The spasmogenic action of oxytocin in the rat uterus – comparison with other agonists

Abstract

1 A low concentration (0.2 nM) of oxytocin induced phasic tension development in the isolated uterus of the day-22 pregnant rat. Tonic spasm was also induced by higher concentrations of oxytocin (2 and 20 nM). Spasmogenic responses to bradykinin and potassium chloride (KCI) also contained phasic and tonic components while acetylcholine induced tonic spasm only. 2 The phasic component of the responses to oxytocin and to bradykinin and both components of the response to KCI were inhibited by (+ )-cis diltiazem (0.1 and I JsM). The tonic component of the responses to oxytocin and to bradykinin and the responses to acetylcholine were only reduced by (+ )-cis diltiazem at concentrations >10O M. 3 (-)-cis Diltiazem was less potent than (+ )-cis diltiazem as an inhibitor of calcium (Ca2+)-induced spasm in a depolarizing medium and of the phasic spasms induced by oxytocin. The two isomers were of similar potency as inhibitors of oxytocin-induced tonic spasm. 4 Spasmogenic responses to oxytocin, bradykinin, acetylcholine and KCI were decreased when uteri were bathed in media which were Ca2+-free or of low Na+ content. However, there was no correlation between the rank order of sensitivity of the four spasmogens to the changed media and to their inhibition by (+ )-cis diltiazem. 5 Oxytocin (0.2 nM) increased the frequency, duration and amplitude of spike activity, measured by extracellular electrical recording, in parallel with enhancement of phasic tension development. With higher concentrations of oxytocin (2 and 20 nM) spike firing was initially continuous but often subsequently ceased despite the associated tonic contracture. After incubation in (+)-cis diltiazem (1OILM), oxytocin (0.2, 2 and 20 nM) produced graded tonic spasm without spike activity. 6 Oxytocin (0.2 nM) produced a small increase in 45Ca2+ influx into myometrium as assessed by the 'lanthanum method'. Higher concentrations of oxytocin (2 and 20 nM) did not increase 45Ca2" influx.7 It is concluded that the phasic component of the response of the uterus to oxytocin and bradykinin is associated with Ca2" influx via voltage-dependent Ca2+ channels. The tonic component is due to another mechanism(s) which does not appear to involve Ca2+ influx. All of the spasmogenic response to KCl can be explained by Ca2+ influx through voltage-dependent Ca2+ channels. These channels do not appear to be involved in the spasmogenic response to acetylcholine.

The relaxant action of BRL 34915 in rat uterus

“…These observations were extended using the extracellular electrical recording technique. As shown by Edwards et al (1986) and in Figure 3, phasic spasms to oxytocin (0.2 nM) were temporally associated with spike bursts while continuous electrical spiking was seen at least initially during tonic spasms to oxytocin (20nM [Oxytocin] (nM) with phasic spasms. BRL 34915, as an inhibitor of phasic spasms to oxytocin (0.2 nM), was antagonized by procaine.…”

“…Oxytocin (0.2 nM) produces an increase in the amplitude and frequency of phasic spasms while an additional tonic component is seen with higher concentrations (2 and 20 nM) (Edwards et al, 1986). In control experiments the log concentration-effect curve of oxytocin was slightly but progressively depressed when repeated in PSS (Figure 2a).…”

Effects of cyclopiazonic acid on rhythmic contractions in uterine smooth muscle bundles of the rat

“…L-type Ca2l channels were also shown to be responsible for the inward currents which were blocked by a dihydropyridine Ca2l channel antagonist (Jmari et al, 1986;Honore et al, 1989). Agonists like oxytocin and prostaglandins can increase the force and frequency of rhythmic contractions (Mironneau, 1976), which are also suppressed by L-type Ca2l channel blockers or by removal of extracellular Ca2" (Edwards et al, 1986;Kawarabayashi et al, 1986;Tasaka et al, 1991).…”

Diltiazem pharmacokinetics in the rat and relationship between its serum concentration and uterine and cardiovascular effects

“…A number of these compounds have been shown dependent channels in the plasma membrane (Edman to be potent inhibitors of tension development by uterine & Schild, 1962;Bolton, 1979). A group of structurally smooth muscle in vitro (Granger et al, 1985;Edwards et al, 1986). Gallopamil, verapamil, (+ )-cis-'Author for correspondence diltiazem (hereafter referred to as diltiazem) and nifedipine also inhibited uterine contractions in vivo in the ovariectomized (ovx) post-partum rat after bolus i.v.…”