EP₄ prostanoid receptor‐mediated vasodilatation of human middle cerebral arteries

Abstract

1 Dilatation of the cerebral vasculature is recognised to be involved in the pathophysiology of migraine. Furthermore, elevated levels of prostaglandin E 2 (PGE 2 ) occur in the blood, plasma and saliva of migraineurs during an attack, suggestive of a contributory role. In the present study, we have characterised the prostanoid receptors involved in the relaxation and contraction of human middle cerebral arteries in vitro. 2 In the presence of indomethacin (3 mM) and the TP receptor antagonist GR32191 (1 mM), PGE 2 was found to relax phenylephrine precontracted cerebral arterial rings in a concentration-dependent manner (mean pEC 50 8.070.1, n ¼ 5). 3 Establishment of a rank order of potency using the EP 4 4EP 2 agonist 11-deoxy PGE 1 , and the EP 2 4EP 4 agonist PGE 1 -OH (mean pEC 50 of 7.670.1 (n ¼ 6) and 6.470.1 (n ¼ 4), respectively), suggested the presence of functional EP 4 receptors. Furthermore, the selective EP 2 receptor agonist butaprost at concentrations o1 mM failed to relax the tissues. 4 Blockade of EP 4 receptors with the EP 4 receptor antagonists AH23848 and EP 4 A caused significant rightward displacements in PGE 2 concentration-response curves, exhibiting pA 2 and pK B values of 5.770.1, n ¼ 3, and 8.4, n ¼ 3, respectively. 5 The IP receptor agonists iloprost and cicaprost relaxed phenylephrine precontracted cerebral arterial rings (mean pEC 50 values 8.370.1 (n ¼ 4) and 8.170.1 (n ¼ 9), respectively). In contrast, the DP and FP receptor agonists PGD 2 and PGF 2a failed to cause appreciable relaxation or contraction at concentrations of up to 30 mM. In the absence of phenylephrine contraction and GR32191, the TP receptor agonist U46619 caused concentration-dependent contraction of cerebral artery (mean pEC 50 7.470.3, n ¼ 3). 6 These data demonstrate the presence of prostanoid EP 4 receptors mediating PGE 2 vasodilatation of human middle cerebral artery. IP receptors mediating relaxation and TP receptors mediating contraction were also functionally demonstrated.

Presynaptic Prostaglandin E 2 EP 1 -Receptor Facilitation of Cerebral Nitrergic Neurogenic Vasodilation

“…36 PGE 2 can actually have dual effects depending on predominance of the receptor subtype; direct stimulation of EP 1 and EP 3 receptors on the smooth muscle can cause vasoconstriction, whereas EP 2 and EP 4 receptor stimulation can lead to vasodilation. 17,37,38 The cerebral vasculature, however, is subjected not only to the actions of COX metabolites, but also other arachidonic acid metabolites from the lipoxygenase and cytochrome P450 pathways. 39 -41 The present study, however, was focused on elucidating the role of PGE 2 in cerebral nitrergic neurotransmission using 2 different selective pharmacological inhibitors of the EP 1 receptor subtype, ie, downstream of COX.…”

Prostaglandins mediate tonic contraction of the guinea pig and human gallbladder

“…Although it is well established that TxA 2 contracts most muscle cells that have been studied (7, 19 -21), PGE 2 contracts or relaxes gastrointestinal muscle cells depending on the population of receptors present in these cells. EP1 and EP3 receptor mediate contraction, whereas EP2 and EP4 mediate relaxation (1,18). PGE 2 relaxes muscle cells in the circular muscle layer, but it contracts muscle cells in the longitudinal layer of the gastrointestinal tract (47).…”

“…The actions of PGE 2 , however, are more complex because it can activate four sets of E prostanoid (EP) receptors (6,44). EP1 and 3 mediate contraction (25,40,45,54), whereas EP2 and 4 mediate relaxation (1,18). Thus the muscle response to PGE 2 depends on the population of receptors present in each muscle cell type.…”

Signaling via the prostaglandin E2 receptor EP4 exerts neuronal and vascular protection in a mouse model of cerebral ischemia

“…In our studies, AE1-329 administration increased levels of activated eNOS in cerebral microvessels, which suggests NO as one mechanism by which endothelial EP4 could improve reperfusion. As human MRI studies now suggest that rescue of cerebral perfusion may be possible at later time points than previously realized (49,50), reperfusion-based strategies may extend the effective time window for therapeutic interventions in stroke.…”