Neuroprotective effects of MK 801 and hypothermia used alone and in combination in hypoxic-ischemic brain injury in neonatal rats.

Although accumulating evidence suggests that increased extracellular glutamate concentrations may play an important role in hypoxic-ischemic brain injury, dopamine and other catecholamines also seem to be involved. The N-methyl-D-aspartate receptor antagonist MK 801 and moderate hypothermia (32-34 degrees C) are each known to be neuroprotective, but their combined effect on the release and metabolism of neurotransmitters is unknown. Seven-day-old pups (n: 150) underwent right common carotid artery ligation to induce hemispheric ischemia, and were later subjected to 120 minutes of hypoxia with 8% O2 and 92% N2O. Half the rats (Group I, n: 74) were subjected to normothermic conditions throughout the hypoxic period. Moderate hypothermia (30-32 degrees C) was induced in the other pups (Group II, n: 76) immediately after artery occlusion, and was maintained throughout the hypoxic period. Prior to inducing hypoxia, half of the rats in each group (Groups IA and IIA) received vehicle solution (0.9% NaCI) and the other rats (Groups IB and IIB) received MK 801 (0.5 mg/kg) subcutaneously at 45 and 120 minutes after occlusion. Intracerebral temperature was recorded every 15 minutes after occlusion. Infarct area (n: 40) was calculated after staining with 2% 2,3,5 triphenyltetrazolium chloride. Neuronal damage (n: 42) was assessed by quantifying CA1-CA3 neuronal loss at five hippocampal levels. The amount of damage to the monoamine system of the corpus striatum was determined based on the dopamine and 3,4 dihydroxyphenylacetic acid levels in the corpus striatum in both hemispheres (n: 46), as measured by high-pressure liquid chromatography and compared with normal control pups' values (n: 10). The normothermia/saline-treated pups had significantly larger infarct areas than the MK 801 only, hypothermia only, or MK 801/hypothermia combination groups. Neuropathological examination and striatal tissue monoamine data also confirmed marked neuronal damage in this group. Although MK 801 treatment alone resulted in significantly smaller infarct area and less tissue damage than was observed in the normothermia/saline-treated group, the moderate hypothermia and the MK 801/hypothermia combination treatment groups both exhibited better neuronal protection, especially in the corpus striatum. The rats that received combined treatment also had a significantly lower mortality rate.

Effects of fetal septal grafts on memory and learning performance with hippocampal acetylcholine and choline metabolism in fimbria transected rats.

Female Sprague-Dawley rats underwent aspirative lesion of the fimbria to produce septohippocampal disconnection. Two weeks after the lesion surgery, fetal septal grafts prepared from ventral forebrain of 13-15 days old fetuses of the same outbred strain were placed into the lesion cavity (grafted group). Three months after grafting, all rats were tested for spontaneous motor activity (SMA), step through passive avoidance (STPA) and in Morris' water maze (MWM). Six months after grafting, both basal and stimulated acetylcholine (ACh) and choline (Ch) release and their tissue levels were measured in ipsilateral hippocampal slices. Septohippocampal disconnection caused a significant impairment in Morris' water maze tasks, but did not alter spontaneous motor activity and step through passive avoidance. Fimbrial lesion, moreover, also declined both stimulated ACh release and tissue ACh levels in hippocampal slices. While lesion-induced change in Morris' water maze was ameliorated partially, declines in both stimulated ACh release and tissue ACh levels were raised to the control levels by fetal septal graft placed into the lesion cavity. These data show that grafted cholinergic neurons can work biochemically which may not result with a complete behavioral amelioration which is, in fact something more complex.

The Effects of Sublingual Administration of Captopril on Parameters of Exercise Test and Neurohormonal Activation in Patients With Stable Angina Pectoris

A prospective randomized, double-blind, and placebo-controlled study was designed to investigate the effects of sublingual administration of captopril on the parameters of exercise test and neurohormonal activation in patients with stable angina pectoris. A total of 31 patients (28 male, 3 female; mean age 55.4 +/- 9.4 years) took part in the study. Coronary angiography and left ventriculography were performed in all cases and the patients were classified according to the ejection fraction (EF). Following sublingual placebo or 25 mg captopril, plasma levels of renin, angiotensin II, norepinephrine, and serum aldosterone levels were measured at rest and maximal exercise. test was performed. Hormone levels were remeasured immediately after the exercise. The same procedure was repeated the next day using captopril or placebo. Sublingual captopril administration increased the time to angina, the time to 1 mm ST depression, maximal exercise capacity, maximal exercise duration and decreased maximal ST depression, maximal systolic blood pressure, and maximal double product (p < 0.001-0.01). After the maximal exercise test following captopril, the % difference of angiotensin II, aldosterone, and norepinephrine levels was found to be significant lower and the % difference of the renin level was found to be significantly higher than those of placebo (p < 0.001). The effects of sublingual captopril on exercise parameters were additionally assessed in different left ventricular systolic function subgroups. The favorable effects were more prominent in cases with left ventricular systolic dysfunction. There were no adverse effects related to sublingual captopril use. As a result, sublingual administration of captopril improved the parameters of maximal exercise test and suppressed the neurohormonal activation during exercise. We suggest that sublingual captopril may be used effectively before planned daily activities in patients with stable angina pectoris.