Effects of chronic nitric oxide synthase inhibition on responses to acute exercise in swine.

Nitric oxide (NO) is potentially involved in several responses to acute exercise. We tested the hypotheses that inhibition of NO formation reduces maximal O(2) delivery to muscle, but does not affect O(2) utilization by muscle, therefore lowering maximal O(2) consumption. To test these hypotheses, swine (approximately 30 kg) drank either tap water (Con, n = 25) or water with N(G)-nitro-l-arginine methyl ester (8.0 +/- 0.4 mg x kg(-1) x day(-1) for >or=4 wk; LN, n = 24). Treatment efficacy was reflected by higher mean arterial pressure and lower plasma NO metabolite concentration in LN than Con (both P < 0.05). Swine completed two graded treadmill running tests to maximum. In the first test, O(2) consumption was determined at rest through maximal exercise intensity. O(2) consumption did not differ between groups at rest or at most exercise intensities, including maximum (Con, 40.8 +/- 1.8 ml x min(-1) x kg(-1); LN, 40.4 +/- 2.9; not significant). In the second test, tissue-specific blood flows were determined using the radiolabeled-microsphere technique. At rest, blood flows were lower (P < 0.05) in LN compared with Con for a number of tissues, including kidney, adrenal, lung, and several skeletal muscles. During both submaximal and maximal exercise, however, blood flows were similar between Con and LN for all 16 muscles examined; only blood flows to kidney (Con, 99 +/- 16 ml x min(-1) x 100 g; LN, 55 +/- 15; P < 0.05) and pancreas (Con, 25 +/- 7; LN, 6 +/- 2; P < 0.05) were lower in LN at maximum. Endothelium-dependent, but not -independent, relaxation of renal arterial segments was reduced (P < 0.05) in vitro. These data indicate that exercise-induced increases in muscle blood flows are maintained with chronic inhibition of NO formation and that maximal O(2) consumption is therefore preserved. Redundant vasodilatory pathways and/or upregulation of these pathways may underlie these findings.     

Pyruvate and ethanol as electron donors for nitrite reduction by Escherichia coli K12

Pyruvate and ethanol were both effective electron donors for nitrite reduction by Escherichia coli K12. The pyruvate-dependent rate decreased by approximately 50% when either a cysG mutation, which results in loss of NADH-dependent nitrite reductase activity (EC 1.6.6.4), or a chl mutation, which results in loss of the formate-nitrite oxidoreductase activity, was introduced into the prototrophic parental strain CGSC4315. A double mutant deficient in both of these previously described activities retained only 2% of the rate of nitrite reduction of the parental strain after growth on glucose or 5% after growth on pyruvate. We conclude that any third pathway for nitrite reduction contributes little to the in vivo rate of nitrite reduction by wild-type strains.     

Poly(DL-lactide-co-glycolide)/norethisterone microcapsules: an injectable biodegradable contraceptive

Microcapsules made from a biocompatible, biodegradable polymeric excipient, poly(DL-lactide-co-glycolide) (DL-PLGA) that contained 22 weight percent (wt %) norethisterone (NET), were prepared by a solvent-evaporation microencapsulation process. The effects of changing both the lactide-to-glycolide ratio of the DL-PLGA and the size of the microcapsules on the rate of NET release and the rate of excipient biodegradation were determined in vivo. NET release rates were determined in baboons after injecting the microcapsule formulations intramuscularly. Serum samples obtained at various times following treatment were analyzed for NET, progesterone, and estrogen by radioimmunoassay (RIA). Biodegradation kinetics were determined by injecting NET microcapsules made from radiolabeled DL-PLGA intramuscularly into the hind legs of rats. Residual radioactivity at the injection site was determined at various times after treatment by combustion analysis of the muscle tissue. Changing the ratio of the comonomers to include more glycolide (DL-lactide:glycolide-96:4, 92:8, 87:13, 74:26) increased the rate of NET release and accelerated the biodegradation of the copolymer excipient. Decreasing the size of the microcapsules increased the rate of NET release. On the basis of these studies a NET microcapsule formulation has been identified for clinical testing which releases NET for 3 months and biodegrades completely within 6 months.     

Activation of suppressor T cells by low-molecular-weight factors secreted by spleen cells from tumor-bearing mice

The spleens of mice bearing large M-1 fibrosarcomas have been shown to contain several populations of cells which nonspecifically suppress antibody synthesis by cocultured normal spleen cells. It has now been shown that the spleens of tumor-bearing mice also contain inducer cells which secrete soluble factors capable of activating suppressor T cells from unprimed precursor cells. The activated suppressor cells are Thy 1+, Lyt 1+2+ and secrete a soluble suppressive factor. They inhibit the in vitro generation of antibody-forming cells by cocultured normal spleen cells stimulated by T-cell-dependent antigens. They do not, however, suppress the antibody response to T-cell-independent antigens and do not inhibit antibody synthesis by cocultured nude mouse spleen cells cultured with T-cell-dependent antigens and exogenous helper factors. In addition, suppression is blocked if conditioned medium containing T-cell growth factors is added to the suppressor cell assays. These data suggest that cells in the spleens of tumor-bearing mice secrete inducing factors which activate suppressor cells. These activated suppressor cells in turn secrete soluble suppressor factors which inhibit antibody synthesis, possibly by interfering with the synthesis or release of T-cell growth factors.