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(Circulation. 1997;96:3192-3200.)
© 1997 American Heart Association, Inc.

Articles

Pulmonary Big Endothelin Affects Coronary Tone and Leads to Enhanced, ET_A-Mediated Coronary Constriction in Early Endothelial Dysfunction

Karl Stangl, MD; Thomas Dschietzig, MD; Michael Laule, MD; Konstantin Alexiou, MD; Klaus D. Wernecke, PhD; ; Gert Baumann, MD

From the Medizinische Klinik und Poliklinik I, and Department of Medical Biometry (K.D.W.), Charité, Humboldt-Universität zu Berlin, Germany.

Correspondence to Karl Stangl, MD, Medizinische Klinik und Poliklinik I, Charité, Humboldt-Universität zu Berlin, Schumannstr 20/21, 10098 Berlin, Germany. E-mail stangl{at}rz.charite.hu-berlin.de

Background Lung tissue produces a variety of mediators; however, little is known regarding how these mediators affect coronary regulation and myocardial contractility. In a novel rabbit lung-heart model, we investigated the possible influence exerted by pulmonary mediators on coronary tone both under normal conditions and in early endothelial dysfunction.

Methods and Results In our model, the effluent from the isolated lung is used to serially perfuse the coronary vessels of the isolated heart of the same animal. Compared with the hearts of control rabbits, isolated hearts of Watanabe rabbits revealed pharmacological evidence of endothelial dysfunction and a significant steeper decrease of coronary flow during serial perfusion of the coronary vessels with lung effluent (75±6% versus 89±3%). This decline in coronary flow was prevented by the nonselective endothelin (ET) antagonist PD-145065, the ET_A antagonists BQ-123 and A-127722, and the endothelin-converting enzyme inhibitor phosphoramidon. The concentration of big ET in lung effluent ranged from 5.5 to 5.8 pmol/L in both control and Watanabe groups, with levels in corresponding coronary effluent falling to 0.9 to 1.1 pmol/L in controls and to 1.0 to 1.2 pmol/L in the Watanabe group. In either group, ET was not detected in lung effluent, but it rose significantly in coronary effluent during serial perfusion.

Conclusions Pulmonary big ET, locally converted into ET during coronary passage, causes an ET_A-mediated elevation in coronary tone under basal conditions as well as an enhanced coronary constriction when early endothelial dysfunction is present.

Key Words: arteriosclerosis • vasoconstriction • endothelin • endothelium

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