The effects of P2Y receptor agonists and adenosine on prostaglandin production by the guinea‐pig uterus

Abstract

1 This study has investigated the eects adenosine 5'-triphosphate (ATP), analogues of ATP, uridine 5'-triphosphate (UTP) and adenosine on prostaglandin output from the guinea-pig uterus superfused in vitro, and from guinea-pig endometrium and myometrium cultured for 24 h. 2 ATP, 2-methylthio ATP and adenosine increased the outputs of prostaglandin F 2a (PGF 2a ) and 6-keto-PGF 1a (re¯ecting PGI 2 production), and UTP increased the output of PGF 2a from the superfused guinea-pig uterus. These ®ndings support the hypothesis that the contractile eects of ATP, 2-methylthio ATP, UTP and adenosine are mediated by prostaglandins. 3 Suramin (a P2 receptor antagonist) and 8-sulphophenyltheophylline (an A receptor antagonist) blocked the stimulatory actions of ATP and adenosine, respectively, on PGF 2a output, suggesting that ATP acts on P2 receptors (probably of the P2Y type) and adenosine acts on A receptors in the guinea-pig uterus to increase PGF 2a production. 4 ATP, 2-methylthio ATP, a,b-methylene ATP, b,g-methylene ATP, UTP and adenosine increased the output of PGF 2a from guinea-pig endometrium and myometrium after 24 h of culture, with a greater stimulatory eect being exerted on the endometrium than on the myometrium. Little or no stimulatory eect was seen after 2 and 8 h of culture. In addition the eects of ATP, ATP analogues, UTP and adenosine on the outputs of PGE 2 and 6-keto-PGF 1a from cultured endometrium and myometrium were more variable, with both stimulation and inhibition being observed. 5 The stimulatory eects of ATP and adenosine on PGF 2a output from the endometrium and myometrium were associated with an increase in the prostaglandin synthesizing capacity of both tissues, due probably to an increase in the amount of prostaglandin H synthase present.

Muscularis mucosae contraction evokes colonic secretion via prostaglandin synthesis and nerve stimulation

“…The present data show this to be because ATP elicits excitatory prostaglandin production, which in turn causes direct stimulation of the muscle. Prostaglandin generation following exposure to endogenous or exogenous purines has been demonstrated in a variety of intestinal and nonintestinal tissues (1,2,8,20,23), and its occurrence in the muscularis mucosae/mucosa of the rabbit distal colon adds to the list of sites where this pathway operates. Paradoxically, ATP exerts its largest motor effects on the muscularis mucosae in the rabbit proximal colon, where prostaglandins elicit minimal contractions (31,33).…”

“…The pharmacological agents used to test this hypothesis were selected on the basis of their respective abilities to 1) directly stimulate either the muscularis mucosae (30) or the mucosa (1,14), 2) initiate prostaglandin production (1,2,8,20,23,25), 3) reproduce the actions of endogenous eicosanoid mediators, 4) stimulate ganglionic nicotinic receptors on submucosal neurons, and 5) block the synthesis or the effects of agents with actions on the muscle or the mucosa and/or their respective innervation.…”

Purinergic signalling in the reproductive system in health and disease

“…Activation of A 2B receptors on endothelial cells contributes to penile erection via PI 3 K/AKT signalling cascade-mediated endothelial NOS activation [432]. It was shown in a study of alloxan-induced diabetic rabbits that there was impairment of both direct P2Y 4 receptor-induced muscle relaxation and endothelium-dependent ADP P2Y 1 receptor-mediated relaxations [72]. The possibility that the responses of the vas deferens to ATP via P2X1 receptors are heightened in overactive ejaculatory reflex associated with premature ejaculation has been considered [1].…”

“…ATP and ADP contract the uterus [100,311] partly through the action of prostaglandins induced by P2Y receptor occupation [4,291,390]. In the longitudinal muscle of the mouse myometrium, ATP produced a biphasic response, an initial hyperpolarisation followed by a depolarisation, which remained the same in both non-pregnant uterus and throughout pregnancy [306].…”

“…Transmural stimulation initiated non-adrenergic, non-cholinergic (NANC) inhibitory junction potentials in parenchymal muscle, but excitatory junction potentials (EJPs) in the sac smooth muscle [161]. It was claimed that ATP released from nerves produces relaxation of cavernosum smooth muscle via P2Y 4 receptors on smooth muscle, while ADP acting via P2Y 1 receptors on endothelial cells produces relaxation via NO [72]. Modulation of cavernosum smooth muscle relaxation occurs by activation of P2Y 6 receptors via nonneuronal and non-NO-dependent mechanisms [224].…”