Prostaglandins and the regulation of motility in non-pregnant isolated uterus

Abstract

Introduction Long before the prostaglandins were identified and recognized as a novel family of biologically active compounds, Kurzrok and Lieb reported the fwst observations of the influences of semen on human uterine contractionsL With hindsight, it is rrtost likely that the effects detected were evoked by prostaglandins present in the seminal fluid. Various pioneer studies showed that exogenous prostaglandins (particularly of the E and F series) potently affected con. tractions of the uterus from several speciesE Some years later it was shown that prostaglandins were released by distention of the uterus and several lines of experimentai evidence strongly suggested that during pregnancy endogenous uterine prostaglandins were able to induce and modulate myometriai activity. In 1973 Vane and Williams' reported that uteri isolated from pregnant rats exhibited intermittent spontaneous contractions and released a prostaglandin-like substance (mainly similar to PGF,.) into the bathing fluid. Both the output of the material and the contractile activity were abolished by indometacin, meciofenamate or acetylsalicylic acid. it was also found that low concentrations of PGF,2 or PGFa,, restored contractions of uteri rendered quiescent by inhibitors of prostaglandin synthetase a. Although until this time it was not gener. ally accepted that prostaglandins generated by the non.pregnant uterus could be effective modulators of its motility, some precedents favoured the contention s-8. The pre. vailing notion was that intramural prostaglandin synthesis by the pregnant rat uterus (and presumably by the non.pregnant uterus as well) was paralleled by tissue spontaneous contractile activity. It must be noticed that, as indicated by Piper and Vane, prostaglandin release can be equated with prostaglandin synthesis, in any event, one question was still unanswered, i.e. whether the generation and release of prostaglandins from the uterus should be considered as a consequence, rather than as a cause of contractions. The answer was not long in arriving. Prostaglandin output from the uterus occmred even when tissue motility was abolished by papaverine, a potent smooth muscle relaxant, precluding the possibility of prostaglandin production and release as a consequence of uterine contractions. Further links be!ween tissue prostaglan. din generation and contractions of the non.pregnant uterus were demonstrated by more recent experiments in which the effects of melatonin, considered as one of the major secretory products of the pineal gland, were tested on prostaglandin output and motility of isolated rat uterus e. The rationale for these studies, based on the structural similarities between melatonin and the prostaglandin inhibitor, indo. metacin, prompted us to examine the possibility that melatonin and indometacin could share biological properties, it was then observed that the pineal indole (10 -s M, or higher) inhibited prostaglandin E and F release and the spontaneous contractions of the rat uterus isolated from ovariectomized rats, as well as its reactivity to added oxyto. cin. lvlelatonin effects on uterine motility coulc!, there,fore be associated with the inhib. ition of prostnglandin synthesis, and the lack of action of oxytocin may be interpreted as resulting from the impairment of its influence on uteri containing low pros. taFlandin levels a. Moreover, the inhibition of contractions was similar to that observed by other investigators and ourselves after incubation with indometacin'.'. On the other hand, the negative inotropic effect was overcome by deSvering POF,., a finding which suggested that the contractile apparatus of the tissue remained undamaged following melatonin incubation.