CORONARY CONSTRICTION AND CONSEQUENT CARDIODEPRESSION IN PULMONARY-EMBOLISM ARE MEDIATED BY PULMONARY BIG ENDOTHELIN AND ENHANCED IN EARLY ENDOTHELIAL DYSFUNCTION

Objectives: Myocardial ischemia plays a central role in the developmen t of right ventricular failure after acute pulmonary embolism. This st udy investigates whether pulmonary mediators act specifically on coron ary tone and cardiac contractile function in acute pulmonary microembo lization and whether such effects are altered in the case of early sys temic atherosclerosis, We employ a novel model of serial perfusion in which an isolated rabbit heart is perfused with the effluent of the sa me animal's isolated lung. Design: Controlled experiment using isolate d organs. Setting: Experimental laboratory, Subjects: Male New Zealand White rabbits (controls), Age-matched, male Watanabe rabbits (hyperch olesterolemic, development of accelerated atherosclerosis), Interventi ons: Seven isolated control and seven isolated Watanabe hearts were pe rfused with the saline effluent of the same animal's isolated lung, Af ter the assessment of the baseline data, the lungs were gradually embo lized with glass beads measuring 100 mu m in diameter to induce an inc rease in mean pulmonary arterial pressure from 6 to 8 mm Hg, at baseli ne, up to 25 mm Hg, Measurements and Main Results: Pulmonary embolizat ion to 25 mm Hg evoked a coronary constriction, measured as coronary f low decrease to 89 +/- 7% of the baseline value in controls. In the Wa tanabe group, coronary constriction was significantly enhanced, compar ed with controls, with coronary flow decreasing to 76 +/- 6% of the ba seline value, In both groups, coronary constriction was followed by a deterioration in cardiac contractile performance, This cardiodepressio n was significantly deeper in Watanabe hearts with respect to both max imum ventricular pressures and maximum rates of pressure development a nd decline, Coronary constriction and cardiodepression were prevented by coronary infusion of the nonselective endothelin antagonist PD-1450 65, the endothelin, antagonists A-127722 and BQ-123, and the endotheli n-converting enzyme inhibitor phosphoramidon. Concentration of big end othelin in pulmonary effluent increased from 5.6 +/- 0.3 pmol/L in con trols and 5.6 +/- 0.2 pmol/L in the Watanabe group, at baseline, to 8. 8 +/- 0.4 pmol/L in controls and 8.9 +/- 0.4 pmol/L in the Watanabe gr oup, at 25 mm Hg pulmonary arterial pressure, Endothelin was not detec t able at any time during the experiment in pulmonary effluent, The co ronary gradient, calculated as a difference in concentration be tween coronary and pulmonary effluent, was negative for big endothelin and p ositive for endothelin in both groups, Conclusions: We have demonstrat ed that an increase in pulmonary release of big endothelin occurs duri ng lung embolism, which, in turn, results in coronary constriction and consequent cardiodepression, This action of big endothelin is based o n its local coronary conversion into endothelin, In addition, coronary endothelial dysfunction, attributed to early systemic atherosclerosis , was shown to represent a specific risk factor in these events.