Sune Bergström

Effect of prostaglandin E2 on central and peripheral catecholamine neurons

Abstract Effects of prostaglandin E2 (PGE2) on catecholamine (CA) release from CA neurons have been studied in two models; influence on field stimulation-induced overflow of tritium from isolated tissues pre-incubated with 3H-CA; influence on dopamine (DA) disappearance in the neostriatum induced by tyrosine hydroxylase inhibition utilizing histochemical fluorescence analysis of catecholamines. In vitro PGE2 (3 × 10−6 M) caused a small but probably significant reduction of the field stimulation-induced tritium overflow from central noradrenaline (NA) and central DA nerve terminals and a significant reduction of the stimulation-induced overflow from peripheral NA nerve terminals. In the in vivo experiments PGE2 in μg amounts was dissolved in Krebs-Ringer bicarbonate buffer and infused into the left neostriatum, whereas buffer alone was infused into the right neostriatum. Infusion of 9–18 μg of PGE2 reduced the disappearance of DA fluorescence after treatment with the tyrosine hydroxylase inhibitor α-methyl-tyrosine methylester ( H 44 68 ) under resting conditions, but could not counteract the increase in H 44 68 - induced DA disappearance caused by electrical stimulation of the nigro-neostriatal DA pathway. The findings suggest that PGE2 can modify but not stop the release of DA and NA from central CA nerve terminals and indicate that prostaglandins might act as modulators of central CA neurotransmission.

The influence of prostaglandin metabolites on the uterine response to PGF2α. A clinical and pharmacokinetic study

Abstract Prostaglandin F 2α (PGF 2α ) is rapidly metabolized in the human body following exogenous administration. Three main metabolites have been isolated and identified: 15-keto-PGF 2α , 15-keto-13, 14-dihydro-PGF 2α and 13, 14-dihydro-PGF 2α . One of these metabolites, 13, 14-dihydro-PGF 2α , stimulated human uterine contractility during midpregnancy both following intravenous and intra-amniotic administration. The activity approaches that of the parent compound, PGF 2α . Since the concentration of the metabolites in peripheral serum during continuous intravenous infusion of PGF 2α is only slightly lower than that found for PGF 2α , it is likely that 13, 14-dihydro-PGF 2α is of importance for the stimulatory effect of PGF 2α on human uterine activity in vivo. Intravenous injection of high doses of 15-keto-13, 14-dihydro-PGF 2α (2–4 mg) slightly stimulated uterine contractility but most likely this effect was not due to the compound itself but to the formation of its metabolite, 13, 14-dihydro-PGF 2α .

EFFECT OF PROSTAGLANDIN E1 ON BLOOD PRESSURE, HEART RATE AND CONCENTRATION OF FREE FATTY ACIDS OF PLASMA IN MAN.

Summary Infusions of PGE1 to human subjects caused an increase in heart rate and in concentration of FFA and glycerol in plasma. When PGE1 was infused intravenously together with norepinephrine the nor-epinephrine induced increase in blood pressure was reduced and the bradycardia was abolished. The increase in concentration of FFA and glycerol in plasma caused by norepinephrine was, however, only slightly reduced by PGE1.

A note on the cardiovascular and metabolic effects of prostaglandin A1: Prostaglandin and related factors 61

Abstract Intravenous infusion of prostaglandin A 1 (PGA 1 , formerly PGE 1 -217) (9-keto-15-hydroxy prosta-10,13-dienoic acid) 0.056 or 0.20 μg/kg/min during 20 minutes, into anesthetized dogs lowered the blood pressure and increased the heart rate. Infusion of PGE 1 produced qualitatively similar cardiovascular effects as PGA 1 . However, the effects of PGA 1 on the cardiovascular system were usually quantitatively more pronounced than those produced by PGE 1 . No consitent changes in the plasma levels of FFA, glycerol or blood glucose were seen during administration of PGA 1 . Studies with rat adipose tissue in vitro showed that PGA 1 had less than 10 per cent of the lipolysis inhibiting activity of PGE 1 .

On the pH-dependent degradation of 15(S)-15-methyl-prostaglandin F2α (Carboprost)

Abstract Acid-catalyzed degradation of the methyl ester of 15(R)-15-methyl-prostaglandin F2α (2b) in acetonitrile afforded methyl 9α,11α-dihydroxy-15-methylprosta-5(Z),13,15-trienoate (3b) as the main product. Treatment of 2b with acidified methanol resulted in the formation of methyl 15(R,S)-9α,11α-dihydroxy-15-methoxy-15-methylprosta-5 (Z),13(E)-dienoate (4b,5b) as well as methyl 13(R,S)-9α,11α-dihydroxy-13-methoxy-15-methylprosta-5 (Z),14(E,Z)-dienoate (6b). In acidified aqueous 1,2-dimethoxyethane, 2b underwent epimerization into the corresponding 15(S) derivative (1b), solvolysis into methyl 13(R,S)-9α,11α,13-trihydroxy-15-methylprosta-5(Z),14(E,Z)-dienoate (9b), and dehydration into methyl 9α,11α-dihydroxy-15-methyl (3b). The same products, as the free acids, were formed from 15(S)-15-methyl-prostaglandin F2α (Carboprost, 1) upon treatment with acid in the solvents indicated. Degradation of the tromethamine salt of 15(S)-15-methyl-prostagla F2α (1c) in aqueous buffers was studied as a function of time, temperature, and pH. A gradual increase in stability of 1c was observed when the pH values of the buffers used were increased from 7.3 to 9.1 and higher. As a result of the stability tests, it was concluded that 1c may be stored at 37°C in tromethamine buffer, pH 9.55, for at least 1 year with less than 3–4% degradation.