THE MECHANISMS OF ENHANCEMENT AND INHIBITION OF FIELD STIMULATION RESPONSES OF GUINEA-PIG VAS-DEFERENS BY PROSTACYCLIN ANALOGS

1 In the guinea-pig isolated vas deferens preparation bathed in Tyrode 's solution, the prostacyclin analogues, cicaprost, TEI-9063, iloprost , taprostene and benzodioxane-prostacyclin, enhanced twitch responses to submaximal electrical field stimulation (20%-EFS). The high potency of cicaprost (EC150=1.3 nM) and the relative potencies of the analogu es (equi-effective molar ratios=1.0, 0.85, 1.6, 17 and 82, respectivel y) suggest the involvement of a prostacyclin (IP-) receptor. 2 Maximum enhancement induced by cicaprost in 2.5 mM K+ Krebs-Henseleit solutio n was similar to that in Tyrode solution (2.7 mM K+), but was progress ively reduced as the Ki concentration was increased to 3.9, 5.9 and 11 .9 mM. There was also a greater tendency for the other prostacyclin an alogues to inhibit EFS responses in 5.9 mM standard K+ Krebs-Henseleit solution; this may be attributed to their agonist actions on presynap tic EP3-receptors resulting in inhibition of transmitter release. 3 Th e EFS enhancing action of cicaprost was not affected by the alpha(1)-a drenoceptor antagonist prazosin (100 and 1000 nM). Cicaprost (20 and 2 00 nM) did not affect contractile responses of the vas deferens to eit her ATP (5 mu M ) or alpha,beta-methylene ATP (1 mu M) in the presence of tetrodotoxin (TTX, 100 nM). In addition, enhancement by cicaprost of responses to higher concentrations of ATP (30 and 300 mu M) in the absence of TTX, as shown previously by others, was not seen. Prostagla ndin E-2 (PGE(2), 10 nM) and another prostacyclin analogue TEI-3356 (2 0 nM) enhanced purinoceptor agonist responses. Unexpectedly, TTX (0.1 and 1 mu M) partially inhibited contractions elicited by 10-1000 mu M ATP; contractions elicited by 1-3 mu M ATP were unaffected. Further st udies are required to establish whether a pre- or post-synaptic mechan ism is involved. 4 In a separate series of experiments, cicaprost (5-2 50 nM), TEI-9063 (3-300 nM), 4-aminopyridine (10-100 mu M) and tetraet hylammonium (100-1000 mu M) enhanced both 20%-EFS responses and the ac companying overflow of noradrenaline to a similar extent. In further e xperiments with the EP1-receptor antagonist AH 6809, TEI-3356 (1.0-100 nM) and the EP3-receptor agonist, sulprostone (0.1-1.0 nM) inhibited both maximal EFS responses and noradrenaline overflow, thus confirming previous reports of the high activity of TEI-3356 at the EP3-receptor . Cicaprost had no significant effect on noradrenaline overflow at 10 and 100 nM, but produced a modest inhibition at 640 nM. 5 In conclusio n, our studies show that prostacyclin analogues (particularly TEI-3356 ) can inhibit EFS responses of the guinea-pig vas deferens by acting a s agonists at presynaptic EP3-receptors. Prostacyclin analogues (parti cularly cicaprost and TEI-9063) can also enhance EFS responses through activation of IP-receptors. The mechanism of the enhancement has not been rigorously established but from our results we favour a presynapt ic action to increase transmitter release.