Cellular adverse actions of dibromoacetonitrile, a by-product in water bacterial control, at sublethal levels in rat thymocytes.

The aim of this study was to investigate the effects of dibromoacetonitrile (DBAN), a by-product in water bacterial control, at sublethal concentrations on rat thymocytes, by using a cytometric technique with appropriate fluorescent dyes. By using this method, the possibility that DBAN induces cellular actions related to oxidative stress was assessed. DBAN reduced the content of cellular nonprotein thiols under Zn2+-free conditions. It elevated the intracellular level of Zn2+, being independent from external Zn2+. DBAN increased cell vulnerability to the cytotoxic action of hydrogen peroxide. These actions of DBAN were likely related to oxidative stress. DBAN is formed by the reaction of bromides and chlorinated oxidants during water disinfection. Hydrolysis of 2,2-dibromo-3-nitrilopropionamide, an antimicrobial used in hydraulic fracturing fluids for production of shale gas and oil, produces DBAN. Therefore, the concern regarding the levels of DBAN in industrial water systems is necessary to avoid the environmental risk to humans and wild mammals.

Hydroxyhydroquinone, a by-product of coffee bean roasting, increases intracellular Ca2+ concentration in rat thymic lymphocytes.

Hydroxyhydroquinone (HHQ) is generated during coffee bean roasting. A cup of coffee contains 0.1-1.7 mg of HHQ. The actions of HHQ on mammalian DNA were examined because HHQ is a metabolite of benzene, which causes leukemia. Currently, information on the cellular actions of HHQ is limited. We examined the effects of sublethal levels of HHQ on the concentration of intracellular Ca2+ in rat thymic lymphocytes by using a flow cytometric technique with fluorescent probes. HHQ at 10 µM or more significantly elevated intracellular Ca2+ levels by increasing the membrane permeability of divalent cations, resulting in hyperpolarization via the activation of Ca2+-dependent K+ channels. HHQ-induced changes in the intracellular Ca2+ concentration and membrane potential may affect the cell functions of lymphocytes. HHQ-reduced coffee may be preferable in order to avoid the possible adverse effects of HHQ.

Selective endothelin ET(B) receptor antagonist improves left ventricular function but exaggerates degeneration of cardiomyocytes in J2N-k hamsters.

BACKGROUND: Endothelin-1 (ET-1) receptor antagonist is expected to improve the prognosis of patients with heart failure, but the role of the ET(B) receptor in cardiac function and structure is complicated. In the present study the NADPH diaphorase activity and ET-1 content in the failing heart treated with ET(A) or ET(B) receptor antagonist were evaluated in a model of dilated cardiomyopathy. METHODS AND RESULTS: Selective ET(A) receptor antagonist, ABT-627 (10 mg/kg per day), or selective ET(B) antagonist, A-192621 (30 mg/kg per day), was given to 22-week-old J2N-k cardiomyopathic hamsters for 8 weeks. The effects of ABT-627 and A-192621 on cardiac function, left ventricular (LV) histology, ET-1 content and NADPH diaphorase activity in the LV were evaluated. Treatment with ABT-627, but not A-192621, significantly decreased ET-1 content and NADPH diaphorase activity. Although the improvement of LV function was modest, ABT-627 prevented tissue damage in J2N-k hamsters. In contrast, A-192621 worsened the degeneration of cardiomyocytes despite improving hemodynamic parameters. CONCLUSIONS: Selective ET(A) antagonist, but not ET(B) antagonist, reduced the ET-1 content as well as the NADPH diaphorase activity, and preserved the fine structure of LV myocardium in cardiomyopathic hamsters. Long-term blockade of ET(B) receptor might worsen the degeneration of cardiomyocytes through the ET-1/ET(A) system even if LV function could be improved.

Role of endothelin ETB receptor in the pathogenesis of monocrotaline-induced pulmonary hypertension in rats.

We investigated the role of endothelin ETB receptor in the development of monocrotaline-induced pulmonary hypertension, by using the spotting-lethal (sl) rat, which carries a naturally occurring deletion in the endothelin ETB receptor gene. Three weeks after injection of saline or monocrotaline (60 mg/kg, s.c.), hemodynamics, cardiac hypertrophy and endothelin-1 levels in right ventricle were determined. Monocrotaline produced a marked pulmonary hypertension associated with increases in right ventricular pressure and hypertrophy, pulmonary arterial medial thickening and the endothelin-1 levels. The monocrotaline-induced alterations tended to be enhanced in ETB-deficient homozygous rats, compared with cases in wild-type rats. The treatment with selective ETA receptor antagonist ABT-627 [2R-(4-methoxyphenyl)-4S-(1,3-benzodioxol-5-yl)-1-(N,N-di(n-butyl)aminocarbonyl-methyl)-pyrrolidine-3R-carboxylic acid] for 3 weeks (10 mg/kg/day, twice daily) almost completely suppressed the monocrotaline-induced pulmonary hypertension and related organ damage both in ETB-deficient and wild-type animals to the same levels. Thus, we suggest that the antagonism of the ETA receptor is essential for the protection from monocrotaline-induced pulmonary hypertension, irrespective of the presence of the ETB receptors, although a protective role of ETB receptor-mediated action in the pathogenesis of this disease model cannot be ruled out.