PULMONARY BIG ENDOTHELIN AFFECTS CORONARY TONE AND LEADS TO ENHANCED,ETA-MEDIATED CORONARY CONSTRICTION IN EARLY ENDOTHELIAL DYSFUNCTION

Background Lung tissue produces a variety of mediators; however, littl e is known regarding how these mediators affect coronary regulation an d myocardial contractility. In a novel rabbit lung-heart model, we inv estigated the possible influence exerted by pulmonary mediators on cor onary tone both under normal conditions and in early endothelial dysfu nction. Methods and Results In our model, the effluent from the isolat ed lung is used to serially perfuse the coronary vessels of the isolat ed heart of the same animal. Compared with the hearts of control rabbi ts, isolated hearts of Watanabe rabbits revealed pharmacological evide nce of endothelial dysfunction and a significant sleeper decrease of c oronary 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, th e ETA antagonists BQ-123 and A-127722, and the endothelin-converting e nzyme inhibitor phosphoramidon. The concentration of big ET in lung ef fluent ranged from 5.5 to 5.8 pmol/L in both control and Watanabe grou ps, 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 si gnificantly in coronary effluent during serial perfusion. Conclusions Pulmonary big ET, locally converted into ET during coronary passage, c auses an ETA-mediated elevation in coronary tone under basal condition s as well as an enhanced coronary constriction when early endothelial dysfunction is present.