The effects of sodium cyanide (NaCN) were investigated on the contractile and electrophysiological properties of rat diaphragm muscles in vitro. Sodium cyanide (0.1-1.0 mM) produced an initial potentiation of directly elicited twitch tensions, followed by a slow progressive depression. The potentiation and depression were both dependent on the NaCN concentration and stimulation frequency. Muscles exposed to NaCN exhibited marked reductions of creatine phosphate concentration, but ATP levels were not significantly lowered. Sodium cyanide had no effect on the resting potential, input resistance or action potential, indicating that the toxicity of the metabolic inhibitor is not mediated by alterations of membrane excitability or passive electrical properties. Sodium cyanide reduced the amplitude of contractures elicited by 70 mM K(2)SO(4), suggesting that the actions of NaCN cannot be explained by a failure of action potentials to propagate across the muscle surface or within t-tubular membranes. Sodium cyanide suppressed the first phase of the caffeine contracture, an observation consistent with an impaired release of, or reduced sensitivity to, sarcoplasmic reticular Ca(2+), but did not alter the amplitude of the second phase, which represents rigor following ATP depletion. These results, in conjunction with those of previous studies, suggest that the depression in muscle tension following exposure to NaCN may result from alterations in Ca(2+) homeostasis, intracellular acidosis or from accumulation of one or more products of phosphocreatine breakdown.

Acidosis↗

PubMedDate not supplied

Sublobular compartmentation of pharmacologic events (SCOPE): metabolic fluxes in periportal and pericentral regions of the liver lobule.

New techniques have been developed employing microlight guides and miniature O2 electrodes which permit metabolic events to be studied noninvasively in periportal and pericentral zones of the liver lobule. These events include O2 uptake, fat and carbohydrate metabolism, monooxygenation and glucuronidation. The lobular distribution of maximal enzyme activities measured by immunohistochemical or microchemical techniques does not always correlate with metabolic flux rates as measured in periportal and pericentral regions with the new noninvasive methods. The region of the liver lobule exhibiting highest metabolic flux rates can be shifted to another region of the lobule by changing the direction of flow from anterograde to retrograde. These data are consistent with the hypothesis that many metabolic pathways (e.g., oxygen, carbohydrate and fat metabolism which are under dynamic short-term regulation) operate below maximal velocity in intact hepatocytes.

Animals↗

PubMedDate not supplied

Sublobular distribution of transferases and hydrolases associated with glucuronide, sulfate and glutathione conjugation in human liver.

Activities of glucuronosyltransferase, sulfotransferase, glutathione S-transferase, beta-glucuronidase and sulfatase were determined in microdissected samples of periportal and pericentral sublobular regions from four human livers obtained at immediate autopsy. New methods are presented for the microdetermination of sulfotransferase and sulfatase activities in microdissected samples weighing 0.1 to 4 micrograms dry weight using umbelliferone and 4-methylumbelliferone sulfate as substrates. The three transferases were distributed heterogeneously across the liver lobule. Glucuronosyltransferase and glutathione S-transferase were localized predominantly in pericentral regions. In contrast, sulfotransferase activity was greater in periportal than pericentral regions. Average activities for glucuronosyltransferase and sulfotransferase were 23, and 50 mumoles X gm dry wt-1 X hr-1, respectively, in periportal regions, and 34 and 38 mumoles X gm dry st-1 X hr-1, respectively, in pericentral regions. Activities of glutathione S-transferase were considerably higher than those of the other transferases and were 8.3 mmoles X gm dry wt-1 X hr-1 in periportal areas and 12.2 mmoles X gm dry wt-1 hr-1 in pericentral areas. The two hydrolases studied, beta-glucuronidase and sulfatase, were evenly distributed across the liver lobule. The presence of significant hydrolase and transferase activities in both zones of the liver lobule supports the idea that net production of both sulfate and glucuronide conjugates may be influenced by futile cycling of conjugation-deconjugation reactions in both zones of the liver. Based on enhanced formation of sulfate but not glucuronide conjugates in homogenates of human liver treated with inhibitors of the hydrolases, it is suggested that futile cycling is more pertinent to the regulation of sulfation than glucuronidation.

Adolescent↗

PubMedDate not supplied

Role of Kupffer cells in storage and metabolism of benzo(a)pyrene in the liver.

This study investigates the possible role of Kupffer cells in storage and metabolism of benzo(a)pyrene in the liver. In perfused liver, benzo(a)pyrene (4-120 microM) in 0.3% albumin increased fluorescence (366-->405 mm) on the liver surface in a dose-dependent manner, suggesting that it accumulated in liver tissue. The maximal increase of benzo(a)pyrene fluorescence was diminished by 60% when Kupffer cells were destroyed by gadolinium chloride treatment (10 mg/kg iv). Gadolinium chloride also decreased the yield of isolated nonparenchymal cells by 65%. In frozen sections of livers perfused with 4 microM benzo(a)pyrene for 1 hr, fluorescence was approximately 5 times greater in cells lining the sinusoids than in parenchymal cells. Moreover, yellow-green fluorescent particles were detected in cultured Kupffer cells, but were barely visible in parenchymal and Ito cells, indicating that Kupffer cells actively accumulated benzo(a)pyrene. In contrast to the cell specificity for benzo(a)pyrene accumulation, rates of monooxygenation of benzo(a)pyrene were up to 20-fold higher in isolated parenchymal than in Kupffer cells. In nonparenchymal cells, basal rates of production of benzo(a)pyrene phenols were approximately 50 pmol/10(6) cells/hr. In contrast, rates were approximately 335 pmol/10(6) cells/hr in parenchymal cells. Further, total [3H]benzo(a)pyrene metabolism was approximately 8-fold higher in parenchymal than in nonparenchymal cells. Albumin increased production of benzo(a)pyrene phenols by 3-fold in parenchymal cells, but was without effect in nonparenchymal cells. Pretreatment of rats with gadolinium chloride increased the production of benzo(a)pyrene phenols in perfused liver by > 50%.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗