Selective Activation of the Prostanoid EP ₃ Receptor Reduces Myocardial Infarct Size in Rodents

Abstract

Abstract-The cardioprotective effects of E-type prostaglandins (EPs) have been attributed to vasodilatation, inhibition of platelet and neutrophil function (EP 2 mediated), and an unknown "cytoprotective effect." We have hypothesized that selective activation of EP 3 receptors may cause cardioprotection. The prostanoid derivative ONO-AE-248 selectively binds to murine EP 3␣ receptors expressed in Chinese hamster ovary (CHO) cells (K i , 15 nmol/L) and prevents the rise in cAMP caused by forskolin in CHO cells (IC 50 Ϸ1 nmol/L) in which the EP 3␣ receptor had been expressed. In anesthetized rats subjected to regional myocardial ischemia for 25 or 45 minutes and 2 hours of reperfusion, infusion of ONO-AE-248 (5 g ⅐ kg Ϫ1 ⅐ min Ϫ1 IV) caused a significant reduction in infarct size, from 60Ϯ3% (nϭ8) to 36Ϯ6% (nϭ7) and from 78Ϯ2% (nϭ11) to 58Ϯ4% (nϭ9), respectively. The reduction in infarct size caused by ONO-AE-248 in rats subjected to 25 minutes of ischemia and reperfusion was abolished by a selective inhibitor of ATP-sensitive potassium (K ATP ) channels, 5-hydroxydecanoate (nϭ6), and the protein kinase C inhibitors staurosporine (nϭ6) and chelerythrine (nϭ6). In anesthetized rabbits subjected to coronary artery occlusion for 45 or 60 minutes and 2 hours of reperfusion, infusion of ONO-AE-248 (5 g ⅐ kg Ϫ1 ⅐ min Ϫ1 IV) caused a significant reduction in infarct size, from 61Ϯ2% (nϭ10) to 36Ϯ4% (nϭ8) and from 63Ϯ4% (nϭ7) to 42Ϯ4% (nϭ7), respectively. The reduction in infarct size caused by ONO-AE-248 in the rabbit was also abolished by 5-hydroxydecanoate. The cardioprotective effect of ONO-AE-248 in rats or rabbits was not associated with any hemodynamic effects. Selective activation of the prostanoid EP 3 receptor reduces myocardial infarct size in rodents by a mechanism(s) that may involve the activation of protein kinase C and the opening of K ATP channels.

Therapeutic Potential of HDL in Cardioprotection and Tissue Repair

“…This enhanced prostanoid availability/activity may contribute to the HDL-mediated cardioprotection, by acting directly on cardiomyocytes (Zacharowski et al 1999) and/or by inhibiting cardiac TNF-α production (Shinomiya et al 2001); (3) HDL may reduce the expression of TLR 4 (Van Linthout et al 2011), which has recently been shown to play an important role in cardiac apoptosis in diabetic cardiomyopathy.…”

Stimulation of prostaglandin E2-EP3 receptors exacerbates stroke and excitotoxic injury

“…This finding implies a direct role for EP3 receptors in various neurodegenerative disorders, such as stroke and Alzheimer disease. In addition, Zacharowski and colleagues (Zacharowski et al, 1999) reported that ONO-AE-248, a selective EP3 agonist, prevented the forskolin-induced increase in cAMP in CHO cell lines. Recently, Yamazaki et al (2005) showed that EP3 receptor protein expression was significantly elevated in placenta 24 h after ischemia-reperfusion injury.…”

“…Because previous studies have shown that the EP3 receptor significantly affects outcomes after ischemia-reperfusion injury in peripheral organs (Martin et al, 2005;Yamazaki et al, 2005;Zacharowski et al, 1999), our goal in this study was to determine the role of EP3 in brain injury induced by ischemia-reperfusion injury. Therefore, we investigated the effects of the EP3 agonist ONO-AE-248 [Ki estimated at 10000, 3700, 7.5, and 4200 for EP1, EP2, EP3, and EP4, respectively (Kiriyama et al, 1997;Narumiya and FitzGerald, 2001;Suzawa et al, 2000)] on middle cerebral artery occlusion (MCAO)-induced infarct volume, relative cerebral blood flow (CBF), mean arterial blood pressure (MABP), and other physiological parameters.…”

Changes in the Effect of Spinal Prostaglandin E2during Inflammation: Prostaglandin E (EP1-EP4) Receptors in Spinal Nociceptive Processing of Input from the Normal or Inflamed Knee Joint

“…ONO-AE-248 is an agonist at the EP3␣ receptor that is coupled to G i and decreases cAMP (Zacharowski et al, 1999). When the knee joint was normal, the EP3␣ agonist did not significantly change the responses of the neurons to mechanical stimulation of the knee joint and the ankle (Fig.…”

“…The following agonists were used: the EP1 receptor agonist ONO-DI-004 [doses in the present experiments were 0.1 ng/l (2.36 M) to 100 ng/l (2.36 mM); Ono Pharmaceutical, Osaka, Japan], the EP2 receptor agonist butaprost [doses in the present experiments were 0.1 ng/l (2.44 M) to 100 ng/l (2.44 mM); Cayman Chemical, Ann Arbor, MI], the EP3␣ receptor agonist ONO-AE-248 [doses in the present experiments were 1 ng/l (26.28 M) to 100 ng/l (2.628 mM); Ono Pharmaceutical], and the EP4 receptor agonist ONO-AE1-329 [doses in the present experiments were 1 ng/l (21.9 M) to 100 ng/l (2.199 mM); Ono Pharmaceutical]. The compounds ONO-DI-004, ONO-AE-248, and ONO-AE1-329 have been generated and characterized recently and have been used in different studies (Yamamoto et al, 1999;Zacharowski et al, 1999;Suzawa et al, 2000;Maruyama et al, 2001;Shinomiya et al, 2001 (Yamamoto et al, 1999;Suzawa et al, 2000). EC 50 values are as follows: ONO-DI-004, 0.42 M at the EP1 receptor; ONO-AE-248, 0.0052 M at the EP3␣ receptor; ONO-AE1-329, 0.0031 M at the EP4 receptor (Yamamoto et al, 1999).…”