Even though dimethylthiourea (DMTU) effectively scavenges O2 metabolites in vitro, it is often unclear if scavenging of O2 metabolites is the mechanism by which DMTU decreases tissue injury in biological models. Since DMTU not only scavenges O2 metabolites but is also consumed in a dose-response manner following reaction with hydrogen peroxide (H2O2) in vitro, we wondered whether DMTU would also be consumed by O2 metabolites in biological systems and if DMTU consumption would then reflect O2 metabolite concentrations and O2 metabolite-mediated injury. Our results supported this possibility. We found that selected nonprotecting concentrations of DMTU were consumed in isolated rat lungs perfused with H2O2 and that the amounts of DMTU consumed reflected both the added amounts of H2O2 and the corresponding degrees of H2O2-induced acute edematous injury. DMTU consumption was relatively specific for reaction with H2O2 occurring in isolated lungs that were injured by H2O2 but not lungs injured by elastase, oleic acid, histamine, or a venous pressure challenge. Our results suggest that measurement of DMTU consumption may be useful for assessing the presence and toxicity of O2 metabolites and the specificity of the protective effects of DMTU in biological systems.

We examined exercise-induced changes in indicator-dilution estimates of the angiotensin-converting enzyme first-order kinetic parameter, the ratio of a normalized maximal enzymatic conversion rate to the Michaelis constant (Amax/Km), which, under stable enzymatic conditions, will vary with the pulmonary vascular surface area accessible to vascular substrate, the extravascular lung water (an index of the proportion of lung tissue perfused), and the central blood volume (from pulmonary trunk to aorta). Experiments were performed in 10 mongrel dogs at rest and through two increasing levels of treadmill exercise, with the use of two vascular space tracers (labeled erythrocytes and albumin), a water space tracer ([1,8-14C]-octanediol), and a vascular endothelium surface area marker, benzoyl-Phe-Gly-Pro ([3H]BPGP), which is a pharmacologically inactive angiotensin-converting enzyme substrate. The exercise-induced increase in cardiac output was accompanied by a linear increase in central blood volume, and dilutional extravascular lung water rapidly increased to an asymptotic proportion close to 100% of postmortem vascular lung water. There was an average 55% [3H]BPGP hydrolysis, which did not vary with flow, and the computed Amax/Km increased linearly with exercise. We conclude that exercise results in complete lung tissue recruitment and increases the pulmonary vascular surface area available for BPGP hydrolysis linearly with flow, so that pulmonary vascular recruitment continues after full tissue recruitment.

The lungs metabolize a variety of vasoactive substances, including bradykinin (BK), angiotensin I (AT I), PGE2 and F2α, norepinephrine, 5-HT, 5’-ATP and 5’-AMP. In contrast, the lungs od not metabolize angiotensin II (AT II), PGA2, histamine and epinephrine. Of the substances metabolized, all (with the possible exceptions of the prostaglandins) are processed primarily by the pulmonary endothelial cells. Furthermore, the means by which the substances are processed suggest that endothelial cells determine the vasoactive substances allowed to enter the systemic arterial circulation. BK is inactivated while AT I is converted to its potent homolog, AT II. AT II enters the arterial circulation. The metabolism of BK and AT I may be effected by the same enzyme. Pulmonary endothelial cells are a rich source of thromboplastin, an enzyme capable of degrading BK and AT I. However, the relationship of thromboplastin to the fates of these hormones is not clear : The metabolic products produced are not those produced by intact lungs nor by endothelial cells in culture. In addition, thromboplastin degrades substances (e.g. AT II), which are not degraded by intact lungs. Possibly the extrinsic clotting system plays a role when activated but not under physiologic conditions.

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Isolation of glomeruli was done by microdissection. Tubuli were isolated after "dissociative" treatment with collagenase, according to Guder. (Hoppe-Seyler's 2. PhysioI. Chemie 352,1319Chemie 352, 1971. We observed a linear dose dependency of enzyme in microdissected glomeruli and in isolated tubuli. Enzyme activity of 80 glomeruli was the lowest measurable. 90% in inhibition of Kinin formation was observed by the use of Trasylol. Carboxypeptidase B completey destroyed the uterus contracting material. There was no effect on rat blood pressure even after application of an incubation mixture with high doses of urine glomeruli and tubuli. Renin and Angiotensin II was not detectable. There were several hints of a tubular Iocalisation of renal Kininogenase. Now it is evident, that renal Kininogenase is located in glomeruli as well as in tubuli. Bradykinin has different spectroscopic properties in polar compared to non-polar environments. These spectroscopic differences are assumed to reflect a reorientation of the amide dipoles with respect to each other and with respect to the solvent environment. This assumption is based on analogy with spectroscopic changes known to occur in model polypeptides such as poly-~'-benzyI-L-glutamate in solvents of differingoolarity. Strong evidence has been accumulated from biophysical studies which indicates that the conformations of cyclic depsipeptides differ in polar and non-polar environments and also when complexed with a cation. These transitions have been related to the ion-transport properties of the depsipeptides indicating conformational changes of the depsipeptides upon association with the hydrophobic environment in a membrane. Similarly, the apparent conformation changes of bradykinin associated with the change from polar to non-polar solvents may reflect possible changes involved in its pharmacological effects. In addition we have found that sodium dodecyl sulfate (SDS)induces changes in the circular dichroism (CD) spectrum of bradykinin equivalent to those found in non-polar solvents. SDS in association with proteins has been suggested by Reynolds and Tanford (J. Biol. Chem., 1970, 245, 5161) to provide a model system for studies of the conformational properties of membrane-associated proteins. Analogs of bradykinin where small modification have been carried out on the proline residue in the third position from the cx-amino terminal demonstrate different aqueous CD spectra from the parent