Interaction between myocardial depressant factor and vasoactive mediators with ischemia and shock.

A variety of endogenously formed vasoconstrictor substances circulate in the blood and act as mediators in ischemia and shock states. These humoral substances are chemically diverse and include peptides, lipids, and aromatic amines. One of the novel peptides, myocardial depressant factor (MDF) and several interesting lipids, including thromboxane A2 (TxA2), leukotriene D4 (LTD4), and platelet-activating factor (PAF) are very potent substances having a broad profile of pathophysiological actions. Some of the effects of MDF include myocardial depression, constriction of splanchnic vessels, and impairment of phagocytosis. TxA2 primarily constricts blood vessels, aggregates platelets, and increases membrane permeability. LTD4 is a potent vasoconstrictor and bronchoconstrictor and promotes leakage of fluid out of blood vessels. PAF activates platelets, depresses cardiac function, constricts airways, and enhances fluid leakage from the intravascular compartment. Thus vasoconstriction is common to all these mediators. Moreover, these vasoactive substances have common mechanisms of release and interact to exacerbate ischemia and contribute to the pathogenesis of a variety of shock states. New pharmacological approaches to blocking the formation and action of these mediators have provided interesting insights into the pathophysiology of shock.

[Acute pancreatitis in dogs. A literature study]. / Acute pancreatitis bij de hond. Een literatuuronderzoek.

The aetiology of acute pancreatitis in dogs is rather obscure. Although experimental studies may reveal a number of causative factors, an aetiological diagnosis is rarely established in 'spontaneous' pancreatitis. The pathogenesis and pathophysiology are reviewed. Activated trypsin plays a leading role in the injury to the pancreas, the ischaemia of the tissues and the disseminated intravascular coagulation. Vomiting, abdominal pain and general malaise are prominent features in the externally perceptible symptoms. Examination of the blood is of importance both in establishing the diagnosis and in determining the course of the disease. Great caution is indicated in setting store by individual results of haematological studies. There is neither a biochemical nor a haematological method of estimation today, by which acute haemorrhagic necrotic pancreatitis can be shown to be present or ruled out with one hundred per cent certainty. Treatment of the disease is mainly symptomatic. Complete withdrawal of food and water is the most important factor. Intravenous fluid therapy, anti-emetics, analgesics and possibly antibiotics are the main adjuncts to treatment. The prognosis will largely depend on the stage of the disease and the extent to which complications have occurred at the time.

Indomethacin suppresses the early cardiodepressant factor released by endotoxin in the rat: possible involvement of a prostacyclin-related material.

UNLABELLED: The aim of this study was to determine if a prostaglandin-related material--in particular prostacyclinlike substance--could explain our previous findings showing that a sublethal dose of endotoxin caused the early release of a serum lipid-soluble factor able to decrease various activities of cultured rat heart cells (CRHC) through an intracellular calcium dysregulation. Sera were sampled from rats 4 h after administration of 2 mg/kg E coli endotoxin (E) and their cardiodepressant effect on CRHC determined by an electrooptical technique. E-treated rat serum (ETRS) cardiodepressant effect was compared to that of 0.1 ng/ml prostacyclin (PGI2) and of 0.029 ng/ml nifedipine, a calcium antagonist. The reversal effect of caffeine, a substance known for its positive inotropic effect by increasing intracellular calcium availability at the sarcoplasmic reticulum site, has been tested against the depressant effect of ETRS, PGI2, and nifedipine. RESULTS: 1) Compared to control, serum from endotoxin-treated rats with or without imidazole pretreatment depressed contractility of CRHC in a similar fashion, whereas pretreatment with indomethacin had a much less marked effect; 2) PGI2, nifedipine, and ETRS depressed CRHC contractility in much the same way; 3) caffeine reversed the depressant effect of PGI2 and ETRS, but was much less effective against nifedipine effect. These results suggest that the cardiodepressant effect of ETRS is mediated by a prostaglandinlike substance, other than thromboxane, acting through reduced intracellular calcium availability. PGI2 or PGI2-related material is consistent with such a depressant effect and such a mechanism.

The pathophysiologic role of myocardial depressant factor as a mediator of circulatory shock.

Myocardial Depressant Factor (MDF) is a small peptide circulating in the blood of all mammalian species tested in a variety of shock states including endotoxic, hemorrhagic, cardiogenic, bowel ischemic, acute pancreatitis, burn, and traumatic shock. MDF is produced by the action of proteolytic enzymes released by the ischemic pancreas. MDF acts to depress myocardial contractility, constrict the splanchnic arteries and impair reticuloendothelial system phagocytosis. Several pharmacologic agents prevent the formation of MDF including membrane stabilizers (e.g., glucocorticoids), protease inhibitors (e.g., aprotinin), converting enzyme inhibitors (e.g., captopril), prostaglandins (e.g., PGE1 and PGI2), thromboxane synthetase inhibitors (e.g., imidazole, PTA2) and local anesthetics (e.g., lidocaine). Prevention of MDF formation or action improves survival. Thus, MDF is an important mediator of shock pathophysiology and should be considered in the therapy of circulatory shock states.

Protective actions of naloxone in hemorrhagic shock.

The opiate antagonist, naloxone, was infused at 8 mg x kg-1 x h-1 in cats to determine its effect in hemorrhagic shock. Hemorrhaged cats treated with naloxone maintained postreinfusion mean arterial blood pressure at a higher value compared to those receiving only the vehicle. Final pressures were 77 +/- 9 mmHg for cats receiving vehicle compared to 120 +/- 6 mmHg for cats receiving naloxone. These values represent 58 +/-7 and 98 +/- 6% of initial pressures for vehicle- and naloxone-treated cats, respectively (P < 0.001). Naloxone also moderated increases in circulating lysosomal hydrolase activity (4- vs. 23-fold increase) and total plasma proteolysis (33 vs. 100% increase). Plasma myocardial depressant factor activity was also significantly reduced in naloxone-treated hemorrhaged cats compared to shock cats given 0.9% NaCl (16 +/- 3 vs. 58 +/- 4 U, respectively; P < 0.001). Studies on cat papillary muscles demonstrated that naloxone at concentrations slightly higher than estimated plasma values during shock exerted a moderate positive inotropic effect. Our results show that naloxone improved the hemodynamic and biochemical state of cats in hemorrhagic shock. Inhibition of proteolysis and stabilization of lysosomal membranes appear to be ivolved in the protective action of naloxone, along with the well-known opiate-antagonistic action of this agent.