Vasomotor tone and the role of nitric oxide.

Vasomotor tone is the end result of a complex set of interactions that control relaxation and contraction of blood vessels. The critical role of nitric oxide (NO) in modulating vasomotor tone has become increasingly apparent over the last 15 years. A phenomenal amount of resources have been invested in the study of this simple molecule, and the volume of scientific literature that has resulted is astounding. In this review, we discuss the pertinent physiology and biochemistry of NO as it relates to the control of vasomotor tone. Methods of measuring NO in basic science and clinical settings are outlined, and the derangements of endothelial NO production and release (endothelial dysfunction) in pathophysiologic and disease states are discussed. Finally, potential therapies aimed at preserving endothelial function and augmenting NO production also are reviewed.

Evidence for superoxide formation during hepatic metabolism of tamoxifen.

Spin trapping of free radicals during the hepatic metabolism of tamoxifen was investigated; the spin trap employed in this study was 5,5-dimethyl-1-pyrroline-1-oxide (DMPO). The spin adduct 2-hydroxy-5,5-dimethyl-1-pyrrolidinyloxyl (DMPO-OH) was detected in an in vitro incubation mixture of phenobarbital-treated rat hepatocytes containing tamoxifen, dimethyl sulfoxide, and DMPO. However, since the spin adduct 2,5,5-trimethyl-1-pyrrolidinyloxyl (DMPO-CH3) was not observed, the DMPO-OH resulted from the cellular bioreduction of 2-hydroperoxy-5,5-dimethyl-1-pyrrolidinyloxyl (DMPO-OOH) by glutathione peroxidase. Addition of superoxide dismutase (SOD) to the in vitro system indicated that superoxide production was intracellular. When noninduced hepatocytes were utilized, free radical production was not evident. Thus, the cytochrome P450 monooxygenase system was responsible, in part, for the intermediacy of superoxide anion during hepatic metabolism.

Detection of free radicals during the cellular metabolism of adriamycin.

Experiments were conducted to determine which free radicals are generated during the metabolism of adriamycin (ADM) by canine tracheal epithelial (CTE) cells, guinea pig enterocytes, and rat hepatocytes. The technique employed in this study was spin trapping; the spin trap utilized was 5,5-dimethyl-1-pyrroline-1-oxide (DMPO). The spin adduct 2-hydroxy-5,5-dimethyl-1-pyrrolidinyloxyl (DMPO-OH) was observed during the metabolism of ADM by CTE cells. However, the addition of dimethyl sulfoxide to the in vitro system suggested that superoxide is initially spin trapped by the nitrone, and that the adduct 2-hydroperoxy-5,5-dimethyl-1-pyrrolidinyloxyl (DMPO-OOH) is rapidly bioreduced to afford DMPO-OH. The addition of superoxide dismutase to the system indicated that superoxide generation was primarily intracellular. The adriamycin semiquinone free radical (ADM-SQ) was produced during the metabolism by enterocytes and hepatocytes. The rate of the production of ADM-SQ was enhanced under anaerobic conditions, suggesting that molecular oxygen was responsible for the degradation of this carbon-centered free radical. However, spin trapping of oxygen radicals was not observed; this observation suggests that these reactive intermediates are not produced at concentrations sufficient for detection by spin-trapping experiments.