Potentiation of the protective effects of a converting enzyme inhibitor and a thromboxane synthetase inhibitor in hemorrhagic shock.
The effect of a specific inhibitor of thromboxane (Tx) A2 synthesis, CGS-13080, a new angiotensin converting enzyme inhibitor, CGS-16617, and a combination of both drugs was studied in hemorrhagic shock in rats. Treatment with CGS-16617 (1 microgram/kg) or CGS-13080 (200 micrograms/kg) alone did not alter significantly postoligemic hypotension or the increase in plasma cathepsin D activity in shocked rats, compared with hemorrhaged rats receiving only their vehicle. Combined treatment with both drugs maintained postreinfusion mean arterial blood pressure and attenuated the increase in plasma cathepsin D activity in hemorrhaged rats. Treatment of shocked rats with each drug alone attenuated the accumulation of a myocardial depressant factor activity in the plasma, but the lowest myocardial depressant factor activities were observed in rats treated with the drug combination. Additionally, animals treated with the drug combination exhibited significantly longer postreinfusion survival times than rats receiving either the vehicle (P less than .01), CGS-16617 (P less than .05) or CGS-13080 (P less than .02). CGS-16617 (1 microgram/kg) attenuated significantly the pressor response to angiotensin I throughout the shock period. CGS-13080 attenuated the increase in TxB2 plasma concentrations in shock when compared with hemorrhaged rats receiving the vehicle (P less than .05). Greater attenuation of TxB2 was found after treatment with the drug combination (P less than .01 from vehicle, P less than .05 from CGS-13080 alone). CGS-16617, but not CGS-13080, was also found to have a direct antiproteolytic action in pancreatic homogenates. However, the drug combination (CGS-16617 and CGS-13080) decreased proteolytic activity even further (P less than .001) from CGS-16617 alone.(ABSTRACT TRUNCATED AT 250 WORDS)
D000803:Angiotensin I / Q000494:pharmacology; D000806:Angiotensin-Converting Enzyme Inhibitors; D000818:Animals; D001552:Benzazepines / Q000008:administration & dosage / Q000627:therapeutic use*; D001794:Blood Pressure / Q000187:drug effects; D002402:Cathepsin D / Q000097:blood; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D007093:Imidazoles / Q000008:administration & dosage / Q000627:therapeutic use*; D008297:Male; D009201:Myocardial Depressant Factor / Q000097:blood; D011725:Pyridines / Q000008:administration & dosage / Q000627:therapeutic use*; D051381:Rats; D011919:Rats, Inbred Strains; D012771:Shock, Hemorrhagic / Q000188:drug therapy* / Q000503:physiopathology; D013929:Thromboxane B2 / Q000097:blood; D013930:Thromboxane-A Synthase / Q000037:antagonists & inhibitors
D000806:Angiotensin-Converting Enzyme Inhibitors; D001552:Benzazepines; D007093:Imidazoles; D009201:Myocardial Depressant Factor; D011725:Pyridines; D013929:Thromboxane B2; D000803:Angiotensin I; C037787:pirmagrel; D002402:Cathepsin D; D013930:Thromboxane-A Synthase; C052134:libenzapril