The chemotactic peptide N-formyl-L-methionyl-L-leucyl-L-phenylalanine (FMLP) is a constrictor of bronchial smooth muscle. Recently it has also been shown to contract rabbit coronary arteries by an unknown mechanism. This prompted us to investigate whether the chemotactic peptide has an effect on the tone of human coronary arteries obtained during heart transplantation. FMLP was found to be a potent and efficacious myotropic agent on strips of human coronary artery. Contractions were generally transient and subject to tachyphylaxis. The FMLP-induced vasoconstriction was not dependent on the presence of endothelial cells. The response was unaffected by the histamine H1-antagonist diphenhydramine or the antagonist of peptido-leukotrienes FPL 55712. However, the contractions were completely abolished in the presence of the fatty acid cyclooxygenase inhibitors aspirin or indomethacin. Stimulation of rings of human coronary artery with FMLP resulted in a marked production of prostaglandin (PG)F2 alpha, a smaller production of PGD2, and a slight increase in thromboxane B2. All these prostanoids constricted the artery, but the stable thromboxane mimetic U44069 was 100 times more potent than PGF2 alpha or PGD2. These data indicate that FMLP activates cells of unknown identity in the adventitia or media of human coronary arteries to produce a mixture of vasoconstrictor cyclooxygenase products. These compounds are likely to mediate the myotropic effect of FMLP on this artery. The mechanism may participate in the pathogenesis of some forms of coronary vasospasm.