Aminoguanidine inhibits the development of accelerated diabetic retinopathy in the spontaneous hypertensive rat

Abstract

Summary Arterial hypertension has been identified as a major secondary risk factor for diabetic retinopathy. However, the mechanisms by which hypertension worsens retinopathy are unknown. Inhibition of advanced glycation product formation prevents the development of experimental diabetic retinopathy in normotensive diabetic rats. In this study the effect of hypertension on the rate of diabetic retinopathy development and the formation of arteriolar thrombosis was evaluated. We also evaluated the effect of aminoguanidine, an inhibitor of advanced glycation end product formation on retinal pathology of diabetic hypertensive rats. After 26 weeks of diabetes, hypertension accelerated the development of retinopathy despite a lower mean blood glucose level than in the non-hypertensive group (diabetic spontaneous hypertensive rats (SHR) 16.00 + 6.83 mmol/l; diabetic normotensive Wistar Kyoto rats (WKY) 34.9 + 3.64 mmol/1; p < 0.0001). Diabetic SHR had nearly twice as many acellular capillaries as diabetic WKY (SHR diabetic: 91.9 + 7.5 acellular capillaries per mm 2 of retinal area vs WKY diabetic: 53.7 + 8.5 acellular capillaries per mm 2 of retinal area), and a 3.8-fold increase in the number of arteriolar microthromboses (SHR diabetic 23504 + 5523 gm 2 vs SHR non-diabetic 6228 + 2707 gm2). Aminoguanidine treatment of SHR diabetic rats reduced the number of acellular capillaries by 50 %, and completely prevented both arteriolar deposition of PASpositive material and abnormal microthrombus formation. These data suggest that hypertension-induced deposition of glycated proteins in the retinal vasculature plays a central role in the acceleration of diabetic retinopathy by hypertension. [Diabetologia (1994) 37: 32-35] Key words Diabetic retinopathy, rat model, hypertension, SHR, aminoguanidine, glycation.Over the past few years, hypertension has been identified as a major secondary risk factor for diabetic microvascular complications [1][2][3]. Hypertension accelerates the progression of diabetic nephropathy, and antihypertensive treatment has been shown to reduce declining renal function even in normotensive diabetic subjects [4].Systolic hypertension is also a risk factor for diabetic retinopathy [5][6][7] and in patients with unilateral carotid The mechanisms by which hypertension worsens diabetic retinopathy are unknown. In non-hypertensive diabetic animals, inhibition of advanced glycation product formation (AGE) by aminoguanidine prevents the development of experimental diabetic retinopathy [9]. Since AGEs induce a procoagulatory state in endothelial cells in vitro [10], we hypothesized that increased deposition of glycated plasma proteins in the microvasculature of hypertensive diabetic animals would accelerate diabetic retinopathy by inducing microvascular thrombus formation.In order to test this hypothesis, we examined the effect of aminoguanidine treatment on the retinal pathology of diabetic spontaneously hypertensive rats.

Generation of Superoxide Anions during the Reaction of Guanidino Compounds with Methylglyoxal.

“…[36][37][38][39] AG reacts with biological compounds with carbonyl groups, 40) and therefore it was suggested that AGE formation is inhibited by reaction with Amadori-derived compounds, including 3-deoxyglucosone. 40) In the present study, it was found that methylglyoxal reacted earlier with AG than guanidino compounds.…”

Methylamine and benzylamine induced hypophagia in mice: Modulation by semicarbazide‐sensitive benzylamine oxidase inhibitors and aODN towards Kv1.1 channels

“…There has been considerable debate about the physiopathological signi®cance of these observations. Because formaldehyde is an angiotoxic compound, the high levels of both MET and Bz-SSAO may have a role in the cardiovascular degeneration observed in diabetes, and may contribute to explaining the favourable e ects of Bz-SSAO inhibitors in this pathology (Lyles & McDougall, 1989;Hammes et al, 1994;Yu & Zuo, 1997;Ekblom, 1998). Moreover, in considering the hypophagic e ect of MET, it can also be hypothesized that the increased levels of this aliphatic amine in diabetes represent a part of the physiological mechanisms involved in the control of hyperglycaemia.…”

Advanced glycation end products and their receptors co-localise in rat organs susceptible to diabetic microvascular injury

“…Hammes et al have reported in both normotensive [8] and hypertensive [36] diabetic rats that aminoguanidine prevented the development of retinopathy, characterised by acellular capillaries and pericyte loss. The co-localisation of AGEs and RAGE within the retina may represent a ligand-receptor interaction involved in the genesis of diabetic retinopathy.…”