The aims of this study were to assess the relevance of hypertension as a risk factor for diabetic retinopathy through experimental studies, and to develop a model of hypertension and diabetes using non-invasive techniques. To determine the effect of coincident hypertension and diabetes on retinopathy we studied the spontaneously diabetic BB rat. The BB rat has early retinopathic changes analogous to those in human IDDM. Hypertension was induced by unilateral nephrectomy, mineralocorticoid injections and oral saline. Tight glycaemic control was maintained with insulin. We found a synergistic effect of hypertension and diabetes on pathological ultrastructural changes in retinal capillaries. Specifically, basement membrane thickening and the number of caveolae (plasma membrane-associated vesicles) were significantly increased with hypertension and diabetes compared to either condition alone. Diabetes reduced the number of pericyte-endothelial cell contacts. The development of a model of hypertension and diabetes using non-invasive techniques was attempted via NO synthase inhibition in the BB rat. NO is a potent vasodilator formed from L-arginine by endothelial NO synthase. Competitive inhibition of NO synthase, by the L-arginine analogue L-NAME, increases blood pressure in Wistar rats. Hypertension is reversed when L-NAME treatment is withdrawn. L-NAME had not previously been investigated in BB rats. L-NAME caused significant and sustained hypertension in Wistars in a dose-dependent manner. L-NAME had no pressor effect on BB rats at any dose. Nitrate is the stable end-product of NO metabolism. Urine analysis revealed a significantly reduced rate of nitrate excretion with diabetes. Spontaneously hypertensive rats (SHRs) and spontaneously insulin-dependent diabetic BB rats are accepted models of human disease. We designed a breeding programme between BB rats and SHRs aiming to produce offspring with both spontaneous insulin-dependent diabetes and spontaneous hypertension.