Tissue concentrations of endothelins and functional effects of endothelin-receptor activation in human arteries and veins

In the present study, the tissue content and functional effects of endothelin-1 and endothelin-3 were examined in human vessels of importance in coronary bypass operations. Human coronary arteries (i.e., the left anterior descending coronary artery) were obtained from eight cardiac valve donors within 6 hours after death, pulmonary arteries were perioperatively obtained from 15 patients operated on because of lung tumors, and internal thoracic arteries and great saphenous and cephalic veins were obtained at coronary bypass operations from a total of 28 patients. Endothelin-1 and endothelin-3 content was quantified by radioimmunoassay. For functional experiments, the vessels were mounted in organ baths for recordings of isometric contractions in response to endothelin-1, endothelin-3, and the endothelin(A)- receptor agonist sarafotoxin 6c. In all vessels investigated, the endothelin-1 content was higher than that of endothelin-3. The highest level were found in the left anterior descending coronary artery, followed in declining order by the internal thoracic artery, pulmonary artery, saphenous vein, and cephalic vein. Endothelin-1 contracted ail vessels in a concentration-dependent fashion. This effect,vas enhanced in the left anterior descending and internal thoracic arteries by inhibition of nitric oxide and prostaglandin formation. The contractile effect was attenuated in a concentration-dependent fashion in all vessels by incubation with the endothelin(A)-receptor blocker BQ-123. Furthermore, contractions evoked by endothelin-1 in the left anterior descending coronary and pulmonary arteries were antagonized by the combined endothelin(A)- and endothelin(n)-receptor blocker bosentan. Endothelin-3 contracted the left anterior descending coronary and pulmonary arteries and the saphenous vein, but not the internal thoracic artery, in a BQ-123-sensitive fashion, However, after inhibition with nitric oxide or prostaglandin, endothelin-3 also contracted the internal thoracic artery, and the response in the left anterior descending coronary artery was enhanced. Sarafotoxin 6c evoked a BQ-123-sensitive contraction of the left anterior descending coronary artery. It is concluded that endothelin, receptors mediate the major portion of the vasoconstriction observed on exposure to endothelin-1, endothelin-3, and sarafotoxin 6c in the left anterior descending coronary, pulmonary; and internal thoracic arteries and the saphenous vein. Furthermore, endothelin(n)-receptor activation, with subsequent formation of nitric oxide or prostaglandin (or both), counteracts the vasoconstrictor response to endothelin in the left anterior descending coronary and internal thoracic arteries, but not in the pulmonary artery or saphenous vein. The present findings therefore suggest that endothelin(A)-receptor antagonism might prove beneficial in preventing possible endothelin-induced coronary graft spasm.