Influence of disodium ethane-1-hydroxy-1,1-diphosphonate on vitamin D metabolism in rats

Summary The metabolism and the organ distribution of double labelled vitamin D₃ (1,2-³H-4-¹⁴C-cholecalciferol) has been studied in rats in which the bone mineralization and the intestinal calcium absorption have been inhibited by a large pose (10 mg P/kg s.c. for 7–14 days) of disodium ethane-1-hydroxy-1,1-diphosphonate (EHDP). The most striking difference found was a reduced accumulation of radioactive cholecalciferol and its metabolites in the kidney of EHDP-treated rats. It is unlikely that this effect was due to an unspecific alteration of the functional renal tissue since blood urea, glomerular filtration rate and renal plasm a flow remained unaltered by this dose of EHDP. The EHDP-treated rats were able to form the metabolite eluted with peak IV of the silicic acid chromatographic system, that is 25-hydroxycholecalciferol. In these vitamin D repleted rats fed a high calcium diet, the tritium deficient metabolite eluted with peak V (1,25-dihydroxycholecalciferol) was only found in the intestinal mucosa of both control and EHDP groups three days after the injection of radioactive cholecalciferol, and this in a very small amount. Therefore no definitive conclusion can be drawn as to a possible interference of EHDP treatment on the production of 1,25-dihydroxycholecalciferol. The change in the renal metabolism of vitamin D in rats treated with a rachitogenic dose of EHDP may be caused by the modifications of the calcium metabolism brought about by the diphosphonate. Its relation, if any, with the decreased calcium absorption remains to be established.     

SKIN POTENTIAL, HEART RATE, AND THE SPAN OF IMMEDIATE MEMORY

Relations between orienting response and span of immediate memory were studied by measuring skin potential responses (SPR) and heart rate (HR). Four conditions were studied by presenting letters in a tachistoscope and a 1000 cycle, 100 db tone simultaneous on some but not all trials. The conditions (15 Ss in each) were: tone and letters for 10 trials, then letters alone for 10 trials; tone and letters for 20 trials; only letters for 10 trials, followed by letters and tone for 10 trials; and only letters for 20 trials. The results showed: (1) positive SPR habituated and negative did not, (2) tone produced more SP activity, (3) HR showed a shift from acceleration to deceleration over 20 trials, but tone had no influence, (4) tone had no direct influence on span scores, (5) Ss showed improvement in number ol letters reported correctly. There was a significant correlation between span and negative SPR when tone was sounded (r =. 36).     

A cooling system for prostaglandin infusions

A simple system has been developed-for the prolonged infusion of an iced solution of prostacyclin (PGI₂). In a 24 h period at pH 10, there is a theoretical loss in activity of 6%, while a 5 h infusion leads to a 2% reduction in activity. The stability of the cooling system was demonstrated in six dog experiments where mean arterial pressure (MAP) was reduced to 58±3.8 Torr (x±SEM) over a 5 h period of infusing 500 ng/kg/min. In a saline medium, at 3°C, a 5 h PGI₂ infusion led to a stable reduction in MAP, whereas, at a temperature of 24°C, a 70 loss of infusate activity was noted. Supported in part by The National Institute of Health, Grant No. GM24891-04; The U.S. Army Medical Research and Development Command, Contract No. DAMD17-78-C-8026; The Brigham Surgical Group, Inc., and The Trauma Research Foundation.     

Changes in the nuclear uptake and retention of 3H-estrogen in gonadotrophs and lactotrophs as a function of age

A quantitative autoradiographic immunocytochemical study was performed in which the nuclear uptake and retention of 3H-estradiol (3H-E2) by luteinizing hormone (LH) and prolactin (PRL) cells was examined in 19-21-year-old baboons. 3H-E2 concentrating cells were found in all of the three lobes of the pituitary in varying percentages (38.7%, pars distalis; 17.1%, pars intermedia; 6.3%, pars nervosa). Approximately 80% of PRL cells and nearly 100% of LH cells were labeled. A count of the number of silver grains over nuclei revealed a marked variation of the accumulation of 3H-E2 by LH cells and to a lesser extent in PRL cells. These results suggest functional heterogeneity among LH and PRL cells. The present results are discussed in relation to the physiological state of old animals.     

Systematic investigations on the reactivity of oxazolinium salts

The termination reaction of the cationic polymerization of 2-phenyl- and 2-nonyl-2-oxazolines was examined by reacting the corresponding model oxazolinium salts having tosylate and trifluoromethansulfonate counterions with various nucleophiles. The reaction was monitored by ¹H NMR spectroscopy. Piperidine and KOH react with the oxazolinium salts very fast and quantitatively. In the case of piperidine, the use of a double molar amount of piperidine is necessary to achieve complete conversion. The addition of piperidine, pyridine, 4-dimethylaminopyridine and morpholine takes place in position 5 of the oxazolinium ring, whereas water and KOH add in position 2. The rate of the termination reaction depends on the electron density of the nucleophile which can be correlated with the pK_a value. With CF₃SO as counterion the addition of nucleophiles in position 5 is distinctly faster, whereas the addition of water in position 2 is much slower than with TsO^? as counterion. The ring-opening of the nonyl oxazolinium ion is slower than that of the phenyl oxazolinium ion.     

Pharmacologic analysis of LY188695 (KB-2413), 1-(2-ethoxyethyl)-2-(4-methyl-1-homopiperazinyl)-benzimidazole difumarate,a potent histamine1 receptor antagonist

LY188695 was evaluated bothin vitro andin vivo in the guinea pig to determine its pharmacologic profile. The compound antagonized histamine-induced contractions of ileum, aorta, and trachea, with pK_B values of 9.9, 9.9, and 9.2 respectively. In the lung parenchymal strip, LY188695 caused a rightward shift of the histamine concentration-response curve with a reduction in the maximal response at all antagonist concentrations tested. The reason for this effect is unknown, but it was not due to a nonspecific depressant action of the compound on the parenchyma. Selectivity was shown by its inactivity against leukotriene D₄, bradykinin, prostaglandin F₂, acetylcholine, norepinephrine, and serotonin on various guinea pig and rat smooth muscles. Similary, H₂ receptor-mediated relaxation of the rat uterus was unaltered by LY188695. Increases in total pulmonary impedance caused by i.v. histamine to anesthetized guinea pigs were reduced by as little as 3 g/kg given orally 1 hour prior to histamine challenge. In this system, LY188695 was 15 times more potent than chloropheniramine and 100 times more potent than terfenadine. Similar responses elicited by acetylcholine were not antagonized by LY188695. A duration of action greater than 4 hours was observed in this model. Ovalbumin given i.v. to sensitized guinea pigs increased total pulmonary impedance which was markedly decreased after oral administration of 30 or 100 g/kg LY188695. These results indicate that LY188695 is a very potent antagonist of H₁-mediated responses and suggest that this agent might be useful in disease states characterized by an overproduction of histamine.Presented in part at the Joint Meeting of the American Society for Pharmacology and Experimental Therapeutics and the Society of Toxicology in Baltimore, Maryland, August, 1986.     

Stress and dental caries in the rat

The stress of crowding and exposure to inescapable electric shock increased both the incidence and the severity of dental caries in rats housed in a conventional animal facility. Male Osborne-Mendel rats were inoculated intraorally with cariogenic bacteria, fed a high-sucrose diet, and housed in either a conventional or a sheltered facility. Rats in both housing conditions were subdivided into control and stress groups. At the end of the 56-day trial period, stressed rats from conventional housing had a significant increase in both incidence and severity of dental caries in comparison to their controls. In contrast, stressed rats from sheltered housing had a trend toward increased cariogenesis which reached significance in only one of five scores. These rats also failed to gain weight comparable to their controls, making it possible that stress-induced reduction in appetite partially offset stress-induced exacerbation in cariogenesis.This investigation was supported in part by the following Grants from the United States Public Health Service: CA 20093, HL 22727, and HL 07374.