Exp. Eye Res. (1995) 61, 699-711 AlteredVasoactivity in the Early Diabetic Eye' Measured in the Isolated Perfused Rat Eye ER-NINGSU, DAO-YI YU, VALERIEA. ALDER*, PAULA K. YUAND STEPHEN J. CRINGLE Centre for Ophthalmology and Visual Science, Lions Eye Institute, University of Western Australia, Ned/ands WA 6009, Australia (Received Lund 25 January 1995 and accepted in revised form 26 July 1995) The effect of 4 weeks streptozotocin-induced diabetes on ocular vascular resistance responses to noradrenalin (NA), adrenalin (A), phenylephrine (PHE), isoproterenol (ISOP), prostaglandin F2~(PGF2:). 5-hydroxytryptamine (5-HT) and angiotensin II (ANG II), was determined using a newly-developed, isolated, arterially-perfused rat eye preparation, by comparing responses from control and diabetic eyes. After extensive preliminary experiments to establish optimum parameters, the ophthahnic artery of enucleated control and diabetic rat eyes was cannulated and the retinal and uveal vasculature perfused at a constant flow with Na+-Krebs solution after streptozotocin-induced diabetes had been established for 4 weeks. The eyes were maintained in an environment-controlled organ bath. Perfusion pressure was monitored as increasing log M concentrations of agonists were added to the perfusate. Total ocular resistance could be calculated from knowledge of flow and pressure. In control eyes, NA, A, PHE, PGF2~, and 5-HT all produced dose-dependent increases in total vascular resistance, with the following order of potency: NA = A > 5-HT > PHE = PGF2~ at 10 4 M. The ocular circulation was not sensitive to isoproterenol and angiotensin II. In diabetic eyes responses to NA, A. PGF.2~and 5-HT were altered. Diabetic responses to NA and A had lower thresholds with larger resistance increases at low concentrations. However, the rate of increase in resistance with concentration was more gradual in diabetic eyes so that at lO-4M control responses were larger. Diabetic resistance responses to PGF2~ had the same threshold as in control eyes, but were greater in magnitude with an earlier peak at 10 -4 M. In contrast diabetic resistance responses to 5-HT were reduced, peaked at a lower resistance at 10 4 M, but had the same threshold as those in the control eye. Basal vascular resistances in control: 3" 14 + 0" 32 mmHg min/d-1 (r/ = 28), and diabetic eyes : 3-44 _+0" 19, mmHg min/d 1 (n = 36), were not significantly different. Vasoactivity in the early diabetic eye is disturbed with the effective balance between different agonists altered in favour of catecholamines at physiological concentrations. This may be related to the early changes in blood flow and oxygen distribution already reported in the rat eye, as well as changes to autonomic function. The isolated perfused rat eye is a valuable technique for investigating such vascular reactivity in animal models of retinal disease. © 1995 Academic Press Limited Key words: diabetes; vascular resistance; isolated perfused eye: rat, catecholamines: 5-HT; prostaglandins. 1. Introduction There are numerous reports showing that one functional consequence of diabetic retinopathy is alteration to retinal blood flow and also to the autoregulatory power of the retinal circulation. To date, despite some speculation, there is no evidence for accompanying changes to the choroidal circulation. These retinal circulation disturbances have been observed in both human diabetics and in animal models of diabetes (Kohner et al., 1975; Blair and Riva, 1982, Grunwald et al., 1984, 1986; Small, Stef/~nsson and Hatchell, 1987; Tilton et al., 1989; Sullivan et al,, 1990, Bursell et al., 1992; Cringle et al., 1992). However, there is some controversy regarding the magnitude and direction of the changes, possibly due to several factors. These include differences in the relative time elapsed from diagnosis or induction of diabetes and the time at which the * For correspondence. 0014-4835/95/120699 + 13 $12.00/0 experiments are performed and hence the severity of the disease; the average and peak levels of blood glucose; the methods used to determine blood flow such as laser doppler on major retinal vessels compared to tissue blood flow, or retinal transit time; and finally species differences. Recent studies focussed on the initial stages of diabetic retinopathy have demonstrated early increases in blood flow values in the retinal circulation as well as changes to ocular oxygen distribution within 1-5 weeks after the onset of diabetes in rats as well as an increase in heterogeneity of retinal tissue blood flow (Tilton et al., 1989; Alder et al., 1990; Cringle et al.. 1992). A greater heterogeneity in tissue blood flow values in the retina, implies a redistribution of blood flow. Tissue blood flow distribution normally provides a tight match between blood supply, tissue demands and the satisfactory removal of the waste products of metabolism. It is a dynamic, complex and hierarchical task, The observed redistribution of blood flow so early in diabetes, well before histological © 1995 Academic Press Limited