Monocrotaline-induced cardiopulmonary injury in rats: modification by the nonthiol ACE inhibitors CGS13945 and CGS16617.
Thiol angiotensin converting enzyme (ACE) inhibitors (Captopril, CL242817) and collagen antagonists (D-penicillamine) partially prevent pulmonary hypertension in monocrotaline-treated rats. The purpose of the present study was to determine whether the nonsulfhydryl ACE inhibitors CGS13945 and CGS16617 also ameliorate monocrotaline-induced cardiopulmonary damage in rats consuming the drugs continuously for 6 weeks. D-penicillamine was tested concomitantly as a positive control. Monocrotaline-treated animals developed severe pulmonary histopathology occlusive wall thickening of the pulmonary arteries, adrenomegaly, cardiomegaly, and right heart enlargement. Concomitant administration of CGS13945, CGS16617, or penicillamine ameliorated most of these monocrotaline reactions. Monocrotaline-induced histopathologic changes in the lung were accompanied by pulmonary endothelial dysfunction, including suppressed ACE and plasminogen activator activity and increased prostacyclin and thromboxane production. None of the modifying agents influenced these functional abnormalities in monocrotaline-treated lung endothelium. Thus, the ACE inhibitors CGS13945 and CGS16617 ameliorate monocrotaline-induced cardiopulmonary damage in rats, indicating that the presence of a thiol group is not essential for this class of compounds to exhibit therapeutic activity against monocrotaline lung injury. The present data do not identify the mechanism of action of CGS13945 and CGS16617, but appear to rule out lung ACE inhibition and lung endothelial cell sparing as major therapeutic factors.
D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D001552:Benzazepines / Q000494:pharmacology*; D001835:Body Weight / Q000187:drug effects; D004326:Drinking / Q000187:drug effects; D004435:Eating / Q000187:drug effects; D011464:Epoprostenol / Q000096:biosynthesis; D006976:Hypertension, Pulmonary / Q000139:chemically induced / Q000503:physiopathology / Q000517:prevention & control*; D007211:Indoles / Q000494:pharmacology*; D008168:Lung / Q000201:enzymology / Q000473:pathology; D008297:Male; D008854:Microscopy, Electron; D016686:Monocrotaline; D009929:Organ Size / Q000187:drug effects; D011763:Pyrrolizidine Alkaloids / Q000633:toxicity*; D051381:Rats; D011919:Rats, Inbred Strains; D013928:Thromboxane A2 / Q000096:biosynthesis
D000806:Angiotensin-Converting Enzyme Inhibitors; D001552:Benzazepines; D007211:Indoles; D011763:Pyrrolizidine Alkaloids; D013928:Thromboxane A2; D016686:Monocrotaline; C038810:CGS 13945; D011464:Epoprostenol; C052134:libenzapril