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Endotoxin stimulates synthesis of endothelin which can cause pulmonary and systemic vasoconstriction and bronchoconstriction. Prolonged endotoxemia in sheep results in dramatic increases in pulmonary and systemic vascular resistances in nonsurvivors compared with survivors. Experiments were conducted in 12 conscious sheep (seven survivors, five nonsurvivors) to determine if synthesis of endothelin might contribute to the pathophysiology in nonsurvivors. Endotoxin was infused at 10 ng/min/kg for 12 h followed by a 4 h recovery in survivors. Lung lymph endothelin concentration peaked at 38.7 +/- 5.8 pg/mL during the endotoxin infusion in survivors compared with a peak of 128.7 +/- 33.0 pg/mL (p < .05) in nonsurvivors. Cardiac output was lower, and systemic and pulmonary vascular resistances and the Aa gradient in PO2 were significantly greater in nonsurvivors compared with survivors. These variables are those likely to be affected by increased circulating endothelin concentrations which suggests that endothelin contributes to early mortality during prolonged endotoxemia.

Hemorrhagic shock was produced in dogs by bleeding to a systemic blood pressure of 45 mm Hg for 3 hours, followed by reinfusion of the shed blood. A rapid decrease in pancreatic blood flow occurred and pancreatic perfusion remained at 15-25% of control over the entire 3-hour oligemic period. As a consequence of this marked degree of pancreatic hypoperfusion, autolytic changes occurred in pancreatic acinar cell ultrastructure, particularly in the enlarging of lysosomes which developed many vacuoles. Plasma proteolytic indices (e.g., cathepsin D activity and amino nitrogen concentration) markedly increased during shock as well as the activity of a myocardial depressant factor (MDF). MDF was also produced in incubated pancreatic homogenates obtained from nonshocked dogs and in non-incubated homogenates from shocked dogs. MDF activity in the homogenates was closely correlated with amino nitrogen concentration. These data suggest that pancreatic hypoperfusion plays a key role in MDF formation and ultimately in the pathogenesis of circulatory shock. Moreover, MDF activity was found not to be associated either with pentobarbital concentration or the salt content of active fractions of plasma and pancreatic tissue. Ashing of active fractions was very effective in destroying MDF activity. These data are consistent with the earlier findings that indicate MDF to be a peptide having a molecular weight of 500-1,000.

We evaluated the efficacy of intracoronary administration of verapamil hydrochloride in reducing myocardial injury during acute ischemia and reperfusion. Ischemia was induced by 30% and 45% reductions of circumflex arterial blood flow for successive 2-hour periods. A reperfusion period (1 hour and 45 minutes) followed ischemia upon deflation of a pneumatic occluder. Verapamil (30 micrograms/kg) was slowly injected into the circumflex artery as a bolus 15 minutes after each blood flow reduction step. To prevent verapamil-induced decreases in heart rate, ventricular pacing was established at 170 beats/min before a baseline period and maintained throughout the protocol. Creatine kinase activities (international units per milligram protein) measured in samples obtained from posterior papillary muscles were 15 +/- 1 (mean +/- SEM) and 10 +/- 2 for animals receiving verapamil or its saline vehicle, respectively (p less than 0.05). Quantitative morphometry was performed on left ventricular myocardium after staining with p-nitro blue tetrazolium. Intracoronary administration of verapamil reduced the extent of left ventricular infarction, as disclosed by positive tetrazolium staining of the tissue, from 34 +/- 4% of the left ventricle in vehicle-treated animals to 21 +/- 4% of the left ventricle in verapamil-treated animals (p less than 0.05). We conclude that intracoronary administration of verapamil reduced the extent of myocardial infarction acutely, independent of increases in blood flow through the circumflex coronary artery or decreases in heart rate. Administration of verapamil was not associated with decreases in ventricular afterload, the pressure-rate index, cardiac output, or the maximum rate of pressure development in the left ventricle. Verapamil treatment of animals subjected to ischemia was not associated with sustained elevations of left atrial pressure to values above those measured in animals receiving the vehicle.