STUDIES ON THE IN VITRO PHARMACOLOGY AND METABOLISM OF PROSTAGLANDIN–ETHANOLAMIDES (PROSTAMIDES) IN THE FELINE IRIS

Abstract

Abstract: : Purpose: We investigated whether prostaglandin ethanolamides (prostamides) D₂, E₂ and F_2α exert some of their effects by (i) activating prostanoid receptors either directly or following conversion to the corresponding prostaglandins (ii) interacting with proteins involved in anandamide inactivation and thereby enhancing anandamide levels or (iii) activating TRPV1) (vanilloid) receptors. Methods: Pharmacological studies involved contraction of the feline isolated iris and functional and binding studies using human and feline recombinant PG receptors and human TRPV1 receptors. Uptake studies employed brain synaptosomes and RBL–2H3 cells. Metabolic studies involved cell and tissue homogenates. Results: Prostamides potently stimulated the feline iris sphincter preparation but exhibited no meaningful activity at the recombinant TRPV1 or prostaglandin receptors. Feline iris and ciliary body homogenates showed no detectable conversion of prostamides to the corresponding prostaglandins over a 4 hr incubation, whereas anandamide was approximately 50% hydrolysed. Prostamides did not compete with anandamide for enzymatic hydrolysis by fatty acid amide hydrolase or for uptake into intact cells. Conclusions: The data suggest that the most prominent pharmacological effects of prostamides are not due to transformation into prostaglandins, activation of prostanoid receptors, enhancement of anandamide levels, or gating of TRPV1 receptors. Interaction with novel receptors functional in the feline iris would explain the results.

Keywords: eicosanoids • iris • pharmacology