Free fatty acids accumulate in plant membranes after exposure of plants to environmental stress, such as freezing and desiccation. Fatty acid accumulation has been linked to various biophysical changes and to the occurrence of lipid peroxidation, but the relationships appear complex and inconsistent. The interactions between oxygen free radicals, free fatty acids and lipid peroxidation in plant membranes were examined further by studying peroxidation reactions in a model membrane system composed of a complex mixture of plant phospholipids, including various free fatty acids. Multilamellar liposomes were treated with oxygen free radicals generated from iron ascorbate. Increased concentrations of free palmitic acid up to 10 mol% (fatty acid/phospholipid) reduced the production of aldehydes detected by the thiobarbituric acid assay, but enhanced the production of fluorescent products. By contrast, increased concentrations of free linolenic acid increased aldehyde production and reduced the formation of fluorescent products. The two free fatty acids both enhanced the susceptibility of phospholipids to degradation as shown by the reduced recovery of esterified polyunsaturated fatty acids (linoleic and linolenic). The free radical reactions with or without free fatty acid additions catalyzed the selective degradation of phospholipids in the order phosphatidylethanolamine > phosphatidylcholine > phosphatidylinositol > phosphatidylglycerol. Selective degradation of phospholipids is often observed after periods of environmental stress or during senescence of plants, and has been cited as evidence for the involvement of phospholipases in these degenerative processes. The results indicate that selectivity is not a criterion for eliminating the involvement of oxygen free radicals in these degenerative processes. Furthermore, the results suggest that modifications of lipid composition during a plant's acclimation to adverse environments may determine the types of free radical reactions that occur due to stress.

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Diltiazem (DTZ) is a calcium antagonist widely used in the treatment of angina and hypertension. It is extensively metabolized in humans via N-demethylation, O-demethylation, deacetylation, and oxidative deamination, yielding a host of metabolites, some of which have potent pharmacological properties. After our initial identification of O-desmethyl DTZ (Mx) and N,O-didesmethyl DTZ (MB) as major metabolites of DTZ and our subsequent of identification of their chemical synthesis, an improved high-performance liquid chromatography assay was developed to determine the plasma concentrations of DTZ and seven of its major basic metabolites, including the previously unquantitated Mx and MB. The system consisted of a C18 analytical column protected by a C18 cartridge guard column and a variable wavelength ultraviolet detector set at 237 nm. The mobile phase was a mixture of methanol, 0.04 M ammonium acetate, and acetonitrile (38:36:26) containing 0.08% triethylamine, with final pH of the mobile phase adjusted to 7.5. The system was operated at room temperature isocratically at a flow rate of 1.2 ml/min. Using verapamil as an internal standard, DTZ and the basic metabolites in plasma were determined in young healthy volunteers (n = 21) and in patients with ischemic heart disease (n = 19) at steady state after repeated oral doses of 60 mg DTZ four times daily. Preliminary results show that steady-state plasma concentrations of DTZ and its metabolites were higher in the older patients than in young healthy subjects (p < 0.05).

To determine the clinical effect of diltiazem on the metabolism of adenosine, and its importance in ischemic heart disease, arterial plasma concentrations of the purine metabolites were determined in 21 healthy volunteers (10 female and 11 male) and 19 patients with effort angina (8 female and 11 male) before, during, and immediately after standard treadmill exercise tests conducted before and after they had taken 60 mg diltiazem (Cardizem; Hoechst Marion Roussel, Laval, QC, Canada) four times a day for 1 week. The results showed that the cardiac patients had significantly lower mean plasma concentrations of uric acid (46.82 +/- 25.51 versus 95.47 +/- 35.41 micrograms/ml, p 0.05), inosine (0.25 +/- 0.19 versus 0.84 +/- 0.17 microgram/ml, p < 0.05), and hypoxanthine (0.28 +/- 0.35 versus 0.50 +/- 0.27 microgram/ml, p < 0.05). Diltiazem decreased the mean resting plasma concentrations of uric acid in patients (uric acid 43.47 +/- 22.26 versus 46.82 +/- 25.51 micrograms/ml, p < 0.05) and healthy volunteers (uric acid 85.68 +/- 26.71 versus 95.47 +/- 35.41 micrograms/ml, p < 0.05). There was no statistically significant change in the plasma concentrations of the purine metabolites during exercise (p < 0.05). Female subjects had significantly lower plasma concentrations of uric acid than males (patients, 34.87 +/- 26.93 versus 55.78 +/- 21.25 micrograms/ml; healthy volunteers, 84.79 +/- 32.07 versus 104.22 +/- 37.05 micrograms/ml; p < 0.05 for both). Results of the study suggest that normal therapeutic doses of diltiazem may modulate the metabolism of adenosine and that some of the purine metabolites may be useful markers for specific types of ischemic heart disease.