Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0406810 (NAME)
 13,345 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Endothelium-derived nitric oxide (NO) has recently been reported to be a mediator of ischemic preconditioning in dog hearts. The aim of the present study was to determine the role of NO in ischemic preconditioning in isolated perfused rat hearts. Rat hearts were perfused at either constant pressure (80 mmHg) or constant flow. After aerobic perfusion (37 degrees C) for 10 min, hearts were treated with N omega-nitro-L-arginine methyl ester (L-NAME; 30 microM), which is an inhibitor of NO synthase, or vehicle. Ten minutes later, the hearts were preconditioned (4 episodes of 5 min of global ischemia and 5 min of reperfusion) or perfused normally before a 30-min global ischemic period. All hearts were reperfused for 30 min. Coronary flow or perfusion pressure plus heart rate and contractile function were measured continuously. Hearts perfused at constant pressure and treated with 30 microM L-NAME, a concentration that effectively inhibits endogenous NO synthesis, exhibited decreased coronary flow after 10 min, and flow remained decreased throughout the experiment. Ischemic preconditioning before 30 min of global ischemia resulted in a doubling of contractile function and a reduction of lactate dehydrogenase release at the end of the 30-min reperfusion period compared with nonpreconditioned hearts. The protective effect of preconditioning was not different in L-NAME-treated hearts. In addition, inhibition of NO synthase had no effect on the severity of ischemia in nonpreconditioned hearts. Similar results were obtained in preconditioned hearts that were perfused at constant flow, indicating that the flow reductions caused by L-NAME did not influence the results.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Inhibition of nitric oxide synthesis does not affect ischemic preconditioning in isolated perfused rat hearts. 753 Sep 19

1. The present experiment was undertaken to investigate: (a) the effect of nitric oxide synthase (NOS) inhibition, mediated by oral supplementation of the NOS inhibitor, NG-nitro-L-arginine methyl ester (L-NAME), on measures of myocardial energy metabolism and function: (b) the effect of oral creatine supplementation on these variables, in the absence and presence of L-NAME. 2. In one series of experiments, 4 weeks oral administration of L-NAME (0.05 mg ml-1 day-1 in the drinking water) to Brattleboro rats caused significant reductions in myocardial ATP, creatine, and total creatine concentrations and an accumulation of tissue lactate when compared with control animals. Administration of creatine (0.63 mg ml-1 day-1 in the drinking water) for 4 weeks elevated myocardial creatine and total creatine concentrations and reduced lactate accumulation, but did not significantly affect ATP or phosphocreatine (PCr). Concurrent treatment with creatine and L-NAME prevented the reduction in creatine and total creatine concentrations, and significantly attenuated the accumulation of lactate and the reduction in ATP seen with L-NAME alone. 3. In a second series of experiments, 4 weeks treatment with L-NAME and creatine plus L-NAME increased mean arterial blood pressure in conscious Brattleboro rats. Hearts isolated from these animals showed decreased coronary flow and left ventricular developed pressure (LVDP), and total mechanical performance. Treatment with creatine alone had no measurable effect on either mean arterial blood pressure or coronary flow in isolated hearts. However, there was an increase in LVDP, but not in total mechanical performance, because there was a bradycardia. 4. These results indicate that creatine supplementation can attenuate the metabolic stress associated with L-NAME administration and that this effect occurs as a consequence of the action of creatine on myocardial energy metabolism.
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PMID:Attenuation by creatine of myocardial metabolic stress in Brattleboro rats caused by chronic inhibition of nitric oxide synthase. 871 9

To assess the role of reactive oxygen species and nitric oxide (NO) in the genesis of reperfusion-induced arrhythmias, the effects of reactive oxygen species scavengers and NO synthase inhibitors on the incidence of ventricular fibrillation and irreversible ventricular fibrillation (mortality) were examined. Hearts of anesthetized rats were subjected to 4 min regional ischemia followed by 4 min reperfusion. The animals were treated i.v. with superoxide dismutase, a O2- scavenger, catalase, a H2O2 scavenger, dimethylthiourea, a .OH scavenger, or NG-nitro-L-arginine methyl ester (L-NAME) and NG-nitro-L-arginine (L-NNA), NO synthase inhibitors. Superoxide dismutase (430 and 4300 U/kg/min) reduced the mortality from 93% to 43% and 57%, respectively, whereas treatment with catalase or dimethylthiourea did not affect these arrhythmias. L-NAME (0.1 and 0.3 mg/kg/min) reduced the mortality from 93% to 50% and 43%, respectively. L-NNA (0.3 mg/kg/min) reduced the mortality from 93% to 50%. This reduction by the NO synthase inhibitors was abolished by administration of L-Arg. However, L-Arg blocked neither a small increase in systolic blood pressure nor a decrease in heart rate elicited by the NO synthase inhibitors. The combinated treatment of superoxide dismutase (4300 U/kg/min) with L-NAME (0.3 mg/kg/min) reduced the mortality from 93% to 7%. These results suggest that the genesis of reperfusion-induced arrhythmias observed in this model may be in part due to O2- and NO.
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PMID:Involvement of superoxide and nitric oxide in the genesis of reperfusion arrhythmias in rats. 881 24

1. To study the effect of acute nitric oxide (NO) inhibition on the rat heart both in vitro and in vivo, male Wistar rats received a single bolus injection of saline, N omega-nitro-L-arginine methyl ester (L-NAME; 0.5, 1.5, 5.0, 15.0 and 45.0 mg/kg) and D-NAME (45.0 mg/kg). 2. Animals were killed 72 h after the bolus injection of L-NAME and the hearts were removed and studied under light microscopy. In other groups of animals; saline, L-NAME and D-NAME were administered as above and the mean arterial blood pressure (MABP/carotid) was recorded. Furthermore, L-NAME was also administered in the drinking water (20 mg/kg per day) for 72 h and animals were then killed and their hearts evaluated as described above. Hearts of control animals were perfused in vitro and coronary flow was measured following saline, L-NAME (45 micrograms/heart) and D-NAME (45 micrograms/heart). 3. Areas of necrosis were observed in the left ventricle of animals that had received L-NAME at 5.0, 15.0 and 45.0 mg/kg. Also, only doses higher than 1.5 mg/kg caused an important increase in MABP. The frequency and extent of the lesions paralleled the dose of L-NAME administered and no lesions were observed in D-NAME- and saline-treated animals. 4. The oral administration of L-NAME also caused myocardial lesions similar to those described above, but the frequency and extent of these lesions were more discrete compared with those observed following 5.0 mg/kg, i.v., L-NAME. 5. Bolus injection of L-NAME into control rat hearts in vitro resulted in a small and transient fall in coronary flow (17.2 +/- 1.4 and 12.2 +/- 1.2 mL/min before and after L-NAME administration, respectively) within 30 s and this was followed 4.5 min later by a further (11.5 +/- 1.6 mL/min) decrease. The administration of D-NAME to control hearts caused no change in coronary flow. 6. In conclusion, the acute inhibition of NO biosynthesis by L-NAME causes myocardial necrosis. Both high levels of MABP and a small but significant reduction in coronary flow (associated or not) can be responsible for the lesions we found.
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PMID:Non-specific inhibitors of nitric oxide synthase cause myocardial necrosis in the rat. 914 86

Pathophysiological effects of nitric oxide (NO)-deficient hypertension are much better known than are the potential morphological changes. Hearts and main arteries were studied in 15 week old male Wistar rats administered NG-nitro-L-arginine methyl ester (L-NAME) for 4 weeks. A does of 40 mg/kg/day increased systolic arterial pressure by 30%, while heart rate decreased by 20%. Heart/body weight ratios were not significantly changed. Total cardiac RNA and DNA content and [14C]leucine incorporation into myocardial protein were, however, increased by 15%, 228% and 97%, respectively. Light microscopy of hearts showed subendocardial areas of necrosis along with different stages of healing. Morphometric evaluation demonstrated significant increase in myocardial fibrosis. Serum lactate dehydrogenase increased by 91%. Proliferation cell nuclear antigen (PCNA) immunohistochemistry indicated positive cells in areas of postischemic repair. Chronic inhibition of NO synthase (NOS) resulted in periarterial fibrosis and hyperplasia of the media in coronary arteries and aorta. RNA and DNA content, and [14C]leucine incorporation into protein of aorta increased by 255%, 95% and 49%, respectively. PCNA staining showed numerous positive nuclei in the media of coronary arteries and the aorta. It is concluded that inhibition of NOS leads to systemic hypertension with focal myocardial fibrosis reflecting reparative responses associated to ischemic injury. This sequence of alterations involves impaired arterial relaxation, and uncontrolled vascular medial proliferation attributed to the absence of smooth muscle cell proliferation inhibition by NO.
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PMID:Chronic inhibition of NO synthesis produces myocardial fibrosis and arterial media hyperplasia. 922 43

Preconditioning with monophosphoryl lipid A (MLA) protects rabbit hearts from prolonged ischemic reperfusion injury by a mechanism involving inducible nitric oxide synthase (iNOS) activation. This study was undertaken to determine whether MLA also could precondition rat hearts in a similar manner. Rats were injected with two different doses of MLA (300 microg/kg or 450 microg/kg i.v.) or vehicle (control), and after 24 hr the animals were sacrificed for preparation of isolated perfused rat hearts. Hearts were then perfused by working mode, and then made ischemic for 30 min followed by 30 min of reperfusion. Another group of hearts were treated simultaneously with a nitric oxide (NO) blocker, L-nitro-arginine-methyl-ester (L-NAME) (10 mg/kg) and MLA (450 microg/kg). For arrhythmia studies, 12 hearts were used in each group (total, 48 hearts). Cardiac functions were examined in a separate group of 24 hearts (n = 6/group). MLA-treated hearts (either dose) were tolerant to ischemic reperfusion injury as evidenced by improved postischemic ventricular recovery [coronary flow (ml/min) 19.1 +/- 0.8 (300 microg/kg MLA), 22.6 +/- 1.0 (450 microg/kg MLA) vs. 15.9 +/- 0.7 (control); aortic flow (ml/min) 20.7 +/- 1.8 (300 microg/kg MLA), 25.8 +/- 1.4 (450 microg/kg MLA) vs. 11. 0 +/- 0.8 (control); left ventricular developed pressure (kPa) 13.3 +/- 0.6 (300 microg/kg MLA), 14.6 +/- 0.2 (450 microg/kg MLA) vs. 10. 3 +/- 0.7 (control)]. Incidences of ventricular fibrillation and ventricular tachycardia were decreased compared with the control group only in the 450 microg/kg dose of MLA-treated hearts (92% to 33%). Pretreatment of the hearts with L-NAME inhibited the preconditioning effect of MLA. To examine the induction of the iNOS expression, RNAs were extracted from the control and MLA-treated hearts (after 2, 4,6, 8, 12 and 24 hr of treatment) and Northern blot analyses were performed with a specific cDNA probe for iNOS. A single band of approximately 4.6 kb corresponding to iNOS mRNA was detected after 4 hr of MLA treatment, whereas the maximal iNOS expression was found between 6 and 8 hr of MLA treatment. The results of this study demonstrated that MLA induced the expression of iNOS and protected the myocardium from ischemic reperfusion injury which is blocked by an inhibitor of NO synthesis, which suggests a role of NO in MLA-mediated cardioprotection.
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PMID:Preconditioning of rat heart with monophosphoryl lipid A: a role for nitric oxide. 961 33

The effects of the 5-HT1B/D receptor agonist, sumatriptan, on coronary flow (CF) and left ventricular function in the isolated perfused guinea pig heart were investigated in the presence and absence of coronary endothelial dysfunction induced by nitric oxide (NO) synthase inhibition with Nomega-nitro-L-arginine methyl ester (L-NAME; 10 microM). Hearts were perfused under constant pressure (80 cm H2O) with oxygenated (95% O2/5% CO2) Krebs bicarbonate buffer (pH 7.4) and were driven at 4 Hz. In the absence of L-NAME (n=37), sumatriptan (0.1-32 microM) failed statistically significantly to affect left ventricular developed pressure (LVDP; maximal change, -8.1+/-1.8%; NS vs. vehicle), left ventricular end-diastolic pressure (LVEDP; +10.4+/-9.8%, NS), or CF (-12.2+/-1.4%; NS compared with vehicle). L-NAME per se significantly reduced coronary flow (CF; -26.3+/-2.9%; p < 0.001), thereby increasing coronary vascular tone, and decreased LVDP (-17.1+/-1.8%; p < 0.01). In hearts perfused with L-NAME (10 microM; n=61), sumatriptan (0.1-32 microM) still failed significantly to affect CF (maximal change, 0.2+/-5.7%, NS) but concentration-dependently increased LVEDP [maximal increase, 89.0+/-30.3%; p < 0.05; geometric mean EC50 3.6 (2.9-5.7) microM], which was not prevented by the 5-HT1B/D receptor antagonist, GR 127935 (0.1 microM; maximal increase, 51.8+/-11.1%; n=48, NS compared with sumatriptan alone). In conclusion, sumatriptan failed significantly to affect CF even in the presence of endothelial dysfunction. LV function similarly remained unaffected in normal hearts, but sumatriptan produced diastolic contracture in the presence of coronary endothelial dysfunction by a mechanism apparently not involving 5-HT1B/D receptors. Collectively the data indicate that 5-HT1B/D receptor expression or effector coupling or both are absent or low in the guinea pig heart, because no detectable functional responses were observed.
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PMID:Effects of sumatriptan on coronary flow and left ventricular function in the isolated perfused guinea pig heart. 973 57

Acetylcholine acting through specific muscarinic membrane receptors causes a negative dromotropic effect and, in blood vessels, causes a vasodilation which results from its action on the endothelial cells via release of nitric oxide (NO). We decided to study this effect in isolated Krebs-Henseleit retrogradely perfused guinea pig hearts. A pair of stimulating electrodes was placed in the right atrium and to record the auricular-ventricular interval (A-V delay) one recording electrode was placed on the left atrium and the other on the tip of the ventricle. Hearts were paced at a rate of 3.8+/-0.1 Hz and perfused at a coronary flow rate of 9+/-0.25 ml/min. To obtain dose-response curves, single doses (as boluses) of acetylcholine were infused and the maximal A-V delay induced by each dose was determined. Perfusion of agents that inhibit NO accumulation (L-Arginine methyl ester (L-NAME) (0.5 mM)) or oxyhemoglobin (6 microM) caused displacement of the acetylcholine dose-response curve downward and to the right. Perfusion of NO-sparing agents like superoxide dismutase and dithiothreitol caused an upward and leftward displacement. Infusion of NO solutions or a NO donor (diethylamine-nitric oxide [DEA-NO]) caused a dose-dependent negative dromotropic effect. In contrast, inhibition of the prostaglandin metabolic pathway by Indomethacin (0.01 mM) caused potentiation of acetylcholine effects which were reversed when it was co-perfused with L-NAME. When endothelial intravascular muscarinic receptors were selectively blocked by perfusion of a non-permeable macromolecule: dextran ( > 2000 kDa) covalently complexed to the receptor blocker (3-(2'-aminobenzhydryloxy) tropane)), the negative dromotropic effect of intravascular acetylcholine was diminished in a concentration-dependent manner up to complete blockade. Our data indicate that the dromotropic effect caused by intracoronary administration of acetylcholine is the result solely of activation of intravascular endothelial muscarinic receptors, that nitric oxide and prostaglandins are non-synergistic endothelial mediators of this effect and that there may be an interaction between NO and prostaglandin metabolic pathways.
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PMID:Endothelium-mediated negative dromotropic effects of intravascular acetylcholine. 987 66

Intravascular adenosine may exert its negative dromotropic effect via activation of luminal coronary endothelial receptors, which suggests the presence of transcellular dromotropic mediators of endothelial origin, perhaps nitric oxide (NO) and prostaglandins. We decided to test this hypothesis in isolated guinea pig hearts retrogradely perfused with Krebs-Henseleit solution. A pair of stimulating electrodes were placed in the right atria and the auricular-ventricular (A-V) delay recorded by means of a recording electrode placed on the left atria and an electrode placed on the tip of the ventricle. Hearts were paced at a rate of 3.8 +/- 0.2 Hz and perfused at a coronary flow of 9 +/- 0.25 ml/min. To obtain dose-response curves, single doses (as boluses) of different concentrations of adenosine were infused and the maximal increase in A-V delay induced by each dose was determined. Agents that inhibit NO accumulation, such as N(G)-nitro-L-arginine methyl ester (L-NAME) and oxyhemoglobin, diminished the effect of adenosine while NO-sparing agents, such as superoxide dismutase and dithiotreitol, enhanced the adenosine effect. Infusion of NO and the NO donor morpholinosydnonimine increased the A-V delay in a dose-dependent manner. In addition, the dose-response curve for adenosine was displaced downward and to the right by indomethacin, indicating also the involvement of prostaglandins. Infusion of L-NAME in addition to indomethacin further diminished the effects of adenosine, indicating that NO and prostaglandins acted simultaneously. To selectively activate intravascular endothelial adenosine receptors, adenosine amino congener (ADAC), an adenosine A1 receptor agonist, was covalently coupled to 2 X 10(6) Da dextran. When intracoronarily infused, the dextran-ADAC complex remains in the blood vessel lumen because it is too large to diffuse to the interstitium. On intracoronary administration, the dextran-ADAC complex caused a negative dromotropic effect which was diminished by L-NAME and indomethacin. Our data indicate that the dromotropic effect caused by intracoronarily administered adenosine is the result solely of activation of intravascular endothelial adenosine receptors, possibly type A , and that NO and prostaglandins are synergistic endothelial mediators of this effect.
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PMID:Intravascular adenosine: the endothelial mediators of its negative dromotropic effects. 1032 77

The purpose of this study was to examine the role of the nitric oxide (NO) and cyclic guanosine monophosphate (cGMP) system in the regulation of the ductus arteriosus (DA) patency in fetal rats. Pregnant rats were administered N(G)-nitro-L-arginine methyl ester (L-NAME, 50 mg/kg, ip), an NO synthase (NOS) inhibitor; methylene blue (30, 50 and 100 mg/kg, ip), a soluble guanylate cyclase inhibitor; or indomethacin (3 mg/kg, po), a cyclooxygenase inhibitor, at various times before cesarean section. Dams were decapitated to obtain the fetuses by cesarean section, and fetuses were rapidly frozen in an acetone-dry ice mixture. Using rapid freezing and shaving methods, the calibers of the DA, pulmonary artery (PA) and descending aorta (Ao) were measured to evaluate the effects of treatment. L-NAME reduced the DA calibers to 86% of the initial values, but recovery to the control levels occurred 6 hr after the injection. Indomethacin decreased the DA calibers to 34% of the control values and sustained the DA constriction until 24 hr after the treatment. Methylene blue caused DA constriction to almost the same degree as indomethacin, but the levels normalized within 24 hr after the treatment. We conclude that L-NAME caused a slight constriction of the DA, whereas methylene blue and indomethacin caused marked constriction of the vessels, suggesting that the NO-cGMP system as well as prostaglandins contribute to the DA patency.
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PMID:Role of the nitric oxide-cGMP system in the regulation of ductus arteriosus patency in fetal rats. 1065 Oct 46


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