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

Abstract

on helicoidal strips of guinea-pig isolated tracheae. 2 None of the compounds (10--10-6 M) tested had a direct effect on resting tension of trachea. 3 HxA3 (8S) and HxA3-C (8R) (10-8 M) produced a significant leftward shift of the log concentrationresponse curves to neurokinin A (NKA) (EC50 (nM), control = 29.0 ± 2.8, HxA3 (8S) = 21.7 ± 3.7, HxA3-C (8R) = 13.8 ± 3.8, n = 6 for each). Also the maximal response to NKA was significantly increased when the tissues were exposed to these hepoxilins (% of the maximal response to NKA, control= 100, HxA3 (8S) = 114.5 + 5.3, HxA3-C (8R) = 139.0 ± 6.2, n = 6 for each). The threshold concentrations for both hepoxilins was 10-8 M and their effects were dose-related. 4 Stereochemical specificity was observed. The 8S-isomer of HxA3 was active in potentiating the NKA-induced contraction of the trachea while the 8R isomer was inactive. In contrast, the 8R isomer of HxA3-C was active while the 8S isomer was inactive. The trihydroxy metabolite of the active isomer of HxA3 (8S), i.e. TrXA3 (8S) (10-6 M), was inactive in potentiating the NKA-induced contraction of the trachea. 5 It is concluded that hepoxilins sensitize the guinea-pig isolated trachea to the potent bronchoconstrictor, NKA.

Pathophysiology of the hepoxilins

“…Hence the metabolism of 12(S)-HPETE can be diverted to 12(S)-HETE or the hepoxilins depending on the state of peroxidaase activity in the cell with biological consequences as both pathways produce compounds with differing biological actions. For example 12(S)-HETE causes proliferation of cancer cells [48], it is implicated in diabetes [49], hypertension [50], and certain other diseases, whereas hepoxilin A 3 is a pro-inflammatory mediator and potentiates vascular reactivity of constrictor hormones [51,52]. The stable hepoxilin analogs are pro-apoptotic, anti-inflammatory, anti-thrombotic and antidiabetic (see review in [53]).…”

“…The hepoxilin effect was blocked by nifedipine, a calcium channel blocker. In another study the vascular effects of the hepoxilins and related compounds on the vascular tone of the guinea pig isolated trachea was evaluated [52]. Again, neither of the compounds tested had any effects on the resting tension by themselves.…”

“…The noted sensitization to norepinephrine did not occur either in calcium-free medium or in the presence of nifedipine, a calcium channel blocker. In another study, the effect of hepoxilin A 3 on the guinea pig trachea was investigated [52]. Contraction was induced by neurokinin A and hepoxilin A 3 caused potentiation of the contraction within the concentration range 10 − 9 -10 − 6 M. Again as in the previous study with aorta and portal vein, the 8(S)-epimer of hepoxilin A 3 was active, the 8(R)-epimer was inactive, while the 8(R) epimer of the hepoxilin A 3 -C was active, the corresponding 8(S)-hepoxilin A 3 -C was inactive in modulating the tone of the trachea.…”

Biosynthesis of 14,15‐Hepoxilins in Human L1236 Hodgkin Lymphoma Cells and Eosinophils

“…In human neutrophils, the biological actions of HxA 3 are indicated to be receptor mediated [19], and this metabolite has been found to stimulate human neutrophils to migrate across intestinal epithelia [20]. HxA 3 -C has been reported to induce vascular contraction in guinea pig isolated trachea [21] and increase vascular permeability in rat skin [18].…”

Formation of 14,15-Hepoxilins of the A3 and B3 Series through a 15-Lipoxygenase and Hydroperoxide Isomerase Present in Garlic Roots

“…They have been shown to exert a variety of biological actions likely mediated via their actions on ion fluxes, namely calcium (5,(7)(8)(9)(10)(11) and potassium (12,13) within the cell. The hepoxilins cause the release of insulin (14), potentiate vascular contraction (15,16), block neurotransmitter release (17), regulate cell volume (12), and provoke skin vascular permeability (18). Hepoxilin actions, at least in the human neutrophil, have been shown to be mediated via a hepoxilin-specific receptor (19,20).…”