05, Fisher exact test). Thus, administration of an NO donor (nitroglycerin or nitroprusside) and, to a lesser extent L-arginine, reversed aspirin's antagonism of t-PA thrombolysis. This study may help explain the discrepant results seen with aspirin and thrombolytics.
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PMID:Nitric oxide reverses aspirin antagonism of t-PA thrombolysis in a rabbit model of thromboembolic stroke. 927 62

Central nervous system dysfunction continues to represent significant morbidity and associated mortality in patients undergoing cardiac surgery. Neurological dysfunction is most exaggerated in patients undergoing hypothermic circulatory arrest (HCA). Although surgical techniques, anesthetic management, and postoperative care have significantly improved over the past two decades, the incidence of stroke and other neurocognitive deficits remains problematic. Understanding the mechanisms of cell death associated with HCA may provide information that is germane to all types of cerebral injury involved in cardiac surgery. Using a closed-chest cardiopulmonary bypass model, dogs underwent 2 hours of circulatory arrest at 18 degrees C followed by resuscitation and recovery for 3 days. Animals were assessed functionally by a species-specific behavioral scale, histologically for patterns of selective neuronal necrosis and receptor autoradiography for NMDA glutamate receptor subtype expression. Using a selective NMDA (-glutamate) receptor antagonist (MK801), an AMPA-antagonist (NBQX) and a nonspecific neuroprotectant (GM1-ganglioside), the role of glutamate excitotoxicity in the development of HCA-induced brain injury was documented and validated. Using a similar canine preparation, a microdialysis technique was used to evaluate the role of nitric oxide in neuronal death. Arginine plus oxygen is converted to nitric oxide plus citrulline by the action of nitric oxide synthase. Simultaneous infusion of artificial cerebrospinal fluid containing L-[14C] arginine or L-[14C] arginine and L-NAME (a nitric oxide synthase inhibitor) was performed in contralateral hemispheres. Citrulline recovery in the cerebrospinal fluid, citrulline production in vitro from canine cortical homogenates, and nitric oxide metabolites in the serum were all significantly increased during HCA and reperfusion. These studies demonstrated that neurotoxicity following HCA involves a significant and early induction of neuronal NOS expression and neuronal processes leading to widespread augmented NO production in the brain. Continued research into the pathophysiologic mechanisms involved in cerebral injury will undoubtedly yield a safe and reliable neuroprotectant strategy.
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PMID:Pathophysiology of cerebral injury and future management. 927 60


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