Classification of some GABA antagonists with regard to site of action and potency in slices of rat cuneate nucleus

Compounds reported to be GABA antagonists have been studied quantitatively on dorsal funiculus fibres and terminals in the rat cuneate nucleus in vitro. The potencies of the antagonists against the GABA analogue muscimol were determined as pA₂ values. Distinction was made between three different sites of antagonist action within the GABA receptor and ionophore complex. Competitive antagonists, presumed to act at the GABA receptor, and their pA₂ values were bicuculline (5.98), bicuculline methochloride (5.88), strychnine (5.29) and tubocurarine (4.95). Antagonists which were not competitive and acted predominantly at the ‘picrotoxin site’ on the ionophore were picrotoxin (6.19), picrotoxinin (6.03), isopropylbicyclophosphate (5.82) and leptazol (2.89). A third type of antagonism was shown by frusemide. Attention is drawn to the picrotoxin site and its likely importance in the regulation of GABA-mediated inhibition by drugs.     

Hereditary hyperuricemia and renal disease

Hyperuricemia and gout have long been known to run in families. As well as an apparently multifactorial genetic component to classic gout itself, 2 rather unusual sex-linked single-gene disorders of purine biosynthesis or recycling have been defined: deficiency of the enzyme hypoxanthine-guaninephosphoribosyl transferase (HPRT), and overactivity of PPriboseP synthase. Both result in overproduction of urate, hyperuricemia, and secondary overexcretion that may lead to acute or chronic renal damage. Familial juvenile hyperuricemic nephropathy (FJHN) and autosomal-dominant medullary cystic kidney disease (ADMCKD) are more common but less well-defined hyperuricemic conditions resulting from a decrease in the fractional excretion of filtered urate, with normal urate production. Although having features in common, ADMCKD is distinguished in particular by the presence of medullary cysts. One major group of both disorders is associated with mutations in the gene for uromodulin, but this accounts for only about one third of cases, and genetic heterogeneity is present. Whether the genes involved in these latter disorders contribute to the polygenic hyperuricemia and urate underexcretion of classic gout remains unexplored.     

The effect of a neoprene sleeve on knee joint position sense

The aims of the study were, first, to assess the effect of a neoprene knee brace on prop rioceptive acuity of normal subjects and, second, to assess the relationships between a variety of tests of proprioceptive acuity. Twenty healthy, physically active subjects had absolute error scores measured while carrying out three different established tests of proprioceptive ability (active tracking, active reproduction, and perceived angle tests) under two conditions, either with or without the presence of a neoprene sleeve. The neoprene sleeve significanltly improved the degree of error scores in all tests. For the active tracking, test accuracy was improved by 28% (p = 0.004), the angle reproduction test showed a 23% increase in accuracy (p = 0.029), and the accurancy of the perceived angle test improved by 27% (p = 0.035). The relationship between magnitude of error scores between the test all showed nonsignificant low correlation. The findings of this study support the previous literature, which indicates that the application of a knee sleeve improves proprioceptive acuity. The study also indicates that when testing proprioceptive acuity, a test battery should be used because of the limited correlatiotn between any of the tests used.     

Aprt/Opn double knockout mice: osteopontin is a modifier of kidney stone disease severity

BACKGROUND: Osteopontin (OPN) is reported to have two distinct functions in kidney disease: Promotion of inflammation at sites of tissue injury, and inhibition of calcium oxalate monohydrate stone formation. However, many of the studies supporting these functions were carried out in animal models of acute renal injury or in cultured cells; thus, the role of OPN in chronic renal disease is not well defined. We examined the role of OPN in adenine phosphoribosyltransferase (Aprt) knockout mice, in which inflammation and formation of 2,8-dihydroxyadenine (DHA) kidney stones are prominent features, by generating Aprt/Opn double knockout mice. METHODS: We characterized the phenotypes of six- and 12-week-old Aprt-/- Opn-/-, Aprt-/- Opn+/+, Aprt+/+ Opn-/-, and Aprt+/+ Opn+/+ male and female mice using biochemical, histologic, immunohistochemical, and in situ hybridization techniques. RESULTS: At 6 weeks of age, there was no difference in phenotype between double knockout and Aprt knockout mice. At 12 weeks, there was increased adenine and DHA excretion, renal crystal deposition, and inflammation in double knockout versus Aprt knockout male mice. Double knockout and Aprt knockout female mice at 12 weeks had less pathology than their male counterparts, but kidneys from double knockout females showed more inflammation compared with Aprt knockout females; both genotypes had similar levels of DHA crystal deposition. CONCLUSION: We conclude that (1) OPN is a major inhibitor of DHA crystal deposition and inflammation in male mice; and (2) OPN is a major modifier of the inflammatory response but not of crystal deposition in female mice. Thus, separate mechanisms appear responsible for the tissue changes seen in DKO males versus females.     

Birth weight, infant weight gain, and cause-specific mortality: the Hertfordshire Cohort Study

Low birth weight, a marker of adverse intrauterine circumstances, is known to be associated with a range of disease outcomes in later life, including coronary heart disease, hypertension, type 2 diabetes, and osteoporosis. However, it may also decrease the risk of other common conditions, most notably neoplastic disease. The authors describe the associations between birth weight, infant weight gain, and a range of mortality outcomes in the Hertfordshire Cohort. This study included 37,615 men and women born in Hertfordshire, United Kingdom, in 1911-1939; 7,916 had died by the end of 1999. For men, lower birth weight was associated with increased risk of mortality from circulatory disease (hazard ratio per standard deviation decrease in birth weight = 1.08, 95% confidence interval: 1.04, 1.11) and from accidental falls but with decreased risk of mortality from cancer (hazard ratio per standard deviation decrease in birth weight = 0.94, 95% confidence interval: 0.90, 0.98). For women, lower birth weight was associated with a significantly (p < 0.05) increased risk of mortality from circulatory and musculoskeletal disease, pneumonia, injury, and diabetes. Overall, a one-standard-deviation increase in birth weight reduced all-cause mortality risk by age 75 years by 0.86% for both men and women.     

Two distinct interactions of barbiturates and chlormethiazole with the GABAA receptor complex in rat cuneate nucleus in vitro.

Some pharmacological properties of the GABAA receptor complex in the rat cuneate nucleus slice have been assessed from depolarization responses to the gamma-aminobutyric acid (GABA) analogue muscimol and antagonism of the responses by bicuculline and picrotoxin. Responses to muscimol were potentiated by the following drugs, in descending order of potency with regard to the concentrations required in the Krebs medium: (+/-)-5-(1,3-dimethylbutyl)-5-ethylbarbituric acid [+/-)-DMBB) = (+/-)-quinalbarbitone = (+/-)-pentobarbitone greater than (+/-)-methyl-phenobarbitone = (-)-methylphenobarbitone greater than butobarbitone = chlormethiazole greater than phenobarbitone greater than barbitone = (+)-methylphenobarbitone. Primidone and phenylethylmalonamide were inactive. Calculation of the concentrations likely to be present in membrane lipids for equal potentiations of muscimol revealed little difference between quinalbarbitone, pentobarbitone, phenobarbitone and barbitone. The effect of picrotoxin as a muscimol antagonist was selectively reduced only by DMBB, chlormethiazole, phenobarbitone and (-)-methylphenobarbitone in concentrations that caused only a modest potentiation of muscimol. It is suggested that a specific site of action in the GABAA receptor complex is involved in the reduction of picrotoxin effect and that this may be relevant to the anticonvulsant properties of chlormethiazole, phenobarbitone and (-)-methylphenobarbitone. The potentiation of muscimol by chlormethiazole and the barbiturates in general involves a distinctly different site that is less selective and this may underlie the hypnotic properties of these drugs.