Microvascular effects of selective prostaglandin analogues in the eye withspecial reference to latanoprost and glaucoma treatment

Prostaglandin F-2 alpha analogues have recently been introduced on the mark et for glaucoma treatment. While these drugs have a well-documented intraoc ular pressure reducing effect only a limited number of studies have been pu blished regarding their effects on the microvasculature in the eye. Since m any naturally occurring prostaglandins have marked effects on the cardiovas cular system it is conceivable that synthetic prostaglandins used as glauco ma drugs may exert microvascular effects in the eye, even if they exhibit r eceptor selectivity. Latanoprost, the active principle of Xalatan eye drops . is a selective FP prostanoid receptor agonist. and much of the paper is f ocused on the microvascular effects of latanoprost and some closely related prostaglandin analogues. The purpose of the paper is to review the literat ure on the microvascular effects of prostaglandins in the eve, and to prese nt some unpublished data on the effects of selective prostaglandin analogue s. Most of the prostaglandin analogues studied exhibit selectivity for the FP prostanoid receptor. Results from studies with the following prostaglandin analogues are present ed in the paper: PGF(2 alpha)-isopropyl ester (PGF(2 alpha)-IE), 17-phenyl- 18,19,20-trinor-PGF(2 alpha)-isopropyl ester (17-phenyl-PGF(2a)-IE). 15-ket o-17-phenyl-18,19,20-trinor-PGF(2 alpha)-isopropyl ester (15-keto-17-phenyl -PGF(2a)-IE), 13,14-dihydro-17-phenyl-18,19,20-trinor-PGF(2 alpha)-isopropy l ester (latanoprost), 13,14-dihydro-15R,S-17-phenyl-18,19,20-trinor-PGF(2 alpha)-isopropyl ester (PhXA34), 17-phenyl-18,19,20-trinor-PGE(2)-isopropyl ester (17-phenyl-PGE(2)-IE), and 19R-hydroxy-PGE(2) (19R-OH-PGE(2)). The r egional blood flow has been determined with radioactively labelled microsph eres, the blood volume with Cr-51 labelled erythrocytes and the capillary p ermeability to albumin with I-125 and I-131 labelled albumin. PGF(2 alpha)-IE has been shown to exert marked microvascular effects in the rabbit anterior segment including vasodilatation, increased capillary perm eability, and a breakdown of the blood-aqueous barrier. 17-phenyl-PGF(2 alp ha)-IE, 15-keto-17-phenyl-PGF(2 alpha)-IE, and PhXA34/latanoprost exerted s ignificantly less vasodilatory effect, and little effect on capillary perme ability was seen with the FP receptor agonists when studied with Evens blue . Intravenous administration of PhXA34 at a dose range of 1-100 mu g/kg b.w . had no consistent effect on the regional blood flow in the eye indicating that FP receptors in the ocular blood vessels are not expressed in the rab bit, or alternatively are not functionally coupled to regulation of vascula r tone. In cats topical application of PGF(2 alpha)-IE had no significant effect th e on the regional blood flow in cannulated eyes. No blood flow experiments were performed in intact eyes with PGF(2 alpha)-IE. 17-phenyl-PGF(2 alpha)- IE and latanoprost caused some vasodilation in the anterior segment. None o f the analogues had any significant effect on the blood volume in the ocula r tissues, but an increase in capillary permeability to albumin was seen in several tissues of the eye. However, in the eyelid, nictitating membrane a nd conjunctiva exposed to high concentrations of the prostaglandins no or o nly little leakage of albumin was detected. It appears that the intraocular microvasculature in the cat exhibits some sensitivity to FP prostanoid rec eptor agonists. In the cynomolgus monkey eye PGF(2 alpha)-IE has been shown to cause a dram atic increase in blood flow of the anterior uvea, but only weak effect was detected with the selective FP receptor agonists and an EP1 receptor agonis t after topical administration. Intravenous infusion of latanoprost at a do se range of 0.6-6 mu g/kg b.w. had little effect on the blood flow in most ocular tissues, and the same was true for 17-phenyl-PGE(2), a relatively se lective EP1 receptor agonist, after intracardiac infusion at about the same dose range. Intravenous infusion of the EP2 receptor agonist 19R-OH-PGE(2) markedly reduced the vascular resistance in the rye. No significant effect was seen on the blood volume in the ocular tissues with any of the FP rece ptor agonists after topical administration. PGF(2 alpha)-IE increased the c apillary permeability to albumin in the anterior segment and possibly the r etina, but 17-phenyl-PGF(2 alpha)-IE and latanoprost/PhXA34 had no effect o n capillary permeability in any of the ocular tissues. Based on the results of previous studies and the experiments described in t he present paper it is evident that PGF(2 alpha) has significant microvascu lar effects in the rabbit, cat and monkey eye, causing vasodilation and/or increased capillary permeability, whereas selective FP receptor agonists su ch as latanoprost exert no or minimal effects in the primate eye, and marke dly reduced microvascular effects in the rabbit eye. However, little differ ence between PGF(2 alpha) and the selective FP receptor agonists was seen i n the cat eyes. It also appears that the EP1 receptor like the FP receptor is not involved in the regulation of vascular tone in the primate eye, wher eas stimulation of the EP2 receptor reduces the vascular resistance in the monkey eye. Finally, the microvascular parameters in the control eyes of ca ts and monkeys are compared and discussed. (C) 2000 Elsevier Science Ltd. A ll rights reserved.