Hepoxilins sensitize blood vessels to noradrenaline—stereospecificity of action

Abstract

1 The vascular activity of two stereoisomers of hepoxilin A3 (HxA3) (8R and 8S) and of its glutathione conjugate, hepoxilin A3-C (HxA3-C) (8R and 8S), was investigated on rat helicoidal strips of thoracic aorta and longitudinal strips of portal vein.2 Neither of the hepoxilins tested had a direct effect on the tone of the aortic strip or on the spontaneous contractions of the portal vein. However, the noradrenaline (NA)-induced response of these vessels, as expressed by the dose required for half maximal contraction, (EC50) was greater in HxA3 (8S)-and HxA3-C (8R)-treated aorta. Increased frequency and strength of spontaneous contractions of the portal vein were detected at lower concentrations of NA in the presence of hepoxilins. 3 The threshold dose for both hepoxilins was 10-8M and their effect was not dose-related beyond 10-8m. The effect of hepoxilin appeared after a 45min incubation period and could be observed even if the compounds were washed out after 15 min. 4 Stereochemical specificity was observed. The 8S isomer of HxA3 was active in potentiating the NAinduced contraction of these vessels while the 8R isomer was inactive. In contrast, the 8R isomer of HxA3-C was active while the 8S isomer was inactive. In both tissues, HxA3 (8S) was more potent than its glutathione conjugate, HxA3-C (8R).5 In calcium-free buffer or in the presence of a calcium channel blocker (nifedipine 1 pM), no potentiation of NA-induced contraction by hepoxilins could be observed, suggesting the involvement of extracellular calcium in the actions of hepoxilins. 6 These experiments suggest that hepoxilins may be involved in the modulation of vascular tone and contractility.

Identification of the 11,14,15- and 11,12,15-Trihydroxyeicosatrienoic Acids as Endothelium-derived Relaxing Factors of Rabbit Aorta

“…The hydroxyepoxyeicosatrienoic acids and trihydroxyeicosatrienoic acids of 12-lipoxygenase have been called hepoxilins and trioxilins, respectively (14). The hepoxilins have been shown to release insulin and enhance the vasoconstrictor effects of norepinephrine (14,29). There is no information on the biological effects of the hydroxyepoxy and trihydroxy products derived from 15-lipoxygenase.…”

Hepoxilin Analogs Inhibit Bleomycin-Induced Pulmonary Fibrosis in the Mouse

“…The hepoxilins (HXs) may be candidates for the control of lung fibrosis as they are formed through the 12-lipoxygenase pathway of metabolism of arachidonic acid (Pace-Asciak et al, 1983;Pace-Asciak, 1984;Pace-Asciak and Martin, 1984). These compounds have previously been shown to have significant biological actions (Pace-Asciak, 1984;Dho et al, 1990;Laneuville et al, 1992;Pace-Asciak et al, 1995;Reynaud et al, 1996Reynaud et al, , 1999Sutherland et al, 2000). HXs raise free intracellular calcium in human neutrophils ex vivo through the release from stores and vascular tissue in vitro and block the intracellular calcium rise evoked by inflammatory mediators (Laneuville et al, 1993).…”

Neurokinin A‐induced contraction of guinea‐pig isolated trachea: potentiation by hepoxilins

“…We have recently shown that hepoxilins potentiate the contractile effects of noradrenaline on the rat isolated thoracic aorta and portal vein (Laneuville et al, 1992). Although the threshold doses of hepoxilins described here are identical, 10-M, the following differences were observed.…”

“…the 8S isomer of HxA3 is active while the 8R isomer is inactive and the 8R isomer of HxA3-C is active while the 8S isomer is inactive (Laneuville et al, 1992). It has been shown in human neutrophils that the hepoxilinmediated actions on intracellular calcium and second messenger release are inhibited by pertussis toxin, suggesting that hepoxilin action may be under receptor control coupled to G-protein activation (Dho et al, 1990;Nigam et al, 1990).…”