1 The inflammatory effects of hydroperoxy (HPETE) and hydroxy (HETE) acids, synthesized by arachidonic acid lipoxygenases, have been investigated in rabbit skin.2 High doses (10-20pg) of 5-, 12-or 15-HPETE or the 5,12-di-hydroxy acid, leukotriene B4 (0.1-1 fg), caused small but significant increases in plasma exudation following intra-dermal injection.3 Leukotriene B4 was equipotent with prostaglandin E2 and prostacyclin in potentiating bradykinin-induced plasma exudation, and was 100 times more active in this property than any other lipoxygenase product tested. 4 Leukotriene B4-induced plasma exudation was enhanced by prostaglandin E2. 5 The mono-HETEs were relatively inactive in causing or enhancing plasma exudation.6 Leukotriene B4 (0.1 fg) or prostaglandin El (1.0 pg) significantly elevated leukocyte accumulation in rabbit skin, whereas PGE2, 5-HPETE, 5-HETE, 12-HPETE or 12-HETE were inactive at doses up to 1 pg.

1 The output of immunoreactive (i) 6 keto prostaglandin Fl, (i6ketoPGF1,). iPGE2 and ithromboxane B2 (iTXB2) from isolated colonic epithelium of the rat into the apical and basolateral bathing solution has been measured. In some instances tissues were also voltage clamped at 0 mV to measure short circuit current (SCC). 2 Kallidin (lysylbradykinin) stimulated the output of all three eicosanoids, specifically from the basolateral face of the tissue. The output was similar whether or not the tissues were short circuited. 3 Both the SCC response and eicosanoid output were dependent upon the concentration of kallidin, but not in a strictly proportional manner, there being relatively more eicosanoid output at submaximal kinin concentrations. 4 Indomethacin, 5 JiM, abolished the eicosanoid output, in response to kinin, while some part of the SCC response remained. 5 Calcium removal from the basolateral bathing fluid severely attenuated the SCC response, reduced the output of i6ketoPGFp, to half, but left the output of iPGE2 unchanged. In the presence or absence of calcium it is probable that sufficient PGE material is released to cause part of the SCC changes seen with kinin. 6 Kinin and PGE1 increased the cyclic AMP content of intact epithelia, provided a phosphodiesterase inhibitor was added at the same time.7 It is proposed that kinin causes an increase in calcium influx at the basolateral pole of the tissue. This calcium is necessary for the production of some eicosanoids and the subsequent generation of cyclic AMP, which then increases apical chloride permeability. In addition, calcium may facilitate entry of chloride through the basolateral face of the cells by activating a cotransport mechanism.

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The diterpene, forskolin, is shown to produce a concentration-dependent, increase in short circuit current in two epithelial preparations, amphibian skin and rat colon. In the amphibian tissue the increase is sensitive to amiloride and due to an increase in electrogenic transepithelial sodium transport towards the serosal side. In the rat colon piretanide attenuated the forskolin effect, suggesting the terpene increases electrogenic transepithelial chloride transport towards the mucosal side. Half-maximal activation of both processes was achieved with concentrations of 1-3 pM, similar to those required to activate half-maximally the catalytic subunit of adenylate cyclase.

1Sodium transport has been measured in the isolated epithelium from colons of male SpragueDawley rats. 2 Sodium transport in colons was induced by pretreating the animals with dexamethasone (6 mg kg-) which caused the appearance of an amiloride-sensitive short circuit current within a few hours. 3 Forskolin, a diterpene, which activates adenylate cyclase, was found to increase the cyclic adenosine monophosphate (cyclic AMP) content of rat colons and also to increase short circuit current at the same time. However, measurements of chloride and sodium fluxes across the epithelium indicated that forskolin activates chloride secretion but has no effect on sodium transport.4 In confirmation of (3) it was found that the amiloride-sensitive short circuit current was unchanged after the short circuit current had been increased by forskolin under a variety of conditions. 5The behaviour of the mammalian colon as indicated in (3) and (4) is unlike that of amphibian sodium transporting epithelia. It is shown that in toad urinary bladder forskolin increases amiloridesensitive short circuit current. 6 Procedures were investigated which might make sodium transport in the mammalian colon sensitive to cyclic AMP. Exposing the apical surface to sonicated suspensions of nucleated red cells (frog, toad and duck), followed by washing, gave preparations with amiloride-sensitive short circuit currents which were increased by forskolin or dibutyryl cyclic AMP. 7 It would appear that the sodium channel in the mammalian colon, unlike that of amphibian tissues, has lost the ability to have its properties modified by cyclic AMP. Incubation of colons with sonicated suspensions of nucleated red cells apparently modifies the tissues such that sodium transport across the tissue becomes sensitive to the nucleotide.