Prostaglandins, leukotrienes, and medicine最新文献

The influence of hypoxia on the spontaneous platelet aggregation (SPA) and thromboxane formation was studied. The analysis of aggregation curve was carried out according to Breddin.

The hypoxia enhanced the aggregayility from Q₂norm = 2.46 ±0.40 (normoxia) to Q₂hyp = 4.39±0.39 (hypoxia), n = 52, p < 0.001. 10 samples of those showed no SPA under equilibration with air but the hypoxic stimulus provoked SPA (Q₂norm = 0, Q₂hyp = 1.19±60, n = 10, p < 0.001).

When the results were arranged according to the degree of the stimulation of SPA, two groups could be separated with low and high response to hypoxic.

The hypoxia caused also an augmentation of the TXB₂ level in comparison to normoxia. The stronger enhancement of the TXB₂ formation during the incubation under hypoxic conditions was independent of the fact whether SPA took place or not.

The present study suggests that hypoxic conditions alone may be a reason for a stimulated TXA₂ formation of the platelets and that the enhanced TXA2 formation caused by hypoxic is possibly inducing or reinforcing the SPA.

Oil of cloves (OC) was found to be a potent inhibitor of platelet aggregation induced by arachidonic acid (AA), collagen and epinephrine; in this respect it was most effective against AA-induced aggregation. Inhibition of aggregation by OC seems to be mediated through a reduced formation of thromboxane as indicated by the following experimental evidence. (i) OC inhibited TxB₂ formation in intact as well as lysed platelet preparations from added arachidonate, and (ii) it inhibited the formation of TxB₂ from AA-labelled platelets after activation with Ca²⁺-ionophore A23187. The formation of lipoxygenase derived products was dependent on the concentration of OC used; at its lower concentration their amounts increased but this was found to be reversed at higher concentrations. At all concentrations thromboxane was decreased with a concomitant increase in unused AA.

It has been suggested that the circulating prostacyclin in primarily inactivated by renal NAD+-dependent 15-hydroxyprostaglandin dehydrogenase. Changes in the renal enzyme activity in response to hormones were studied. The renal 15-hydroxyprostaglandin dehydrogenase activity in female rats was lower than that in male rats, and was significantly increased by ovariectomy. The effect of sex steroids on the renal enzyme activity was then studied in ovariectomized rats. Estradiol administration induced a significant decrease in the renal enzyme activity, while testosterone did not show any significant effect. Kinetic parameters for the renal enzyme from control and estradiol-treated groups were compared. An identical apparent Km for prostaglandin E₂ was obtained for the enzyme from both groups. Vmax in the treated group was progressively decreased. The enzyme from both groups decayed at the same rate. The results indicated that estradiol might be the major endogenous sex steroid regulating the renal NAD+-dependent 15-hydroxyprostaglandin dehydrogenase activity, and the inhibitory effect of estradiol on the renal enzyme might be due to the inhibition of the enzyme biosynthesis.

The influences of a period of 15 days of restricted diet (50% of the normal food intake) in rats sacrificed at different stages of the sex cycle (proestrus, estrus, metestrus and diestrus), were explored on: (1) the magnitude of uterine spontaneous phasic contractions (isometric developed tension= IDT); (2) the release of prostaglandins (PGs) F_2α and E₂; from the uterus and (3) the myometrial inotropic responses evoked by methoxamine and indomethacin. At estrus and at proestrus, preparations from restricted diet rats exhibited greater initial (postisolation) IDT and better contractile constancy during 60 min than did uteri from normal fed rats. This enhanced contractile constancy, but not that of preparations from control fed rats, was prevented by incubation “in vitro” with indomethacin (10⁻⁶M). At metestrus and at diestrus, uteri from normal fed rats presented higher initial levels of IDT and even more sustained contractile constancy than at estrus or at proestrus. Moreover, contractile profiles remained unaltered following the dietary restriction and the presence of indomethacin evoked similar negative inotropic actions in both experimental groups (fed and underfed). Dose-response curves for methoxamine documented its possitive, but different, inotropic actions in the two groups and at the four periods of the estrous cycle. Indeed, in the underfed group at estrus and at proestrous, dose-response curves for methoxamine were shifted to the left of those in fed controls,a situation prevented by indomethacin (10-6M); whereas at metestrus and at diestrus, no differences in the inotropic reactivity towards methoxamine between the two experimental groups, were detected. On the other hand, indomethacin shifted to the right dose-response curves for the agonist, both in preparations from normal fed and from restricted diet rats. The generation and release of PGF_2α and of PGE₂ were explored under normal and restricted diet conditions, both at estrus and at diestrus. Following the dietary restriction, the output of PGE₂ from estrous uteri was augmented in comparison to controls, whilst the release of PGF_2α was not affected. At diestrus, dietary restriction failed to alter the uterine output of either one of these PGs. Results suggest that a greater generation and release of PGE₂, following underfeeding, appears to subserve the increased spontaneous motility and the greater sensitivity of the rat uterus for — adrenoreceptor agonists.

The effects of four beta-adrenoceptor blocking agents on platelet aggregation, formation of thromboxane from exogenous arachidonic acid (AA) in platelets, on AA incorporation in platelet phospholipids, and on platelet phospholipase activity were studied. Of the four drugs pindolol inhibited thromboxane formation in a dose-related (0.25–1.0 mM) manner apparently by exerting its influence at the cyclooxygenase (CO) level. This drug also inhibited aggregation induced by AA, collagen, epinephrine and ADP. Atenolol and metoprolol though not showing inhibition of AA-induced aggregation did inhibit collagen- and ADP-induced aggregation; metoprolol reversed ADP-induced aggregation, and abolished second phase of epinephrine-induced aggregation. Timolol did not inhibit aggregation induced by all the aggregating agents. Atenolol inhibited (by ca. 1096) TxB₂ formation in platelets from exagenous as well as endogenous AA at rather high concentrations (1.0 mM). Metoprolol and Tmolol did not do so. The observations reported here can be best explained by taking into account the membrane stabilizing effects and lipophilic properties of the drugs.

In order to investigate prostacyclin production by human myometrium, uterine cervix and leiomyoma, slices of each tissue were incubated.The 6-keto prostaglandin F_1α concentration of the incubation medium was measured by radioimmunoassay. The serosal and endometrial sides of myometrium produce 6-keto prostaglandin F_1α, with no significant difference in production between the two sides. The 6-keto PGF_1α production of leiomyoma was significantly higher than that of myometrium. Our results suggest that human myometrium and leiomyoma produce prostacyclin regardless of vascularization.

Cumulative dose-response curves for histamine induced responses in mesometrial (ME) and antimesometrial (AME) regions of uterine horns isolated from rats at 7th, 16th and 22nd days of pregnancy, were constructed. Histamine inhibited, in dose-related fashion, the isometric developed tension in ME and AME strips obtained at the 7th day of pregnancy, an action antagonized by cimetidine (10⁻⁴–10⁻⁵M). On the contrary, at the 16th and 22nd days, histamine (10⁻⁵–10⁻³M), stimulated spontaneous contractions in the ME region but had no effect in the AME segment. Although histamine and SKF-71481-A₂,aH₁-receptor agonist, both at 10⁻⁴M, enhanced similarly ME inotropism at the 16th and at 22nd days of pregnancy, the positive contractile action of histamine was greater at the 16th than at the 22nd day. Moreover, cumulative dose-response curves for histamine and SKF-71481-A₂ in the ME region of uteri isolated at the 16th day of gestation, showed that both agonists have approximately the same inotropic potency and efficacy. On the other hand, pyrilamine (at 10⁻⁴M, but not at 10⁻⁵M),aH₁-receptor antagonist, shifted to the right the dose-response curve for histamine in ME strips from uteri at the 16th day of pregnancy and attenuated significantly, the magnitude of the positiue inotropism evoked by the amine. Similar findings were observed in the presence of chlorpheniramine (at 10⁻⁶M) another H₁-receptor blacker. In addition, the positive uterine inotropism evoked by histamine in the ME region of preparations isolated at the 16th day of pregnancy, was significantly reduced by an antagonist of phospholipase A₂ (mepacrine, 10⁻⁴M) as well as by acetylsalicylic acid (ASA at 10⁻⁴M), an inhibitor of cyclooxygenase. Results also indicate that the excitatory uterine inotrpism elicited by the agonistic amine in ME strips isolated from rats at the 16 th day of pregnancy, was coincident with an enhanced release of prostaglandins (PGs) E₂ and F₂ α, but not of PGE₁ and that both augmenting actions of histamine were antagonized by histamine H₁ receptor-blockers, namely pyrilamine (mepyramine or chlorpheniramine. Results suggest that histamine at early pregnancy diminished myometrial inotropism via its interaction with H₂-receptors, whereas from mid pregnancy up to the moment of parturition it evokes contractile stimulation, most likely due to the activation of H₁-receptor located at the mesometrial region of rat uterine horns. Altogether the present data suggest that after mid pregnancy, histamine acts at the ME region of the uterus through a cascade of influences: (a) activation of H₁ receptors, (b) stimulation of phospholipase A₂ (via an increased permeability of calcium ions?), which catalyzes the release of