Disruption of mitochondrial function and cellular ATP levels by amiodarone and N-desethylamiodarone in initiation of amiodarone-induced pulmonary cytotoxicity.

Amiodarone (AM), a potent antidysrhythmic agent, can cause potentially life-threatening pulmonary fibrosis. In the present investigation of mechanisms of initiation of AM lung toxicity, we found that 100 microM AM decreased mitochondrial membrane potential in intact hamster lung alveolar macrophages and preparations enriched in isolated alveolar type II cells and nonciliated bronchiolar epithelial (Clara) cells, following 2 h of incubation. This was followed by a drop in cellular ATP content (by 32--77%) at 4 to 6 h, and 30 to 55% loss of viability at 24 h. Supplementation of incubation media with 5.0 mM glucose or 2.0 mM niacin did not reduce AM-induced ATP depletion or cell death in macrophages, and the mitochondrial permeability transition inhibitor cyclosporin A (1.0 microM) did not affect AM cytotoxicity. At 50 microM, the AM metabolite N-desethylamiodarone (DEA) produced effects similar to those of AM, but more rapidly and extensively, with the Clara cell-enriched preparation being particularly susceptible. In isolated whole lung mitochondria, DEA was accumulated to a greater extent than AM. Both AM and DEA inhibited complex I- and complex II-supported respiration, but DEA inhibited complex II to a greater degree than AM. These results demonstrate that AM and DEA disrupt mitochondrial membrane potential prior to ATP depletion and subsequent lung cell death, that DEA is more potent than AM, and that the mitochondrial permeability transition is not involved in mitochondrial perturbation by AM. This suggests that AM- and DEA-induced perturbations of mitochondrial function may initiate AM-induced pulmonary toxicity.

Heme oxygenase activity in term human placenta.

Carbon monoxide (CO) is a novel gaseous chemical messenger, formed during heme oxygenase (HO)-catalysed oxidation of heme. CO is proposed to play a key role(s) in cell function in many organ systems, including vasodilator action in the cardiovascular system. Recently, it has been demonstrated that there is expression of HO protein in the human placenta and this appears to have a regulatory role in placental perfusion. The objective of the present study was to determine HO enzymatic activity in vitro in five different regions of term human placenta. HO activity was determined in the microsomal fraction of tissue homogenate by measuring the rate of formation of CO from heme, using a gas-chromatographic method. HO activity, expressed as nmol CO formed/g tissue wet weight/h, was higher (P< 0.05) in the chorionic plate, chorionic villi, basal plate and chorio-decidua compared with the amnion. The finding that HO enzymatic activity is present in different regions of term human placenta supports the concept that the heme-CO (HO) pathway plays a complementary role with the L -arginine-nitric oxide (nitric oxide synthase) pathway in the regulation of placental haemodynamics.

Severe hypoglycemia as a presenting symptom of carbohydrate-deficient glycoprotein syndrome.

We describe clinical, biochemical, and molecular findings in a 2(1/2)-year-old girl with a phosphomannose isomerase deficiency who presented with severe and persistent hypoglycemia and subsequently developed protein-losing enteropathy, liver disease, and coagulopathy. Six months of therapy with mannose supplementation resulted in clinical improvement and partial correction of biochemical abnormalities.

Effects of dietary vitamin E supplementation on pulmonary morphology and collagen deposition in amiodarone- and vehicle-treated hamsters.

Amiodarone (AM) is a potent antidysrhythmic agent that is limited in clinical use by its adverse effects, including potentially life-threatening AM-induced pulmonary toxicity (AIPT). The present study tested the ability of dietary supplementation with vitamin E (500 IU d,1-alpha-tocopherol acetate/kg chow) to protect against pulmonary damage following intratracheal administration of AM (1.83 micromol) to the male golden Syrian hamster. At 21 days post-dosing, animals treated with AM had increased lung hydroxyproline content and histological disease index values compared to control (P < 0.05), which were indicative of fibrosis. Dietary vitamin E supplementation for 6 weeks resulted in a 234% increase in lung vitamin E content at the time of AM dosing, and maintenance on the diet prevented AM-induced elevation of hydroxyproline content and disease index 21 days post-dosing. Dietary vitamin E supplementation also decreased hydroxyproline content and disease index values in hamsters treated intratracheally with distilled water, the AM vehicle. These results demonstrate a protective role for vitamin E in an in vivo model of AIPT, and suggest that this antioxidant may have non-specific antifibrotic effects in the lung.

Use of nitroglycerin for uterine relaxation.

Data from human and experimental animal research indicate that nitric oxide (NO), a novel messenger, formed during the nitric oxide synthase-catalyzed oxidation of L-arginine to L-citrulline, is involved in maintaining normal uterine tone during gestation. There are demonstrated and potential benefits of manipulating the L-arginine-NO system during pregnancy. Several recent case reports and case series have described the effective use of nitroglycerin (GTN), a NO donor compound, antenatally, intrapartum, and postpartum for acute uterine relaxation. Therapeutic indications for GTN range from facilitating external cephalic version, difficult vaginal or cesarean section delivery, and manual exploration of the uterus, to its use as a tocolytic. The intravenous regimen of GTN required to obtain the desired degree of uterine relaxation is extremely variable; intravenous bolus doses of 50 micrograms to 500 micrograms GTN with up to three repeated injections of 50 micrograms to 250 micrograms have been reported. Other methods of GTN administration include transdermal patches and sublingual spray. GTN, when used in low doses, may provide safe and effective uterine relaxation with no clinically apparent fetal or maternal adverse effects. However, clinical trials with use of objective methods of evaluating uterine tone and comparing GTN to other tocolytic agents are required before widespread use in advocated.

Ontogeny of heme oxygenase activity in the hippocampus, frontal cerebral cortex, and cerebellum of the guinea pig.

Heme oxygenase (HO) catalyzes the oxidation of heme to produce carbon monoxide (CO), biliverdin and iron. CO is considered to function as a novel neuronal messenger in the brain analogous to nitric oxide. The ontogeny of microsomal HO activity in the hippocampus, frontal cerebral cortex, and cerebellum of the immature fetal, mature fetal and adult guinea pig was determined using an optimized assay which quantitated heme-derived CO formation by a gas chromatographic method. There was a distinct developmental profile of HO activity that was similar for all three brain regions. In particular, HO activity was maximal in the mature fetus compared with the immature fetus and the adult. These data demonstrate that HO activity is developmentally regulated and that there is similar ontogeny of HO activity in the hippocampus, frontal cerebral cortex, and cerebellum of the guinea pig.

Selenium status in patients receiving home parenteral nutrition.

Selenium (Se) status was evaluated in patients with intestinal failure requiring home parenteral nutrition (HPN). Ninety-two percent of patients (11 of 12) studied just prior to starting HPN had low serum Se values, and the mean value was 42 ng/ml, significantly less than mean values in disease controls with Crohn's disease not on HPN (76 ng/ml) and healthy controls (88 ng/ml). Eighty-five percent of patients (22 of 26) already on HPN for 2 to 109 months when studied had low serum Se levels (mean 38.4 ng/ml). The mean 24-hr urinary Se values were 3.7 micrograms in patients on HPN who did not have Crohn's disease, 10.9 micrograms in HPN patients with Crohn's, and 17.9 micrograms in healthy controls. In patients with Crohn's disease on HPN, a significant direct correlation existed between serum Se and the activity of whole blood glutathione peroxidase, a selenoprotein ; and a significant inverse correlation was found between serum Se and months of HPN. This study confirms that Se deficiency is very common in patients before starting and during HPN. These data and recent reports of cardiomyopathies associated with Se deficiencies in patients on HPN increase the importance of proper Se replacement and maintenance.

Selenium deficiency and fatal cardiomyopathy in a patient on home parenteral nutrition.

An adult patient with chronic idiopathic intestinal pseudo-obstruction maintained on home parenteral nutrition for 6 consecutive years died from cardiomyopathy and ventricular fibrillation. Postmortem examination of the heart revealed widespread myocytolysis and replacement fibrosis similar to that seen in the selenium deficient cardiomyopathy in China (Keshan disease) and animal models. Selenium deficiency in this patient was documented with extremely low concentrations of selenium and decreased activity of the selenoprotein, glutathione peroxidase, in blood, heart, liver, and skeletal muscle. Reports of selenium deficient diets causing myocardial damage in humans and animals and the findings in our patient strongly suggest that his fatal cardiomyopathy was caused by selenium deficiency.