Background: Excitatory neurotransmitters appear to cause cell death during ischemia by inducing depolarization, influx of ions, and metabolic failure in the postsynaptic neuron. If this hypothesis is correct, then postsynaptic membrane hyperpolarization and inhibition of metabolism may be protective. Antagonists of the excitotoxic amino acid glutamate protect neurons in culture and in animal models of stroke but appear to cause unacceptable side effects in humans. We propose an alternative strategy of protection using agonists of the inhibitory neurotransmitter y-aminobutyric acid.Methods: We caused multifocal cerebral ischemia in rats and rabbits by injecting microspheres into the carotid circulation. We administered saline, muscimol, or MK-801 within 5 minutes of stroke onset. We used a bioassay to measure outcome. In rats, we also used learning to assess cortical function, and we performed detailed quantitative brain morphometry 3 months after infarction.Results: Using the bioassay, we found that muscimol exerted a protective effect in rats (p<0.01). There was a dose-response effect seen in muscimol-treated rabbits. Rats treated with muscimol or MK-801 exhibited significantly better visual-spatial learning compared with saline-treated subjects (p<0.001). Hemisphere volume after ischemia was comparable in all groups.Conclusions: Agonists of y-aminobutyric acid and antagonists of glutamate appear to protect brain during ischemia. Since agonists of y-aminobutyric acid are known to have fewer side effects in humans, they may prove more useful in the clinical setting as neuroprotective agents.

Expression of the human atrial natriuretic peptide (hANP) gene was examined in tissues of 19 to 28-week-old human fetuses. As expected the fetal atria express the hANP gene at a high level, accruing substantial quantities of ANP immunoreactivity and ANP mRNA. The neonatal ventricle also expresses the hANP gene at a significant level. ANP mRNA levels in the ventricle were, on the average, about 20% of those in the right atria. ANP immunoreactivity in ventricle was less that 5% of that in the right atria, suggesting important differences in the way these tissues synthesize and store the ANP peptide. Much lower levels of hANP transcripts were also detected in the lung and aortic arch. Analysis of the 5' termini of cardiac hANP transcripts using three independent techniques suggests the presence of two transcription start sites. A major start site is located approximately 28 basepairs downstream from the primary TATA sequence. A second minor start site is positioned about 110 basepairs further upstream. Immunocytochemistry and in situ hybridization analysis indicate that the hANP gene is expressed in a homogeneous distribution throughout the atrial myocardium. Diffuse low level expression is also present within the ventricular myocardium. In addition, there are scattered foci of increased expression in the ventricle which tend to be concentrated in the subendocardium of that organ. These findings indicate that the developing human ventricles as well as the atria possess the capacity to express the hANP gene at a substantial level and suggest that the ventricle may contribute significantly to the circulating pool of plasma ANP.

Primary cultures of neonatal cardiocytes express the gene for atrial natriuretic peptide (ANP). In general the levels of expression follow the rank order: atrial greater than ventricular much greater than nonmyocardial cells. Following the initial dispersion cardiocytes require 48 to 72 hours before ANP secretion and ANP mRNA accumulation approach a new steady-state level. In situ hybridization analysis indicates that ANP gene expression is concentrated in a subpopulation of cardiocytes in both the atrial and the ventricular cell cultures. These findings suggest that these primary cultures may be of value in defining the factors governing the expression of the ANP gene in the cardiac cell.

Variation in the fatty acid composition of fasting plasma lipids and of cholesteryl esters was studied in 69 sets of adult male twins and 25 of their brothers. Genetic variances were estimated using the twin model. In general, monozygotic (MZ) twins were characterized by the smallest within-pair variance, and brothers of twins by the largest. Variation within dizygotic pairs fell imtermediate to that of MZ twins and brothers. The present study did not reveal consistent significant (P greater than 0.05) genetic variation in plasma fatty acids from total plasma lipids or cholesteryl esters.