Prostaglandins and medicine最新文献

Various therapies during early hours of acute myocardial infarction (AMI) have been suggested to protect ischemic myocardium and reduce infarct size. Despite reports that prostaglandins (PGs) are released during myocardial ischemia, and that prostacyclin (PGI2) and thromboxane A₂ (TXA₂) have opposing effects on vasomotion and platelet aggregation, the physiologic roles of PGs, PGI2 and TXA₂ in AMI have not been clearly defined. However, in pharmacologic doses, experimental evidence suggests that vasodilator PGs might be beneficial, and vasoconstrictor PGs might be deleterious, in AMI. Recent recognition that coronary spasm is frequent in AMI has led to the notion that an increased PGI₂/TXA₂ ratio might be desirable. Thus, exogenous PGEl, exogenous PGI2 or its more stable analogs, drugs that stimulate PGI2 release, and inhibitors of TXA₂ and harmful PGs are potential agents for protective therapy in AMI.

Several authors have reported that salicylate blocks and reverses aspirin inhibition of prostaglandin synthesis by platelets and arterial wall. Male rats were given sodium salicylate 15 or 100 mg/kg i.v. 2 min before receiving aspirin, 10 mg/kg i.v. Right and left carotid arteries were injured electrically before and after drug administration and thrombus generation recorded by measuring downstream temperature. Significant antithrombotic effect of aspirin was observed in all cases regardless of prior salicylate administration and the results were similar to those obtained with aspirin alone. Thus competition between salicylate and aspirin as reported $\text{in vitro}$ does not appear to significantly affect the in vivo antithrombotic action of aspirin in this model.

The secretion of gastric mucus may play a role in the protective effect of prostaglandins against gastric ulcers. To investigate the effect of prostaglandins E₁, E₂, F_1α, F_2α, A_l, A₂ and 15(S)15 methyl prostaglandin E₂, F_1α, ester on gastric mucus secretion, these prostaglandins were given orally to rats at doses of 0.1, 1.0 and 4.0 mg/kg. The anthrone method was used to analyze the amount of mucus washed from the stomach with 2 M NaCl. Gastric secretory volume effects were also observed. All of the compounds tested increased both gastric mucus and secretory volume. The most. active compound was 15(5)15 methyl PGE₂ Me ester. The mucus stimulating effect of these prostaglandins, when administered locally, may be relevant to the understanding of the anti-ulcer effects of prostaglandins.

Mean blood pressure (MBP) was found to be lower, while renal plasma flow (RPF), glomerular filtration rate (GFR), sodium excretion rate (U_NaV), potassium excretion rate (UKV) and urinary prostaglandin E (PGE) concentration were higher in 15 normotensive subjects (15NS) compared with the values obtained in 15 essential hypertensive patients (15EHP) of the same mean age. After volume expansion of the 15EHP with isotonic saline infusion, RPF, UNaV, UKV, urine volume (UV) and urinary PGE increased significantly while plasma renin activity (PRA) decreased significantly. Urinary aldosterone concentration and MBP decreased also but not significantly. After oral administration of 75 mg of indomethacin, in the same saline loaded groupe of 15 EHP, urinary PGE, urinary aldosterone and PRA decreased sianificantly while RPF, GRF, UNaV remained unaltered and MBP increased. When these values obtained in saline loaded and indomethacin treated 15EHP were compared to those obtained in the same group before volume expansion, it was found that RPF, UNaV, UKV and UV were higher after indomethacin-saline administration while MBP, GRF and urinary PGE did not differ significantly and PRA and urinary aldosterone were significantly lower. These findings arque against the suggestion that PGE increases sodium reabsorption at the distal tubule and indicate that the unaltered sodium excretion rate in saline loaded and indomethacin treated unanaesthetized subjects, results from the simultaneous decrease of renomedulary PGE, Renin and aldosterone secretion.

Seven clinically important phenothiazine drugs (chlorpromazine, promazine, triflupromazine, thioridazine, fluphenazine, trifluoperazine and perphenazine) stimulated synthesis of PGE₂ and PGF_2α in RBL-1 cells in culture. Structural differences in the side chain at N10 had little effect on their activities.Some of the metabolites also were active, in keeping with the clinical observation that phenothiazines may have. antipsychotic effects long after the parent compound has been eliminated from the circulation. Among the chlorpromazine metabolites, methoxy substituents on the phenothiazine nucleus did not strikingly affect stimulating activity. Monohydroxy derivatives were slightly more effective than the parent compound; there was little difference between hydroxy substitution at 7 or 8 position. The 7,8 dioxo, the N-oxide, the sulfoxide, and the 7-OH glucuronide derivatives were inactive.

In two of three patients with peripheral vascular disease, systemic infusion of PGE1 inhibited chemotactic factor induced secretion of glucosaminidase from neutrophils.

¹⁴C-Arachidonate (50 nmol) was injected into the pulmonary circulation of isolated perfused lungs of female hamsters and the metabolites were analysed from the nonrecirculating perfusion effluent. Pulmonary infusion of dipyridamole (20 μM) increased the amount of radioactivity in the perfusion effluent of 0-4 min from 12.8 ± 1.0 % to 17.2 ± 1.5 % (2P < 0.05) of the injected amount. Dipyridamole increased the amounts of PGF_2α, PGE₂ and two unidentified metabolite groups in the effluent. An increasing trend was seen also in the amount of 6-keto-PGF_1α and TxB₂. A decreasing trend was, however, seen in the amount of metabolites migrating near to unlabelled 15-keto-PGE₂. When 20 nmol of ¹⁴CPGE₂ was injected into the pulmonary circulation of isolated hamster lungs, the amount of 15-keto-metabolites of PGE₂ in the effluent was decreased and that of unmetabolized PGE ₂ increased by dipyridamole dose dependently. The rate of efflux of radioactivity from the lungs was increased by dipyridamole. Dipyridamole was in vitro not an inhibitor of 15-hydroxyprostaglandin dehydrogenase in the 100.000 supernatant fraction of homogenized hamster lungs. At 20 μM and 100 μM it even caused a slight in vitro activation of 15-hydroxyprostaglandin dehydrogenase. Thus the decreased pulmonary inactivation of PGE₂ by dipyridamole is obviously due to the decreased uptake of PGE₂ into the lungs. This could explain partly the detected changes in the pulmonary metabolism of arachidonic acid by dipyridamole.

In order to investigate involvement of prostaglandins (PGs) in ovulation, we examined whether the antiserum to cyclooxygenase was able to inhibit superovulation in immature female rats as indomethacin did. The antiserum to cyclooxygenase was raised in rabbits using as antigen the solubilized cyclooxygenase extracted and purified from bovine seminal vesicles. The $\text{in}$$\text{vivo}$ administration of the antiserum inhibited superovulation in female rats dosedependently at doses of 0.1, 0.2 and 0.4 ml but did not affect production of progesterone. Inhibition of cyclooxygenase in the follicular cells due to the antiserum causing no effect on steroidogenesis was observed in organ cultures of the follicles excised from rats primed with PMS-hCG and the antiserum. In contrast to this, no inhibition of cyclooxygenase was detected upon adding the antiserum to the culture medium. The present study showed PG is as indispensable a factor in ovulation as are the steroids.

We have previously reported that hyperosmotic solutions of sodium chloride or of xylitol possess potent anti-ulcer activity and reduce gastric acidity in the rat. They also stimulate gastric prostaglandin (PG) biosynthesis, which may bear a causal relationship to the above effects. In the present investigation we studied the effect of intragastric hyperosmolarity on the transmucosal potential difference (PD) and on the permeability to H⁺ ions in the rat stomach. We also studied the effect of the prostaglandin synthetase inhibitors, indomethacin and flufenamic acid, on these parameters. Rat stomach was perfused in vivo, under urethane anesthesia, by xylitol solutions made up in 0.01 N HC1. While moderately hyperosmotic (13%) xylitol was without effect, the perfusion of intensely hyperosmotic xylitol (34.5%) resulted in a long lasting reduction of the transmucosal PD from a mean (±SEM) of −63±4 mV to a trough value of −40±3 mV. This depression of transmucosal PD was inhibited in a dose-related fashion by prior treatment with the PG-synthetase inhibitors. Acid recovery in the effluent was significantly reduced by the 34.5% xylitol solution, and indomethacin pretreatment did not modify the effect of hyperosmotic xylitol. It is concluded that, although intensely hyperosmotic xylitol produces some of the characteristic effects of a barrier breaker, i.e. depression of transmucosal PD and acid back diffusion, these two phenomena probably involve different mechanisms, as indicated by their differential response to indomethacin.

To determine the release and absorption of prostaglandin E₂ from a viscous gel instilled into the vagina for clinical purposes, serial measurements of prostaglandins E and F in amniotic fluid have been made. The results obtained suggest that the exogenous prostaglandins reach the amniotic fluid four hours after administration and following the onset of uterine stimulation. The findings are in agreement with previous clinical observations and indicate that the technique could be used to make further improvements in the prostaglandin carrier vehicles used in clinical practice.