Endogenous brain Na pumps, brain ouabain-like substance and the alpha2 isoform in salt-dependent hypertension.

An endogenous ouabain-like substance (OLS) plays a critical role in the etiology of experimental models of human hypertension induced by a high salt diet. Early on, evidence for a role of this Na, K-ATPase inhibitor in blood pressure regulation was provided mainly by correlations of blood pressure with the levels of circulating Na, K-ATPase inhibitor. However, over the past decade, numerous studies have shown that endogenous Na pump inhibitors in the brain mediate salt-dependent hypertension in a variety of experimental models, including Dahl salt-sensitive (Dahl-S) and spontaneously hypertensive (SHR) rats on a high-salt diet. Other forms of hypertension that are known to be mediated by endogenous ouabain-like substances include steroid/salt- (e.g., DOCA-salt) and ACTH-induced hypertension. Even when exogenous ouabain is peripherally administered and/or the plasma ouabain/OLS level is increased in rats, the resulting hypertension is of CNS origin. After peripheral ouabain administration, ouabain levels increase in the plasma and the inhibitor subsequently accumulates in the brain. The ensuing hypertension is abolished by the intracerebroventricular (icv) administration of an anti-ouabain antibody (but not by the same antibody dose given iv), by discrete excitotoxic lesions in the brain or by ganglionic blockade, demonstrating that the response is neurally mediated. The pressor response to stimuli that increase the brain OLS (high salt diet, icv sodium) or to icv ouabain is abolished by icv losartan, demonstrating that the brain OLS activates the brain renin-angiotensin system (RAS) downstream. There are three isoforms of the catalytic alpha subunit of the Na, K-ATPase in the brain and cardiovascular system (alpha1, alpha2 and alpha3), but it is not known which brain isoform(s) mediate the hypertensive effects of circulating/CNS ouabain. Preliminary studies in gene-targeted mice suggest that the alpha2 isoform plays a critical role.     

Rapid screening of organosulfur agents for potential chemopreventive activity using the murine NA assay

The chemopreventive efficacy of 11 organosulfur compounds was assessed using the murine nuclear aberration (NA) assay in C57BL/6J mice. The sulfur compounds were introduced by stomach gavage. Benzo[a]pyrene (BP), which is a carcinogen known to a) undergo biotransformation by pathways mediated by P-450 and b) induce NA in the intestine, was used as the challenge. All animals were killed 48 hours after BP injection, and NA per crypt were scored. The results indicated that several agents were active in inhibiting BP nucleotoxicity to the colon, most notably, allyl mercaptan, benzyl mercaptan, and phenylethyl mercaptan. The NA assay was useful in effectively prescreening certain compounds for potential interactions with chemical carcinogens, thus serving as one indicator of chemopreventive activity.     

Prognostic value of ultrastructural characteristics of dysplastic changes in the esophagus

Dysplasia foci in the esophageal squamous epithelium against the background of various reactions of proliferation were studied by electron microscopy. Slightly altered tissue showed diverse cellularity, with dark cambial elements invariably present. With dysplasia advancing, the cell composition became uniform, with a high nuclear-cytoplasmic index. The dark cell pattern with numerous ribosomes was seen more often than that of keratinized clear cells. Small-cell focal proliferations are highly suggestive of precancer. Electron microscopy may be instrumental in eliciting more information on the risk of esophageal squamous epithelium precancer progressing to cancer since it provides data on cell composition, degree of cell differentiation and polysome formation as well as early signs of keratinization.     

Comparison of right colon, left colon, and rectal carcinoma

Three hundred fifteen cases of adenocarcinoma were analyzed for differences between lesions in the right colon, left colon, and rectum for the period 1978 to 1983. The right colon cancers accounted for 1/3 of the cases and were associated with a higher incidence of anemia. The incidence of obstruction was the same between the right and left colon but lower for the rectal lesions. Left colon and rectal cancers had a higher incidence of gross bleeding than right colon cancers, but all had a high rate of occult blood in the stool. The Duke stage of the lesions, which was similar throughout the colon and rectum, is a reliable prognostic indicator.