SC-39026, a serine elastase inhibitor, prevents muscularization of peripheral arteries, suggesting a mechanism of monocrotaline-induced pulmonary hypertension in rats.

Abstract

In rats injected with the toxin monocrotaline, altered synthesis and distribution of pulmonary artery elastin suggest that increased elastase activity may be important in the development of vascular changes and progressive pulmonary hypertension. To test this hypothesis, male Sprague-Dawley rats (250-300 g) were given 40 mg/kg of the elastase inhibitor SC-39026 in a carboxymethylcellulose vehicle or vehicle only by gavage, 12 hours before and twice daily for 8 days after a single subcutaneous injection of either monocrotaline (60 mg/kg) or saline. Thirteen days after injection, indwelling cardiovascular catheters were inserted under pentobarbital anesthesia, and at 15 days after injection, pulmonary and systemic hemodynamic measurements were recorded with the animals awake. At post-mortem examination, the lungs were perfused and morphometric techniques applied for light and electron microscopic evaluation. Saline-injected rats given either SC-39026 or vehicle were similar in all features assessed. In contrast, monocrotaline-injected rats given SC-39026 had significantly lower mean pulmonary artery pressure than those given vehicle (21.0 +/- 1.6 vs. 27.5 +/- 0.8 mm Hg, p less than 0.05), and this correlated with a significant reduction in the number of abnormally muscularized arteries at alveolar wall level (r2 = 0.89, p less than 0.001). SC-39026 did not significantly reduce monocrotaline-induced medial hypertrophy of muscular arteries, endothelial injury, and associated subendothelial edema; nor was there a significant increase in the proportion of the medial elastin, although a trend was apparent. Additional groups of monocrotaline injected rats were followed 3 weeks after injection, but both SC-39026 and vehicle-treated rats were similar at this point. Our data suggest that increased serine elastase activity associated with endothelial injury may mediate early abnormal pulmonary vascular smooth muscle differentiation resulting in muscularization of normally nonmuscular peripheral arteries and pulmonary hypertension induced in rats by injection of the toxin monocrotaline. Lack of persistence of this protective effect suggests that there may be continued elastase activity in this model. Failure to inhibit medial hypertrophy with SC-39026 suggests that a different mechanism or a different elastase may be involved in this structural change.

Myocyte Morphological Characteristics Differ Between the Phases of Pulmonary Hypertension-Induced Ventricular Hypertrophy and Failure

“…The death rate from failing myocardium in the right ventricle as a result of MCT administration increases in a dose-dependent manner. [12][13][14][15][16][17] Hirota, et al 2) subcutaneously injected 40 mg/kg of MCT solution into rats. Two weeks later, the right ventricular systolic pressure rose to 25.4 ± 2.2 mmHg in the MCT group and to 13.3 ± 1.4 mmHg in the control group.…”

Targeted overexpression of elafin protects mice against cardiac dysfunction and mortality following viral myocarditis

“…Increased serine elastase activity has been documented in a number of clinical (2)(3)(4) and experimentally induced cardiovascular diseases (5)(6)(7)(8)(9)(10)(11). For example, elevated serine elastase activity has been reported in patients with myocardial infarction and unstable angina (4), peripheral and coronary artery disease (2), and abdominal aortic aneurysm (3).…”

The endogenous vascular elastase that governs development and progression of monocrotaline-induced pulmonary hypertension in rats is a novel enzyme related to the serine proteinase adipsin.

“…This suggested that an enzyme that has elastolytic properties might be involved in the pathophysiology of this poorly understood process. This was further explored in experimental rats in which progressive pulmonary hypertension was induced by injection of the toxin monocrotaline (5)(6)(7)(8)(9). There was an increased number of breaks in the internal elastic lamina observed as early as 4 d after injection of the toxin associated with the initiation of structural changes (7).…”