Vascular activities of prostaglandins and selective prostanoid receptor agonists in human retinal microvessels.
Prostanoid analogs have recently been introduced into clinical use for the management of increased intraocular pressure (IOP). This class of compounds is known to exert effects on vascular components and some endogenous parent prostaglandins have been shown to alter regional ocular blood flow and exhibit significant vasoactive properties in isolated ocular blood vessels, so the possibility exists that prostanoids could affect the ocular microcirculation either by absorption into the systemic circulation or by direct localized activity on the retinal microvasculature. Thus, the aim of this study was to examine systematically the effects of a broad variety of agonists that exhibit preferential activity at EP(1)-, EP(2)-, EP(3)-, FP-, DP-, IP-, and TP-prostanoid receptor sites on microvessel caliber in the microvasculature associated with human retinal tissues grafted into the hamster cheek pouch membrane. The selective DP-receptor agonist, BW245C and the selective TP-receptor agonist, U-46619, were the only compounds tested that exhibited significant vasoactive effects relative to baseline resting diameters in retinal microvessels. A dose-dependent increase in arteriolar caliber was elicited by BW245C over a concentration range of 10(-8)-10(-4)M at the tested 5- and 10-min timepoints. U-46619 evoked a sharp decrease in microvessel diameter within a 10(-7)-10(-4)M gamut, with the dose-response profiles at 5- and 10-min timepoints remaining essentially parallel over the tested range of concentrations. In contrast to the vasoconstriction induced by U-46619, retinal microvessel calibers were not markedly affected by AGN 192093, a thromboxane-like agonist with additional unique properties. No significant changes in human retinal arteriolar diameters relative to baseline were observed in response to a broad panel of parent and derived compounds known to be selective for EP-, FP- and IP-prostanoid receptors.
Department of Biological Sciences, Pharmaceutical Research and Development, Allergan, Inc. Irvine, CA 92612-1599, USA. spada_clayton@allergan.com
Clayton S
CS
Spada
Amelia L
AL
Nieves
David F
DF
Woodward
D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid / Q000494:pharmacology; D000818:Animals; D006224:Cricetinae; D004305:Dose-Response Relationship, Drug; D006801:Humans; D006827:Hydantoins / Q000494:pharmacology; D008833:Microcirculation / Q000033:anatomy & histology / Q000187:drug effects; D011453:Prostaglandins / Q000494:pharmacology*; D011461:Prostaglandins F, Synthetic / Q000494:pharmacology; D011982:Receptors, Prostaglandin / Q000378:metabolism*; D012171:Retinal Vessels / Q000033:anatomy & histology / Q000187:drug effects* / Q000378:metabolism
D006827:Hydantoins; D011453:Prostaglandins; D011461:Prostaglandins F, Synthetic; D011982:Receptors, Prostaglandin; C006326:fluprostenol; C030669:BW 245C; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid