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(Hypertension. 2003;42:818.)
© 2003 American Heart Association, Inc.

Scientific Contributions

Elastase-Induced Suppression of Endothelin-Mediated Ca²⁺ Entry Mechanisms of Vascular Contraction

From the Department of Veterans Affairs Medical Center, West Roxbury, Mass, and the Division of Vascular Surgery, Brigham and Women’s Hospital and Harvard Medical School, Boston, Mass.

Correspondence to Raouf A. Khalil, MD, Harvard Medical School, VA Boston Healthcare-Research, 1400 VFW Parkway, 3/2B123, West Roxbury, MA 02132. E-mail raouf_khalil{at}hms.harvard.edu

Abdominal aortic aneurysm (AAA) is associated with increased endothelin (ET-1), both systemically and locally in the aorta. Also, elastase activity is increased in human AAA, and elastase perfusion of the aorta induces aneurysm formation in animal models of AAA. However, whether elastase directly affects the ET-1-induced mechanisms of aortic smooth muscle contraction is unclear. Isometric contraction and ⁴⁵Ca²⁺ influx were measured in aortic strips isolated from male Sprague-Dawley rats and treated with elastase (5 U/mL). To avoid degradation of the extracellular matrix proteins by elastase, experiments were performed in the presence of elastin (10 mg/mL). In normal Krebs solution (2.5 mmol/L Ca²⁺), ET-1 (10^-7 mol/L) caused contraction of aortic strips that was inhibited by elastase (5 U/mL). The elastase-induced inhibition of ET-1 contraction was slow in onset (4.6±0.4 minutes), time-dependent, complete in 34±3 minutes, and reversible. In Ca²⁺-free Krebs solution, caffeine (25 mmol/L) caused a small contraction that was not inhibited by elastase, suggesting that elastase does not inhibit Ca²⁺ release from the intracellular stores. Membrane depolarization by 96 mmol/L KCl, which stimulates Ca²⁺ entry from the extracellular space, caused a contraction that was inhibited by elastase in a concentration-dependent, time-dependent, and reversible fashion. The reversible inhibitory effects of elastase, particularly in the presence of elastin, suggest that they are not due to dissolution of the extracellular matrix or smooth muscle contractile proteins. Elastase also inhibited ET-1 and KCl-induced ⁴⁵Ca²⁺ influx. Thus, elastase directly inhibits ET-1-induced Ca²⁺ entry mechanisms of vascular smooth muscle contraction, which may explain the role of elastase and ET-1 during the development of AAA.

Key Words: endothelin • muscle, smooth • potassium • calcium • aorta