Biomedical subjects
Publications and source records attributed to H Juan.
From the leaves of Epilobium angustifolium L. (Onagraceae) an antiphlogistic principle was isolated and identified as myricetin 3-O-beta-D-glucuronide. This novel flavonoid exhibited a very strong anti-inflammatory effect on carrageenan-induced edema in the rat hind paw (more than ten times more effective than indomethacin) and an inhibitory effect on prostaglandin biosynthesis (as effective as indomethacin).
The influence of a diet supplemented with MaxEPA (a fish oil concentrate, rich in eicosapentaenoic acid = EPA) on bleeding time in small mesenteric arteries of the rat and on formation of thromboxane B2 (TXB2) by ADP-stimulated platelets was investigated. Since EPA has been found to antagonize noradrenaline (NA) - induced vasoconstriction, the influences on bleeding time of the alpha-receptor antagonist phentolamine and of the adrenergic neuron blocking agent guanethidine alone as well as during dietary supplementation with MaxEPA were studied. Bleeding time slowly increased during the MaxEPA diet over a period of 12 weeks resulting in a final prolongation of about 75%. Indomethacin which dose-dependently increased bleeding time in control rats, further increased the already prolonged bleeding time in rats on the MaxEPA diet. Guanethidine prolonged bleeding time strongly in control animals but caused no further increase in those on the MaxEPA diet. Indomethacin also further increased the bleeding time prolonged by guanethidine, just as it did in animals on MaxEPA diet. In contrast to guanethidine, phentolamine prolonged bleeding time only slightly. The ability of platelets from rats on the diet to generate TXB2 was reduced to 59.5% but was more drastically reduced (to 26.7%) from rats pretreated with indomethacin. The results indicate that MaxEPA feeding prolongs bleeding time by a mechanism other than that of indomethacin. We speculate that EPA prolongs bleeding time rather by antagonizing the vasoconstrictor effect of sympathetic transmitters at the site of the injured vessel than by a reduced formation of TXA2.
The algesic effects of intravascularly injected solutions of sorbitol and ionic and nonionic contrast media (CM) with high and low osmolality were tested in the perfused isolated rabbit ear connected to the body by the great auricular nerve. The threshold for the pain reflex effect was found to be at an osmolality of between 600 and 700 mosm/kg H2O, that is, at about twice the osmolality of blood. This result is consistent with results obtained to date in investigations in the non-anesthetized rat and in diagnostic examinations with CM in humans. The effects of both sorbitol and the ionic CM at a given osmolality were dose dependent only after low doses and not after a high dose. There were no pain reactions after injection of ionic and nonionic CM with a low osmolality. Release of prostacyclin was observed in preliminary tests after injection of ionic substances with high osmolality, but not after injection of CM with low osmolality.
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The vasoconstrictor effect of neuropeptide Y (NPY) was compared with that of noradrenaline (NA) in the isolated perfused rabbit ear. Phentolamine at a concentration which completely abolished the effect of NA, did not diminish the effect of NPY. The combined vasoconstrictor effect of NPY and NA was significantly stronger than the calculated effect of an additive interaction, but not significantly stronger than an independent combination. This can be interpreted as an overadditive effect, and may be an indication for different points of attack with independent actions of these two transmitters in the vessels of the rabbit ear. Eicosapentaenoic acid (EPA) dose-dependently antagonized the effect of NPY to a similar degree as that of NA. In the presence of indomethacin (8.6 mumol/l), neither the effect of NPY nor that of EPA was changed. Moreover, EPA (33 mumol/l) diminished the combined vasoconstrictor effect of NA and NPY. These findings indicate that EPA is a non-selective antagonist of sympathetic transmitters in small peripheral vessels and excludes an interaction at specific receptors.
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Exogenous eicosapentaenoic acid (EPA, 16.5 mumol/l or 33 mumol/l) inhibited dose-dependently the anaphylactic contractile response of guinea-pig lung parenchymal strips suspended in an organ bath. As determined by radioimmunoassay, EPA inhibited in a dose-dependent manner the anaphylactic release of the cyclooxygenase products thromboxane (TX) B2 and 6-keto-prostaglandin (PG) F1 alpha but simultaneously enhanced the release of sulfidopeptide (SP)-leukotrienes (LT). Indomethacin (2.8 mumol/l) abolished the release of cyclooxygenase products but potentiated the release of SP-LT. However, indomethacin treatment did not affect the inhibitory action of EPA on the contractile response of the anaphylactic lung strips. The lipoxygenase inhibitor, esculetin (50 mumol/l), inhibited the release of SP-LT and also that of cyclooxygenase products of polyunsaturated fatty acid metabolism. The combination of esculetin and EPA resulted in enhanced inhibition of the anaphylactic contractile response as compared to EPA alone. By reversed phase high pressure liquid chromatography (HPLC), SP-LT from anaphylactic lung parenchymal strips was shown to consist of LTD4 and LTE4. EPA-pretreated lung strips released upon immunologic challenge additional immunoreactivity comigrating with authentic LTC4, LTC5, LTD5 and LTE5. While anaphylactic control strips also released LTB4, in the bath fluid of EPA-treated strips, an additional immunoreactive compound migrating with the retention time of LTB5 was observed. In non-sensitized guinea-pig lung parenchymal strips EPA inhibited the myotropic activity of exogenous mediators such as histamine (9 mumol/l), LTC4 (16 nmol/l) and the TX mimetic U 46619 (28.4 nmol/l), an effect which was neither affected by indomethacin (2.8 mumol/l) nor by the lipoxygenase inhibitor nordihydroguaiaretic acid (NDGA, 10 mumol/l).(ABSTRACT TRUNCATED AT 250 WORDS)
The effects of infusions of eicosapentaenoic acid (EPA) (6 X 10(-8) mol min-1 and 15 X 10(-8) mol min-1) on the coronary constriction and the release of immunoreactive sulphidopeptide-leukotrienes (SP-LT), thromboxane B2(TXB2) and 6-keto-prostaglandin F1 alpha (PGF1 alpha) from perfused anaphylactic guinea-pig hearts were investigated. EPA dose-dependently inhibited the profound early coronary flow reduction after antigen injection. The less pronounced late phase of anaphylactic coronary flow reduction was, however, not significantly affected. EPA (15 X 10(-8) mol min-1) significantly shortened the average duration of antigen-induced arrhythmias. EPA dose-dependently decreased release of immunoreactive TXB2 and 6-keto-PGF1 alpha from anaphylactic guinea-pig hearts. Release of immunoreactive SP-LT was dose-dependently increased after antigen challenge in the presence of EPA. Inhibiton of the release of SP-LT by the lipoxygenase inhibitor esculetin (1 X 10(-7) mol min-1) was accompanied by a significant attenuation of flow reduction during the late phase of anaphylactic vasoconstriction. Reversed phase h.p.l.c. of perfusates from anaphylactic guinea-pig hearts revealed immunoreactivity comigrating with authentic leukotriene C4 (LTC4), LTD4, and LTE4. In perfusates from hearts treated with EPA infusions, additional immunoreactivity was detected comigrating with LTC5, LTD5 and LTE5. In addition to immunoreactivity migrating with LTB4, as observed in control heart perfusates, in perfusates from EPA-treated hearts, a second peak was observed, which coincides with the retention time described for LTB5. Exogenous LTC5 (1 X 10(-12) mol min-1 and 20 X 10(-12) mol min-1) induced dose-dependent reductions of coronary flow and was found to be a slightly weaker constrictor than LTC4, but no significant differences were observed. Coronary vasoconstriction elicited by infusion of exogenous LTC4 (20 X 10(-12) mol min-1) was dose-dependently inhibited by infusions of EPA. However, the negative inotropic effect of LTC4 remained unaffected. Thus, in the isolated anaphylactic heart of the guinea-pig exogenous EPA was effectively metabolized via the 5-lipoxygenase pathway whereas the cyclo-oxygenase pathway of polyunsaturated fatty acid metabolism was found to be inhibited. The results are in agreement with the suggestion that cyclo-oxygenase products are mediators of the early phase of the anaphylactic coronary constriction, while vasoconstrictor SP-LT are involved in the later phase. However, in spite of enhanced release of SP-LT, EPA infusion did not result in increased coronary constriction. Considering the fact that EPA antagonizes LTC4-induced coronary constriction, it seems possible, that EPA might act as a functional antagonist of vasoconstrictor eicosanoids including EPA-derived SP-LT.
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The isolated perfused rabbit ear was used to investigate the effect of eicosapentaenoic acid (EPA) on the vasoconstriction induced by noradrenaline (NA) and angiotensin II (A II). EPA (0.1, 1.0, 10.0 micrograms/ml) was shown to reduce the vasoconstriction (inhibition of flow) induced by NA in a dose-dependent manner. The dose-response curves of NA were shifted to the right. Emax of NA was reduced in particular at the highest concentration of EPA. The maximum effect of EPA developed slowly and reached a steady state after 150 min (0.1 microgram/ml EPA), 120 min (1.0 microgram/ml EPA), 100 min (3.0 microgram/ml EPA) and 60 min (10 micrograms/ml), respectively. In the presence of indomethacin (3 micrograms/ml), the vasoconstrictor effect of NA was not significantly influenced. The effect of EPA (3 micrograms/ml) was not reduced by indomethacin. In the presence of the lipoxygenase inhibitor nordihydroguaiaretic acid (NDGA, 10 micrograms/ml), the vasoconstrictor effect of NA was not significantly influenced. The effect of EPA (3 micrograms/ml) was not reduced by NDGA. Concomitant addition of indomethacin (3 micrograms/ml) and NDGA (10 micrograms/ml) also did not reduce the effect of EPA. EPA (3.0, 10.0 micrograms/ml) was shown to reduce also the vasoconstrictor effect of A II in the absence and the presence of the cyclooxygenase and lipoxygenase inhibitors. Determination by radioimmunoassay showed that the levels of thromboxane B2 (TXB2)-like immunoreactivity were below the detection limit in the perfusate of the ear. The levels of 6-keto-PGF1 alpha- and PGE2-like immunoreactivity in the perfusate were low. EPA reduced the concentration of 6-keto-PGF 1 alpha.(ABSTRACT TRUNCATED AT 250 WORDS)
Epilobium species have been used as remedies in folk-medicine for the treatment of pathophysiological processes of the prostata. In this paper the influence of extracts of Herba Epilobii angustifolii L. and Herba Epilobii parviflori Schreb. on prostaglandin biosynthesis and the carrageenin rat paw oedema is described. Aqueous extracts of Herba E. angustifolii reduced the release of prostaglandins I2, E2 and D2 (in the perfused rabbit ear) approximately 5 times more effectively than did similar extracts of Herba E. parviflori. Methanolic extracts were inactive. The aqueous extract of E. angustifolium strongly reduced the carrageenin-induced rat paw oedema whereas that of E. parviflorum was inactive. The chemical nature of the active compound(s) is as yet unknown but flavonoids and sitosterol derivatives can be excluded.
The isolated rabbit ear was labeled by perfusion either with 14C-arachidonic acid (AA) or 14C-dihomo-gamma-linolenic acid (DGLA). The influence of unlabeled eicosapentaenoic acid (EPA) on the release and metabolism of the labeled prostaglandin (PG) precursors was studied with the aid of radio-thin-layer-chromatography (TLC). After incorporation of 14C-AA, the ionophore A 23187 (10 micrograms) stimulated the release of products comigrating on TLC plates with authentic PGI2 (measured as 6-keto-PGF1 alpha), PGE2, PGD2 and AA. In unlabeled ears, A 23187 (10 micrograms) stimulated the release of PGI2 and PGE2 (determined by radioimmunoassay) in similarly relative amounts as found for the labeled products. The release of PGD2 was not measured. After incorporation of 14C-DGLA, A 23187 (10 micrograms) stimulated the release of labeled products comigrating in several TLC-systems with 6-keto-PGF1 alpha (but not PGF1 alpha), PGE1, PGD1 and DGLA. After incorporation of 14C-AA, infusion of unlabeled EPA (0.1, 1 and 10 micrograms/ml) reduced the release of 14C-PGI2 but not of the other bisenoic PGs. Furthermore, in ears labeled with 14C-DGLA, EPA strongly reduced the release of a product comigrating with 6-keto-PGF1 alpha and to a lesser extent of a product comigrating with PGE1. Infusion of unlabeled EPA (1 and 10 micrograms/ml) did not reduce the release of 14C-AA or 14C-DGLA indicating that a phospholipase A2 was probably not inhibited by EPA. It is concluded that EPA inhibits PGI2 synthase rather than cyclooxygenase since after incorporation of 14C-AA, only the release of PGI2 is reduced.(ABSTRACT TRUNCATED AT 250 WORDS)
The influence of feeding a marine oil (MaxEPA) with a high content of eicosapentaenoic acid (EPA) to rats for 10 weeks on the development of carrageenin oedema was studied. Since prostaglandins (PGs) are involved in the development of this acute experimental inflammation, the influence of EPA feeding on PG release from aorta (PGI2) and from the subplantar skin of the inflamed foot (PGI2, PGE2) was investigated also. MaxEPA was fed in two daily doses containing 50 or 100 mg EPA/kg/day. In both rat groups there was no influence of EPA on the development of the oedema. However, the capacity of aorta and skin of the plantar region of the experimentally inflamed foot to release PGI2 was strongly reduced by EPA. On the other hand, the release of PGE2 from the skin was not reduced. Indomethacin at a low dose (2 mg/kg perorally) reduced the development of the paw oedema as well as the release of PGs in control rats and rats on an EPA-containing diet. It is concluded that EPA did not influence carrageenin oedema because there was an adequate production of the oedema promoting substance PGE2.
The isolated rabbit ear was perfused with 14C-arachidonic acid (AA), with 14C-eicosapentaenoic acid (EPA) or with 14C-dihomo-gamma-linolenic acid (DGLA). After incorporation of 14C-AA, the ionophore A 23187 (10 micrograms) stimulated the release of products comigrating with authentic PGI2 (measured as 6-keto-PGF1 alpha), PGE2 and PGD2 on the thin layer chromatography plate. After incorporation of 14C-EPA, A 23187 did not release any trienoic 14C-PGs. After incorporation of 14C-DGLA, A 23187 stimulated the release of labeled products comigrating with 6-keto-PGF1 alpha (but not PGF1 alpha), PGE1 and PGD1. Infusion of unlabeled AA (1 and 10 micrograms/ml) did not influence the metabolism of 14C-EPA or 14C-DGLA. Infusion of unlabeled DGLA (10 micrograms/ml) strongly stimulated the release of trienoic 14C-PGs but did not significantly increase the release of bisenoic 14C-PGs. Neither DGLA nor AA influenced the release of any other labeled incorporated PG precursor, indicating that a phospholipase A2 was not affected. The results show that DGLA is able to stimulate the metabolism of incorporated 14C-EPA resulting in an increased release of antiaggregatory trienoic PGs. The mechanism of this effect is unclear but it may be mediated via the formation of a hydroperoxide derivative of DGLA. Thus, an increased generation of antithrombotic trienoic PGs may be expected under special conditions, possibly also in vivo, depending on the supply of unsaturated fatty acids or the level of various hydroperoxide derivatives.