ABSTRACT
Endothelium-dependent hyperpolarizations and relaxations of vascular smooth muscle induced by bradykinin are mediated by endothelium-derived hyperpolarizing factors (EDHFs). In bovine coronary arteries, epoxyeicosatrienoic acids (EETs) appear to function as EDHFs. A 14,15-EET analog, 14,15-epoxyeicosa-5Z-enoic acid (14,15-EEZE) has been characterized as an EET antagonist. Bovine coronary arterial rings were constricted with U46619 and concentration-relaxation curves to increasing concentrations of 14,15-EET (109-105 M) were obtained. 14,15-EET induced maximal relaxations averaging 80%. However, preincubation of the arteries with 14,15-EEZE (105 M) shifted the relaxation curve to the right and inhibited maximal relaxations by over 50%. Concentration-relaxation responses to bradykinin (1012-107 M) were also evaluated. The bradykinin-induced relaxations were not altered by preincubation with miconazole (2 105 M) but were shifted to the right by preincubation with nitro-L-arginine methyl ester (L-NAME, 3 105 M) plus indomethacin (105 M). Incubation with miconazole plus L-NAME and indomethacin maximally inhibited relaxations by 50%. Similarly, incubation with 14,15-EEZE inhibited the indomethacin and L-NAME-resistant relaxations to bradykinin by over 50%. 14,15-EEZE did not alter relaxations to sodium nitroprusside (SNP, 109-106 M). In small cannulated and perfused bovine coronary arteries, incubation with 14,15-EEZE inhibited indomethacin-and L-nitroarginine-resistant dilatations to bradykinin (108 M). Thus, 14,15-EEZE appears to act as an EET antagonist by blocking relaxations to 14,15-EET but not the relaxations induced by SNP. Additionally, 14,15-EEZE inhibits the EDHF component of bradykinin-induced relaxations. These results further support the role of EETs as EDHFs.
