The mechanisms of enhancement and inhibition of field stimulation responses of guinea‐pig vas deferens by prostacyclin analogues

Abstract

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 ®eld stimulation (20%-EFS). The high potency of cicaprost (EC 150 =1.3 nM) and the relative potencies of the analogues (equi-e ective molar ratios=1.0, 0.85, 1.6, 17 and 82, respectively) suggest the involvement of a prostacyclin (IP-) receptor. 2 Maximum enhancement induced by cicaprost in 2.5 mM K + Krebs-Henseleit solution was similar to that in Tyrode solution (2.7 mM K + ), but was progressively reduced as the K + concentration was increased to 3.9, 5.9 and 11.9 mM. There was also a greater tendency for the other prostacyclin analogues to inhibit EFS responses in 5.9 mM standard K + Krebs-Henseleit solution; this may be attributed to their agonist actions on presynaptic EP 3 -receptors resulting in inhibition of transmitter release. 3 The EFS enhancing action of cicaprost was not a ected by the a 1 -adrenoceptor antagonist prazosin (100 and 1000 nM). Cicaprost (20 and 200 nM) did not a ect contractile responses of the vas deferens to either ATP (5 mM) or a,b-methylene ATP (1 mM) in the presence of tetrodotoxin (TTX, 100 nM). In addition, enhancement by cicaprost of responses to higher concentrations of ATP (30 and 300 mM) in the absence of TTX, as shown previously by others, was not seen. Prostaglandin E 2 (PGE 2 , 10 nM) and another prostacyclin analogue TEI-3356 (20 nM) enhanced purinoceptor agonist responses. Unexpectedly, TTX (0.1 and 1 mM) partially inhibited contractions elicited by 10 ± 1000 mM ATP; contractions elicited by 1 ± 3 mM ATP were una ected. Further studies are required to establish whether a pre-or post-synaptic mechanism is involved. 4 In a separate series of experiments, cicaprost (5 ± 250 nM), TEI-9063 (3 ± 300 nM), 4-aminopyridine (10 ± 100 mM) and tetraethylammonium (100 ± 1000 mM) enhanced both 20%-EFS responses and the accompanying over¯ow of noradrenaline to a similar extent. In further experiments with the EP 1 -receptor antagonist AH 6809, TEI-3356 (1.0 ± 100 nM) and the EP 3 -receptor agonist, sulprostone (0.1 ± 1.0 nM) inhibited both maximal EFS responses and noradrenaline over¯ow, thus con®rming previous reports of the high activity of TEI-3356 at the EP 3 -receptor. Cicaprost had no signi®cant e ect on noradrenaline over¯ow at 10 and 100 nM, but produced a modest inhibition at 640 nM. 5 In conclusion, our studies show that prostacyclin analogues (particularly TEI-3356) can inhibit EFS responses of the guinea-pig vas deferens by acting as agonists at presynaptic EP 3 -receptors. Prostacyclin analogues (particularly 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 presynaptic action to increase transmitter release.

EP3 receptor deficiency attenuates pulmonary hypertension through suppression of Rho/TGF-β1 signaling

“…EP3 receptor deficiency attenuates pulmonary hypertension through suppression of Rho/TGF-β1 signaling (21)(22)(23)(24)(25)(26). Likewise, diminished relaxation of PAs in response to iloprost, treprostinil, and beraprost was reported in MCT-induced PAH in rats via a mechanism that involves stimulation of the contractile EP3 receptor (27,28).…”

Prostaglandin E2 Inhibits Spontaneous Inhibitory Postsynaptic Currents in Rat Supraoptic Neurones via Presynaptic EP Receptors

“…We have shown that spontaneous IPSCs are under inhibitory control by presynaptic GABAB and α 2 adrenoceptors ( 22, 23). Although EP 3 receptors have been found in presynaptic terminals of other central nervous system (CNS) or peripheral neurones and shown to mediate inhibition of transmitter release from synaptosome preparations ( 24–26), presynaptic EP receptors have not been reported in the supraoptic nucleus or any other nuclei in the hypothalamus. We have previously reported that PGE 2 had little effect on glutamate receptor‐mediated excitatory postsynaptic currents (EPSCs) in the supraoptic nucleus ( 13), indicating that there is no functional EP receptors in presynaptic terminals of glutamate neurones in the supraoptic nucleus.…”

Characterization of Murine Vasopressor and Vasodepressor Prostaglandin E 2 Receptors

“…At least 2 constrictor EP receptors, designated EP 1 and EP 3 , exist. [7][8][9][10][11] The EP 1 receptor signals through increased cell calcium and is highly active in vas deferens and ileal smooth muscle. 7,8,12,13 The EP 3 receptor signals through an inhibitory G protein (G i ) to decrease cAMP and is selectively activated by MB28767 and SC46275.…”