Remiprostol

Abstract—Four E-prostanoid (EP) receptors, designated EP1, EP2, EP3, and EP4, mediate the cellular effects of prostaglandin E2(PGE2). The present studies pharmacologically characterize the vasopressor and vasodepressor EP receptors in wild-type mice (EP2+/+mice) and mice with targeted disruption of the EP2receptor (EP2−/−mice). Mean arterial pressure (MAP) was measured via a carotid artery catheter in anesthetized male mice. Intravenous infusion of PGE2decreased MAP in EP2+/+mice but increased MAP in EP2−/−mice. Infusion of EP3-selective agonists, including MB28767, SC46275, and sulprostone, increased MAP in both EP2+/+and EP2−/−mice. Pretreatment with SC46275 desensitized mice to the subsequent pressor effect of sulprostone, but the vasodepressor effect of PGE2in EP2+/+mice remained intact. Although PGE2alone increased MAP in EP2−/−mice, prior desensitization of the pressor effect with SC46275 allowed a residual vasodepressor effect of PGE2to be seen in the EP2−/−mice. An EP4-selective agonist (prostaglandin E1-OH) functioned also as a vasodepressor in both EP2−/−and EP2+/+mice. High levels of EP3receptor mRNA were detected in mouse aortas and rabbit preglomerular arterioles by nuclease protection, with lower expressions of EP1, EP2, and EP4mRNA. The findings suggest that combined vasodepressor effects of EP2and EP4receptors normally dominate, accounting for the depressor effects of PGE2. In contrast, in EP2−/−mice, EP4receptor activity alone is insufficient to overcome the EP3vasopressor effect. These findings suggest that a balance between pressor and depressor PGE2receptors determines its net effect on arterial pressure and that these receptors may be important therapeutic targets.

1. Four types of prostanoid receptor are present on pulmonary arterial vessels of man. Thromboxane (TP) receptors mediate constriction and are blocked by antagonists such as BAY u‐3405, GR 32191 and EP169. Prostaglandin (PG) EP3 receptors also mediate constriction, the agonist potency ranking being SC 46275 > sulprostone > misoprostol≥PGE2; this action needs to be borne in mind when PGE analogues are used therapeutically.2. Prostaglandi. E2 causes relaxation in a few pulmonary artery preparations: an EP2 receptor may be involved. Prostacyclin, acting through IP receptors, consistently produces relaxation and studies are in progress to determine the contribution made by K+‐channel opening. Agonist potencies of stable prostacyclin analogues and non‐prostanoid prostacyclin mimetics, such as BMY 45778 and the novel diphenylindole CU 23, on human pulmonary artery and platelets are well correlated. Interestingly, the non‐prostanoid mimetics show persistent relaxant effects in vitro, which may be related to their high lipophilicities.3. Prostacyclin and iloprost are being used to treat severe pulmonary hypertension; further study of the pharmacodynamic and pharmacokinetic properties of other IP receptor agonists could produce improve. therapy.