Inhibition of elastolysis by SC-37698 reduces development and progression of monocrotaline pulmonary hypertension.
Our previous studies showed that increased pulmonary artery elastolytic activity is associated with monocrotaline-induced pulmonary hypertension in rats, and the latter is reduced by the elastase inhibitor SC-39026. This agent, given orally, decreases monocrotaline-induced muscularization of normally nonmuscular peripheral arteries but not medial hypertrophy of muscular arteries. To establish whether constant infusion of an elastase inhibitor would reduce both vascular lesions induced by monocrotaline injection, SC-37698 (an analogue of SC-39026) was given intravenously by osmopump. To separately assess whether SC-37698 would inhibit development of the vascular changes as well as their progression, SC-37698 or vehicle was infused for the first 2 wk (2-wk study) or was delayed until 1 wk after monocrotaline injection (3-wk study). Hemodynamic data were recorded from indwelling catheters, and the lungs were evaluated morphologically. Saline-injected control rats given SC-37698 or vehicle were similar at both time points. Monocrotaline-injected rats given SC-37698 compared with those given vehicle alone had lower pulmonary artery pressures, 17.9 +/- 0.5 vs. 23.7 +/- 0.8 mmHg (P less than 0.01) in the 2-wk study and 24.0 +/- 1.8 vs. 33.5 +/- 3.1 mmHg (P less than 0.05) in the 3-wk study. This was associated with significant decreases in muscularization of peripheral arteries and reductions in medial hypertrophy of muscular arteries. In the hilar pulmonary arteries assessed at 3 wk only, SC-37698 significantly decreased monocrotaline-induced endothelial injury, subendothelial edema, migration of smooth muscle cells into subendothelium, medial hypertrophy, collagen accumulation, and abnormal distribution of elastin as interlamellar islands. Pulmonary artery elastolytic activity was reduced in SC-37698-treated compared with untreated monocrotaline-injected rats (P less than 0.05). Thus infusion of SC-37698 reduces monocrotaline-induced pulmonary hypertension when administered before or even after development of early vascular changes.
Department of Cardiology, Hospital for Sick Children, Toronto, Ontario, Canada.
C L
CL
Ye
M
M
Rabinovitch
D000818:Animals; D002723:Chlorobenzoates / Q000494:pharmacology*; D006352:Heart Ventricles; D006439:Hemodynamics / Q000187:drug effects; D006976:Hypertension, Pulmonary / Q000139:chemically induced / Q000517:prevention & control*; D008297:Male; D008855:Microscopy, Electron, Scanning; D016686:Monocrotaline; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D009206:Myocardium / Q000473:pathology; D009929:Organ Size / Q000187:drug effects; D010196:Pancreatic Elastase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011651:Pulmonary Artery / Q000187:drug effects / Q000201:enzymology / Q000648:ultrastructure; D051381:Rats; D011919:Rats, Inbred Strains
D002723:Chlorobenzoates; C071305:SC 37698; D016686:Monocrotaline; D010196:Pancreatic Elastase