dizocilpine-maleate and Hyperemia

N-methyl-D-aspartate (NMDA) receptors were found to be dysfunctional in hypertensive rats. Methyl palmitate (MP) has been shown to diminish the nicotine-induced increase in blood flow in the brainstem. The aim of this study was to determine how MP modulated NMDA-induced increased regional cerebral blood flow (rCBF) in normotensive (WKY), spontaneously hypertensive (SHR), and renovascular hypertensive (RHR) rats. The increase in rCBF after the topical application of experimental drugs was measured using laser Doppler flowmetry. Topical NMDA application induced an MK-801-sensitive increase in rCBF in anesthetized WKY rats, which was inhibited by MP pretreatments. This inhibition was prevented by pretreatment with chelerythrine (a PKC inhibitor). The NMDA-induced increase in rCBF was also inhibited by the PKC activator in a concentration-dependent manner. Neither MP nor MK-801 affected the increase in rCBF induced by the topical application of acetylcholine or sodium nitroprusside. Topical application of MP to the parietal cortex of SHRs, on the other hand, increased basal rCBF slightly but significantly. MP enhanced the NMDA-induced increase in rCBF in SHRs and RHRs. These results suggested that MP had a dual effect on the modulation of rCBF. MP appears to play a significant physiological role in CBF regulation.

Topics: Animals; Dizocilpine Maleate; Hyperemia; Hypertension; N-Methylaspartate; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Receptors, N-Methyl-D-Aspartate

The goal of this study was to determine whether neuronally derived nitric oxide mediates responses of cerebral blood flow (CBF) to N-methyl-D-aspartate (NMDA). In anesthetized Sprague-Dawley rats, regional CBF of the parietal cortex was monitored by laser-Doppler flowmetry. Topical application of either NMDA or acetylcholine produced concentration-related increases in CBF. Responses of CBF to NMDA (10(-5) M) but not to acetylcholine were inhibited (0+/-3% vs 21+/-5%, p < 0.05) by 7-nitroindazole (50 mg/kg, i.p.). MK-801 (0.5 mg/kg, i.v.) and tetrodotoxin (10(-6) M, topical application) also inhibited NMDA-induced responses. These results suggest that nitric oxide of neuronal origin mediates NMDA-induced increases in CBF.

Topics: Acetylcholine; Animals; Cerebrovascular Circulation; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Hyperemia; Male; N-Methylaspartate; Neurons; Nitric Oxide; Rats; Rats, Sprague-Dawley; Tetrodotoxin

The purpose of this study was to compare the effects of dizocilipine maleate (MK-801) and NG-nitro-L-arginine methyl ester (L-NAME) on focal excitotoxic brain injury and associated hemodynamic response in the newborn lamb. A 27 gauge needle was placed into the right striatum in 28 anesthetized newborn lambs. Seven animals were placed in each group. A negative control group received 0.2 mL of buffered saline, a positive control group received 5 mumol of N-methyl-D-aspartic acid (NMDA) alone, and two groups received NMDA and pretreatment with L-NAME. Ultrasound images and cerebral blood flow determinations (microspheres) were obtained before, and at 20, 40, and 60 min after, intrastrial injection. Three animals in each group underwent histopathologic evaluation. Sonographic lesions were visible immediately after intracerebral injection. Saline injection resulted in small lesions (mean volume; 13.6 +/- 5 mm3) without hyperemia. NMDA alone resulted in larger lesions (92.9 +/- 24 mm3) and hyperemia to both hemispheres, whereas pretreatment with MK-801 reduced lesion size (11.7 +/- 6 mm3) and completely ablated cerebral hyperemia. Pretreatment with L-NAME showed no effect on lesion size (69.9 +/- 20 mm3) and hyperemia only in the ipsilateral hemisphere. Sonographic lesions correlated well with gross and histopathologic appearance. We concluded that NMDA-induced focal brain injury and associated hyperemia in the newborn lamb appear to be specific NMDA receptor-mediated events. NO production probably does not play a major part in NMDA-induced neonatal neuronal injury, and may be only partly responsible for regional hyperemia during NMDA injection.

Topics: Animals; Animals, Newborn; Arginine; Brain Diseases; Cattle; Disease Models, Animal; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Hemodynamics; Hyperemia; N-Methylaspartate; Neuroprotective Agents; NG-Nitroarginine Methyl Ester; Nitric Oxide; Nitric Oxide Synthase; Receptors, N-Methyl-D-Aspartate; Sheep

MK-801 and (+)SK&F 10047 produced a dose-related inhibition of the EEG suppression and cortical hyperemia associated with cortical spreading depression (CSD) and reduced the CSD propagation rate; ED50 = 1 mg/kg, i.v. and 15 mg/kg, i.v., respectively. MK-801 had a delayed onset of action (inversely related to dose) and a prolonged duration of action at all doses (> 2 h). In contrast, (+)SK&F 10047 had a rapid onset of action (< 30 min) and a predictable dose-related duration of action. These results suggests that an efficacious compound acting with moderate affinity as a non-competitive antagonist at the NMDA-receptor channel may possess a preferable time-course and toxicity profile when compared to agents acting similarly, but with high affinity.

Topics: Animals; Cerebrovascular Circulation; Cortical Spreading Depression; Dizocilpine Maleate; Dose-Response Relationship, Drug; Electroencephalography; Hyperemia; Injections, Intravenous; Male; Microinjections; N-Methylaspartate; Phenazocine; Potassium Chloride; Rats; Rats, Sprague-Dawley; Stereotaxic Techniques

The purposes of this study were to determine whether cortical spreading depression occurs outside of the infarct produced by photothrombotic vascular occlusion, and also the direction of spreading. Focal cerebral thrombotic infarction was produced by irradiating the exposed skull of anesthetized rats with green light (560 nm) following systemic injection of rose bengal dye. At proximal sites (approximately 2 mm anterior to the infarct border), transient, severe hyperemic episodes (THEs) lasting 1-2 min were intermittently recorded. THE frequency was greatest in the first hour and declined over a 3-h period. THEs were accompanied (and usually preceded) by a precipitous rise in [K+]0 (from approximately 3 to > 40 mM) and were associated with increases in local tissue oxygen tension (tPO2). Following the rise in [K+]0, clearance of [K+]0 to its pre-THE baseline preceded baseline recovery of CBF. These data indicate that THEs were reactive to physiologic events resembling cortical spreading depression (CSD), which provoked increased demand for oxygen and blood flow, and which spread from proximal sites to areas more distal (approximately 4 mm) from the rim of the evolving infarct. MK-801 (1 mg/kg, i.v.) inhibited subsequent CSD-like episodes. We conclude that photothrombosis-induced ischemia provoked CSD which was triggered either within the infarct core or in the infarct rim and spread to more distal sites. Whether multiple episodes of CSD during infarct generation are responsible for the remote consequences of focal brain injury remains to be determined.

Topics: Animals; Brain; Cerebral Infarction; Cortical Spreading Depression; Dizocilpine Maleate; Hyperemia; Intracranial Embolism and Thrombosis; Light; Male; Radiation Injuries, Experimental; Rats; Rats, Wistar