Biomedical subjects
Publications and source records attributed to H Bult.
Inflammatory models in rats, depleted of prostaglandin precursors, are discussed as a novel approach to investigate anti-inflammatory drug mechanisms independent of interaction with the production of prostaglandins and to study the ambivalent (pro- or anti-inflammatory) role of endogenous prostaglandins.
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Rat platelet rich plasma (PRP) generates prostaglandin endoperoxide-like activity, thromboxane A2 (TXA2) and stable prostaglandins (PGs) after collagen addition. Of the stable PGs, PGE is the main product and its formation is related to the dose of collagen. Indomethacin and eicosatetraynoic acid (TYA), both cyclo-oxygenase inhibitors, inhibit TXA2 and PGE formation simultaneously. PRP of essential fatty acid deficient (EFAD) rats, however, generates far less PG-endoperoxide like activity, TXA2 and PGE, though the release of serotonin (5-HT) is unaltered. In normal rats a marked inhibition of the cyclo-oxygenase by TYA also has no effect on 5-HT release. For these 2 reasons the role of PG endoperoxides and TXA2 seems to be unimportant for the 5-HT release reaction. The diminished biosynthesis of PGs and TXA2 in EFAD PRP is not due to an impaired cyclo-oxygenase activity since addition of AA causes an equal formation of PGE in both types of PRP. The use of platelets as in-vitro model for testing anti-inflammatory activity of drugs is discussed. The results, obtained with platelets support the hypothesis that the main reason for the decreased acute inflammatory reaction in EFAD rats is a diminished supply of endogenous PG precursors.
The carrageenin-induced paw oedema was used to study anti-inflammatory drugs in normal rats and in those deprived of endogenous precursors of prostaglandins. The latter condition was achieved by permanently keeping the rats on essential fatty acid deficient (EFAD) food. Indomethacin inhibited the carrageenin-oedema in normal rats, but failed to further suppress the poorly developed delayed phase of the carrageenin-induced inflammation in EFAD rats. In contrast, aspirin exhibited equal inhibition of the carrageenin oedema in both normal and EFAD rats. The anti-inflammatory effect of dexamethasone was also indentical in both normal and EFAD rats. Since in EFAD rats the inflammatory role of an increased output of prostaglandins is of negligible importance, the results with aspirin and dexamethasone shed some doubt on such views, that suppression of the release of prostaglandins alone explains the acute anti-inflammatory effects of these drugs. The inflammatory response of EFAD rats is a model situation appearing to be useful in studying anti-inflammatory mechanisms which, under normal conditions, might be masked by interference with the release of prostaglandins.
Paw oedema, induced by carrageenan, was potentiated in normal rats by arachidonic acid and bishomo-gamma-linoleic acid, but not by 5,8,11-eicosatrienoic acid. The latter is not an endogenous prostaglandin precursor, but replaces the other two in essential fatty acid deficient (EFAD) rats. Carrageenan oedema was partially suppressed in these EFAD rats. Aspirin exhibited equal suppression of carrageenan oedema in both normal and EFAD rats, despite the fact that, in the latter, prostaglandins are of negligible importance. The anti-inflammatory effect of dexamethasone was also identical in both normal and EFAD rats. The view that interference with the prostaglandin-system explains the acute anti-inflammatory effects of the two drugs, is discussed, in relation to the present results.
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The specificity of the isolated rabbit aorta for identification and assay of prostaglandin endoperoxides, formed during aggregation of platelet rich plasma (PRP) from rats, was investigated in the superfused organ cascade. The use of cumulative dose-response curves in this design is quicker than conventional step-wise dosing while delivering identical results. On the rabbit aorta, in contrast to the rat fundus strip, methysergide is too weak an antagonist to rule out responses due to 5-HT. After pretreatment with phenoxybenzamine, in the presence of methysergide, the rabbit aorta retains its sensitivity towards oxygenated fatty acids, while being virtually unreactive towards 5-HT. The prostaglandin endoperoxide PGH2 is more potent than prostaglandin E2 when assayed on the rabbit aorta, while on the rat fundus the situation is reversed. Combining the rabbit aorta and rat fundus strip with pre-filtration on Amberlite XAD-2 columns showed that during collagen induced aggregation rat PRP generated both a labile RCS-most probably a prostaglandin endoperoxide- and a lipophylic prostaglandin-like material, along with 5-HT.
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Vernolepin, a sesquiterpene lactone, was isolated from the dried fruit of Vernonia amygdalina Del. The different steps used during the extraction were: continuous extraction with chloroform, partition of the chloroform-extract between pertroleum ether and 10% aqueous methanol, column chromatography of the methanol extract, isolation of the active fractions by pharmacological and chemical characterization. Vernolepine was obtained as colorless prisms and identified by melting point, uv, ir, 1H nmr, optical rotation, and mass spectrometry. The total content of the dried fruit was 0.09% vernolepin. The first pharmacological characterization of vernolepin revealed: (1) a competitive antagonism against histamine in guinea pig ileum (pA2 = 5.61; 15 min incubation); (2) a biphasic enhancement/inhibition of coaxial stimulation of guinea pig ileum; (3) an antiaggregating and disaggregating activity against rabbit platelet aggregation induced by arachidonic acid (1 X 10(-4) g/ml; 3.3 X 10(-4)M) or ADP (4 X 10(-6) g/ml; 1 X 10(-5)M) without inhibition of cyclo-oxygenase or lipoxygenase. All these reactions were time dependent and occurred at concentrations of 5 X 10(-6) to 1 X 10(-5) g/ml vernolepin (1.8 to 3.5 X 10(-5)M).
The roles of vasoactive intestinal polypeptide (VIP) and nitric oxide (NO) in nonadrenergic noncholinergic (NANC) nerve-mediated relaxations were investigated in longitudinal muscle strips of the rat gastric fundus. Transmural stimulation (1-16 Hz for 2 min), VIP and noradrenaline evoked a prolonged relaxation of the rat gastric fundus, whereas NO evoked a transient relaxation. Only the electrically induced responses were blocked by tetrodotoxin. The inhibitor of NO biosynthesis NG-nitro-L-arginine (L-NNA) preferentially inhibited the relaxations induced by low frequency stimulation. In contrast, trypsin mainly reduced the electrically induced relaxations to high frequency stimulation; the NANC relaxations resistant to trypsin were further inhibited by L-NNA. VIP-induced relaxations were abolished by trypsin, but remained unaffected by L-NNA. NO- or noradrenaline-induced relaxations were not inhibited by either L-NNA or trypsin alone, whereas the combination of L-NNA and trypsin slightly reduced the noradrenaline-induced responses. These results suggest that NANC responses in the rat gastric fundus at low frequency are mediated mainly by NO, whereas at higher frequency NO together with a peptide, probably VIP, are released.
The kinetic parameters Vmax and Km of the carrier-mediated uptake of serotonin by the lung can be used as an index of endothelial distress. To this purpose we have recently developed a new mathematical model which estimates the kinetic parameters of the double uptake mechanism of serotonin by the rabbit lung (MODEL3, Peeters et al., 1989). The aim of the present study was to evaluate the behavior of this new model after inhibition of the uptake by clomipramine and after reduction of the perfused lung surface with glass bead embolization. Clomipramine administration did not cause distinct hemodynamic alterations, but decreased the serotonin extraction and Vmax/Km (the sum of all first order rate constants). After clomipramine, Vmax1, i.e., the maximal velocity for the first uptake pathway, was significantly decreased, while Km1 tended to increase without reaching significance. The virtual inhibition constant of clomipramine was about 1 microM. Glass bead embolization resulted in large hemodynamic responses, decreased extraction of serotonin and decreased values for Vmax/Km and Vmax1. This is consistent with a diminished vascular surface available for serotonin extraction. We conclude that MODEL3 was able to detect changes in intrinsic uptake capacity and vascular surface area, which were especially reflected in a decrease of Vmax/Km and Vmax1.