SummaryTo elucidate the mechanisms triggering disseminated intravascular coagulation (DIC) in shock, acidosis was produced in dogs by intravenous infusions of lactic acid over a period of 4 h. As the pH of the blood dropped, the blood pressure increased and the heart rate fell. The platelet counts dropped and whole blood clotting times shortened. The partial thromboplastin times and prothrombin times decreased as did the r-times and maximal amplitudes of the thrombelastograms. Simultaneously, the levels of prothrombin, fibrinogen, factors V and VIII decreased with time in acidosis. There was no evidence of a systemic activation of the fibrinolytic system. The euglobulin lysis times increased as did the thrombin times and there was no lysis observed in the thrombelastograms.Thrombi in the lungs, liver, spleen and kidneys, together with the coagulation changes indicated that the infusion of acid produced DIC, with the changes being similar to those produced in shock. The glomeruli were especially affected and the pictures were identical to those described in kidneys of animals having experienced a generalized Sanarelli-Shwartzman phenomenon.A pH value of 7.20 or lower appeared to be a potent trigger of intravascular coagulation. The lower the pH, the more thrombi were found in the tissues. The consumption of clotting factors and thrombus formation thus corresponded to the degree of acidosis.A generalized fibrinolytic state was induced using Streptokinase, after a 4 h period of acidosis and 1 h of compensation with sodium bicarbonate. Streptokinase was infused along with human euglobulin fractions on the basis of the streptokinase tolerance test of each dog’s blood and plasma. Thrombolysis was maintained for 3-4 h and this was reflected in the reduction of fibrin deposits in the tissues. Of 100 glomeruli counted/dog’s kidney, the average containing fibrin was 44 ± 11% after acidosis and 0.4 ± 0.3% after thrombolysis.

SummaryA reproducible method is described for quantitating either spontaneous or ADP- induced platelet aggregation in circulating dog blood after heparinization. An extra- corporeal shunt containing screen material with openings 53 microns square was placed in the dog’s arterial circulation. The blood pressure was measured proximal to this filter. The blood pressure decreased upon opening the shunt to the circulation and increased when the filter became occluded. The degree and rate of aggregation was determined by means of measuring these blood pressure changes. Phase and electron microscopy demonstrated platelet aggregates occluding the filters. Platelet aggregation on the filter was experimentally accelerated by infusing ADP before the filter. The administration of ADP in concentrations between 0.625 and 10 μg/ml until occlusion, produced a dose response relationship between log of ADP concentration and rate of filter occlusion. Macrodex, a known inhibitor of platelet aggregation was given intravenously and was found to delay filter occlusion. Similar results were obtained with high intravenous doses of phenylbutazone. The method was used to compare the drug effects with their in vitro effects measured photometrically. It would appear that this technique can be used for demonstrating and quantitating the effects of drugs on the process of platelet adhesion and aggregation in vivo.

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The synthesis and pharmacological activity of partial retro‐inverso modified rat atrial natriuretic factor (rANF) analogs is described. The route to these compounds utilized a combination of solution and solid‐phase methods. The analogs prepared all contain a reversed amide bond (Ψ[NHCO]) at the Ser25 to Phe26 linkage. This bond has been suggested to play a key role in the metabolic inactivation of ANF. The analogs are of comparable potency to the endogenous peptide rANF1‐28 in binding to cultured rat vascular smooth muscle cells, in relaxing serotonin contracted rabbit aortic rings, and as natriuretic/diuretic agents in anesthetized rats. None of the peptides has an extended duration of action in vivo.