Relaxing effects of 17(18)-EpETE on arterial and airway smooth muscles in human lung

Abstract

Human cytochrome P-450 epoxygenase enzymes metabolize eicosapentaenoic acid (EPA), an omega-3-polyunsaturated fatty acid (PUFA), and leads to the production of 17(18)-epoxyeicosatetraenoic acid, or 17(18)-EpETE. The aim of the present study was to delineate the mode of action of 17(18)-EpETE on human pulmonary artery (HPA) and distal bronchi. Isometric tension measurements demonstrated that 17(18)-EpETE induced concentration-dependent relaxing effects in pulmonary artery and airway smooth muscles. Iberiotoxin (IbTx) and glyburide (Glyb), known BK(Ca) and K(ATP) channel inhibitors, respectively, reversed the relaxation induced by 17(18)-EpETE on both tissues types. Microelectrode measurements showed that exogenous addition of 17(18)-EpETE hyperpolarized the membrane potential of HPA and bronchial smooth muscle cells. These induced electrophysiological effects were reversed by the addition of 10 nM IbTx and 10 muM Glyb. Complementary experiments performed on human bronchi, using the planar lipid bilayer reconstitution technique, demonstrated that 17(18)-EpETE activated reconstituted BK(Ca) channels at low free Ca(2+) concentration. Moreover, in bronchi, the relaxing responses induced by 17(18)-EpETE were also related to reduced Ca(2+) sensitivity of the myofilaments, since free Ca(2+) concentration-response curves, performed on beta-escin-permeabilized cultured explants, were shifted toward higher Ca(2+). Together, these results provide new insight into the mode of action of 17(18)-EpETE in lung tissues and highlight this eicosanoid as a potent modulator of tone on both HPA and distal bronchi in vitro, which may be of clinical relevance in the pathophysiology of pulmonary hypertension and airway diseases.

Basal omega-3 fatty acid status affects fatty acid and oxylipin responses to high-dose n3-HUFA in healthy volunteers

“…However, RBCs and plasma lipids also showed minor reductions in MUFA and PUFA pools. In a similar study of men on a Mediterranean diet fed 4 g/day n3-HUFA ethyl esters for 2 months, the magnitude of HUFA changes were similar to those observed in the current study; however, changes of platelet aggregation ( 44 ), and pulmonary smooth muscle relaxants ( 45 ). Although the literature pertaining to the production and function of n3 epoxides is limited, the similarity of their effects to the well-described AA-derived epoxides (46)(47)(48) suggest that future research focusing on the relative potency of these n3 and n6 metabolites is needed to fully appreciate the potential impact and mechanisms of P-OM3 treatments and the association to infl ammation and CVD risk in the population.…”

Role of CYP eicosanoids in the regulation of pharyngeal pumping and food uptake in Caenorhabditis elegans

“…17,18-EEQ shares and, in several vascular beds, even largely exceeds the vasodilatory ( 57 ) and BK channel activating effects of EETs ( 58 ). Moreover, 17,18-EEQ relaxes airway smooth muscle cells in the human lung ( 59 ) and potently modulates the contractility of cardiomyocytes ( 37 ). Interestingly, a synthetic compound developed to mimic the effect of 17,18-EEQ on cardiomyocytes ( 21 ) was also effective when assayed in our C. elegans model.…”

Stereoselective epoxidation of the last double bond of polyunsaturated fatty acids by human cytochromes P450

“…CYP epoxygenases also convert the 3-PUFA eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) to epoxy-derivatives ( 9 ), which are potent dilators of coronary arterioles ( 10-12 ) or pulmonary artery ( 13 ) and inhibit platelet aggregation ( 14 ). The EPA-derived epoxides account for fi ve epoxyeicosatetraenoic acids (5,8,11,14,and 17,, whereas the DHA-derived epoxides account for six epoxydocosapentaenoic acids (4,7,10,13,16,and 19,. A high regio-and stereoselectivity has been observed when testing the effects of chemically synthesized epoxides from AA and EPA.…”