Beneficial action of new angiotensin-converting enzyme inhibitor (SQ 14,225) in hemorrhagic shock in cats.

Abstract

SUMMARY A new angiotensin-converting enzyme inhibitor (CEI), SQ 14,225, was infused at 0.5 mg/kg per hr, iv, into cats to determine its effect in hemorrhagic shock. Cats were bled to a mean arterial blood pressure (MABP) of 40 nun Hg for 150 minutes; this was followed by reinfusion and a 120-minute postoligemic observation period. Hemorrhagic shock and sham shock controls were given an infusion of the CEI or its vehicle (0.9% NaCl). The degree of converting enzyme inhibition was assessed by measuring pressor responses to angiotensin I and II and by radioimmunoassay determination of plasma angiotensin II concentrations. In vitro studies on cat papillary muscles and vascular smooth muscle strips revealed no direct inotropic or vasoactive effect of SQ 14,225. Nevertheless, hemorrhaged cats given the CEI demonstrated a significantly higher final arterial pressure than hemorrhaged cats given 0.9% NaCl (96 vs. 51 mm Hg) (P < 0.01), indicating a significant prolongation of circulatory stability which is closely related to survival. Circulating lysosomal hydrolase (i.e., cathepsin D) activity (3.5 vs. 11-fold increases) and total plasma proteolysis (25% vs. 100% increases) were significantly reduced in the shocked cats given the CEI compared to the untreated shocked animals. Formation of a myocardial depressant factor (MDF) also was significantly diminished by CEI treatment (26 vs. 62 U). These results indicate that CEI improved the hemodynamic and biochemical status of cats in hemorrhagic shock and suggest that blockade of angiotensin II formation may be beneficial in hemorrhagic shock. Abolition of other actions of converting enzymes (e.g., potentiation of bradykinin action or inhibition of proteolysis) may also be involved in the protective mechanisms.