nitroarginine and Cerebrovascular-Disorders

Endothelial dysfunction occurs in conduit and cerebral resistance arteries with advancing age. Lifelong caloric restriction (CR) can prevent the onset of age-related dysfunction in many tissues, but its effects on cerebral resistance artery function, as compared with conduit artery function, have not been determined. We measured endothelium-dependent dilation (EDD) in the carotid artery and middle cerebral artery (MCA) from young (5-7 months), old ad libitum fed (AL, 29-32 months), and old lifelong CR (CR, 40 % CR, 29-32 months) B6D2F1 mice. Compared with young, EDD for old AL was 24 % lower in the carotid and 47 % lower in the MCA (p < 0.05). For old CR, EDD was not different from young in the carotid artery (p > 0.05), but was 25 % lower than young in the MCA (p < 0.05). EDD was not different between groups after NO synthase inhibition with N(ω)-nitro-L-arginine methyl ester in the carotid artery or MCA. Superoxide production by the carotid artery and MCA was greater in old AL compared with young and old CR (p < 0.05). In the carotid, incubation with the superoxide scavenger TEMPOL improved EDD for old AL (p > 0.05), with no effect in young or old CR (p > 0.05). In the MCA, incubation with TEMPOL or the NADPH oxidase inhibitor apocynin augmented EDD in old AL (p < 0.05), but reduced EDD in young and old CR (p < 0.05). Thus, age-related endothelial dysfunction is prevented by lifelong CR completely in conduit arteries, but only partially in cerebral resistance arteries. These benefits of lifelong CR on EDD result from lower oxidative stress and greater NO bioavailability.

Topics: Aging; Animal Feed; Animals; Caloric Restriction; Carotid Arteries; Cerebrovascular Circulation; Cerebrovascular Disorders; Disease Models, Animal; Electron Spin Resonance Spectroscopy; Endothelium, Vascular; Follow-Up Studies; Male; Mice; Middle Cerebral Artery; Nitric Oxide; Nitric Oxide Synthase; Nitroarginine; Oxidative Stress; Time Factors; Vascular Resistance; Vasodilation

Oxidized low-density lipoprotein (oxLDL) is elevated during several neurologic conditions that involve cerebral edema formation, including severe preeclampsia and eclampsia; however, our understanding of its effect on the cerebral vasculature is limited. We hypothesized that oxLDL induced blood-brain barrier (BBB) disruption and changes in cerebrovascular reactivity occur through NADPH oxidase-derived superoxide. We also investigated the effect of MgSO₄ on oxLDL-induced changes in the cerebral vasculature as this is commonly used in preventing cerebral edema formation. Posterior cerebral arteries from female rats were perfused with 5 µg/mL oxLDL in rat serum with or without 50 µM apocynin or 16 mM MgSO₄ and BBB permeability and vascular reactivity were compared. oxLDL increased BBB permeability and decreased myogenic tone that were prevented by apocynin. oxLDL increased constriction to the nitric oxide synthase inhibitor nitro-L-arginine that was unaffected by apocynin. oxLDL enhanced dilation to the NO donor sodium nitroprusside that was prevented by apocynin. MgSO₄ prevented oxLDL-induced BBB permeability without affecting oxLDL-induced changes in myogenic tone. Thus, oxLDL seems to cause BBB disruption and vascular tone dysregulation through NADPH oxidase-derived superoxide. These results highlight oxLDL and NADPH oxidase as potentially important therapeutic targets in neurologic conditions that involve elevated oxLDL.

Topics: Acetophenones; Animals; Antioxidants; Blood-Brain Barrier; Cerebrovascular Disorders; Enzyme Inhibitors; Female; Lipoproteins, LDL; Magnesium Sulfate; Muscle Contraction; Muscle Tonus; Muscle, Smooth, Vascular; Nitric Oxide; Nitric Oxide Donors; Nitric Oxide Synthase; Nitroarginine; Nitroprusside; Permeability; Posterior Cerebral Artery; Rats; Rats, Sprague-Dawley; Superoxides; Vasodilation

1. To observe the effect of nitric oxide (NO) on the myocardium, the NO synthesis inhibitor NG-nitro-L-arginine (L-NNA) was administered to hypercholesterolaemic stroke-prone spontaneously hypertensive (SHRSP) rats. 2. Hypercholesterolaemic SHRSP were produced by feeding SHRSP a high fat and high cholesterol diet (HFC) for 2 weeks. The rats were then divided into three groups: (i) the N group, which were fed the HFC diet containing 0.023% L-NNA and 1% NaCl in their drinking water (n = 10); (ii) the NH group, which were fed the HFC diet containing 0.023% L-NNA and 1% NaCl in their drinking water which also contained 80 mg/L hydralazine (n = 10); and (iii) the C group, which were fed the HFC diet and 1% NaCl in their drinking water (n = 10). 3. All rats in the N and NH groups died within 35 days of the initiation of L-NNA administration. Rats in the N and NH groups had significantly increased serum creatine phosphokinase, lactate dehydrogenase, glutamic oxaloacetic transaminase and serum total cholesterol levels compared with rats in the C group. 4. Fibrosis in response to necrosis was histopathologically observed in the hearts of all rats in the N and NH groups without exception. Occlusion or intimal thickening in the arteries adjacent to the necrotic regions was also observed. 5. These results suggest that nitric oxide deficiency induces myocardial infarction in hypercholesterolaemic SHRSP. These NO-deficient hypercholesterolaemic SHRSP offer a new model of myocardial infarction in rats.

Topics: Animals; Blood Pressure; Cerebrovascular Disorders; Coronary Vessels; Enzyme Inhibitors; Fibrosis; Hydralazine; Hypercholesterolemia; Male; Myocardial Infarction; Myocardium; Necrosis; Nitric Oxide; Nitroarginine; Rats; Rats, Inbred SHR

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 is

Topics: Acetylcholine; Animals; Basilar Artery; Cerebrovascular Disorders; Enzyme Inhibitors; Muscle Contraction; Nitric Oxide; Nitric Oxide Synthase; Nitroarginine; Potassium Chloride; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Serotonin

Diminished nitric oxide (NO) production has been implicated in the pathogenesis of salt-sensitive hypertension. We questioned whether such a defect is responsible for the malignant hypertension and nephrosclerosis in stroke-prone spontaneously hypertensive rats (SHRSP) fed a high-salt/stroke-prone diet (S) versus a regular diet (R). NO release from 30-minute incubates of cortex and outer and inner medulla were studied in SHRSP at 10, 12, and 16 weeks of age on the S diet versus R diet. SHRSP-S (n=16) exhibited a marked age-dependent increase in NO release, especially in the cortex. Increases were only modest in SHRSP-R (n=21). At 16 weeks, cortical NO was 93+/-25 versus 6+/-1 pmol/mg tissue in SHRSP-S versus SHRSP-R (P<.001). Immunohistochemical staining increased mostly for neuronal, slightly for endothelial, and negligibly for inducible isoforms of NO synthase and was predominantly in the cortex of SHRSP-S versus SHRSP-R. Despite similar hypertension in SHRSP-S versus SHRSP-R (mean arterial pressure, 174+/-7 versus 177+/-2 mm Hg), malignant nephrosclerosis was seen only in SHRSP-S, affecting 22+/-6% of glomeruli and 23+/-4 vessels per 100 glomeruli by 16 weeks. N omega-nitro-L-arginine (15 mg/kg per day) in SHRSP-S (n=6) abrogated the increase in cortical NO but further augmented the hypertension and accelerated lesion development. Wistar-Kyoto rats at 16 weeks on the R diet (n=8) had NO levels similar to those of SHRSP-R, showed increased cortical NO to only 28+/-10 pmol/mg on the S diet (n=9) (P<.05 versus SHRSP-S), but remained normotensive and lesion-free. We conclude that hypertension and lesion development in SHRSP are not due to deficient renal NO. Accelerated onset of malignant nephrosclerosis by NO synthase inhibition suggests that NO is protective in these animals, mitigating the effects of hypertension and S diet on renal pathology.

Topics: Aging; Animals; Blood Pressure; Cerebrovascular Disorders; Hypertension; Kidney Cortex; Kidney Glomerulus; Kidney Medulla; Male; Nitric Oxide; Nitric Oxide Synthase; Nitroarginine; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Renal Circulation; Sodium, Dietary

Inhibition of an endothelium-derived relaxing factor (EDRF) may contribute to the pathogenesis of thrombotic arterial occlusions.. We measured the blood pressure and urinary excretion of protein, sodium, and potassium and histologically examined the brains, hearts, and kidneys in normotensive Wistar Kyoto rats (WKY) and stroke-prone spontaneously hypertensive rats (SHRSP) fed on a diet containing: (a) EDRF inhibitor (L-N-nitroarginine:L-NNA); (b) L-arginine, which reverses the effect of L-NNA; or (c) both L-NNA and L-arginine for 1 to 8 weeks. In addition, we examined L-NNA-treated SHRSP, the blood pressures of which were lowered using hydralazine. Furthermore, we produced and examined Goldblatt's renal hypertensive rats, which are of a different type from those resulting from the L-NNA treatment.. Both WKY and SHRSP rats fed on a diet containing L-NNA suffered from hypertension and cerebral infarctions in a dose-dependent manner. Cerebral infarctions occurred whether or not SHRSP rats were treated with an antihypertensive agent when they were fed a high dosage of L-NNA. In contrast, SHRSP rats, treated simultaneously with both L-NNA and L-arginine, suffered few cerebral infarctions, although they were severely hypertensive. In addition, there were no cerebral infarctions in Goldblatt's renal hypertensive rats, although they suffered from advanced hypertension.. The data indicate that the inhibition of EDRF injures the vessel walls and encourages platelet adhesion to the damaged areas. The adhering platelets narrow the lumen with resultant thrombotic arterial occlusions. Pathophysiologic conditions that decrease EDRF synthesis appear to play an important role in cerebral, renal, and myocardial infarctions.

Topics: Animals; Arginine; Arterial Occlusive Diseases; Blood Pressure; Blood Vessels; Cerebrovascular Disorders; Dose-Response Relationship, Drug; Hydralazine; Hypertension, Renovascular; Incidence; Microscopy, Electron; Nitric Oxide; Nitroarginine; Potassium; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Sodium; Thrombosis; Time Factors; Vascular Diseases

1. Endothelium-dependent relaxation by alpha-adrenoceptor agonists was examined in the thoracic aorta from normotensive Wistar-Kyoto (WKY) rats and stroke-prone spontaneously hypertensive rats (SHRSP). 2. In ring preparations from both strains, noradrenaline-induced contraction was increased by L-nitro arginine (L-NNA), a NO synthesis inhibitor. 3. L-NNA increased the contraction induced by phenylephrine, an alpha1-adrenoceptor agonist. UK-14304 and clonidine, alpha2-adrenoceptor agonists, did not contract the preparations with intact endothelium. However, these agents contracted preparations when NO synthesis was inhibited. 4. In a precontracted preparation, clonidine and UK-14304 induced relaxations. The relaxations in SHRSP aorta were smaller than those in WKY aorta. 5. These results indicate that alpha-agonists release NO from endothelium in WKY and SHRSP aorta. The mechanism related to NO release by alpha2-adrenoceptor agonist is impaired in SHRSP aorta.

Topics: Adrenergic alpha-Agonists; Animals; Aorta, Thoracic; Cerebrovascular Disorders; Enzyme Inhibitors; Hypertension; In Vitro Techniques; Muscle Contraction; Muscle, Smooth, Vascular; Nitric Oxide; Nitric Oxide Synthase; Nitroarginine; Norepinephrine; Rats; Rats, Inbred SHR; Rats, Inbred WKY

1. The experiments were carried out by an ordinary and a microsphere method in order to clarify the effects of three nitric oxide-synthase inhibitors and -donor on the circulating system between SHRSP and WKY. 2. Intravenous administration of each compound possessing the nitric acid-synthase inhibiting action markedly elevated the systolic blood pressure both in SHRSP and WKY, but more prominently in the former. 3. The hypotensive and tachycardic responses to glyceryl trinitrate were more enhanced after treatment with NG-nitro-L-arginine and NG-nitro-L-arginine methyl ester but not with NG-monomethyl-L-arginine compared with the non-treated one. 4. All peripheral organs except the brain decreased their regional blood flow after administration of NG-nitro-L-arginine, indicating a crucial involvement of nitric oxide in the peripheral circulation. 5. It was suggested that the nitric oxide system worked more sensitively and actively in SHRSP than in WKY in order to maintain the peripheral blood flow and systemic blood pressure.

Topics: Animals; Blood Pressure; Cerebrovascular Disorders; Enzyme Inhibitors; Heart Rate; Hemodynamics; Hypertension; Microspheres; NG-Nitroarginine Methyl Ester; Nitric Oxide Synthase; Nitroarginine; Nitroglycerin; omega-N-Methylarginine; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Regional Blood Flow; Vasodilator Agents

The effect of a calcium antagonist, manidipine, on blood pressure and proteinuria induced by the inhibition of endothelial-derived relaxation factor (EDRF) formation was examined. Manidipine attenuated the increase in blood pressure and prevented proteinuria caused by renal damage associated with the inhibition of EDRF formation in stroke-prone spontaneously hypertensive rat (SHRSP) and Wistar Kyoto (WKY) rats.

Topics: Animals; Arginine; Blood Pressure; Calcium Channel Blockers; Cerebrovascular Disorders; Dihydropyridines; Hypertension; Male; Nitric Oxide; Nitroarginine; Nitrobenzenes; Piperazines; Proteinuria; Rats; Rats, Inbred SHR; Rats, Inbred WKY