An aldose redutase inhibitor prevents the intimal thickening in coronary arteries of galactose-fed beagle dogs

Abstract

Macrovascular complications such as myocardial infarction, angina pectoris and cerebrovascular accidents are the major causes of mortality in diabetic patients [1,2]. Although the maintenance of a good glycaemic control for a long period can decrease the risk of the development of diabetic microangiopathy [3], the development of diabetic macroangiopathy cannot be prevented by glycaemic control [3,4]. Therefore, it is very important to establish the pathogenesis of diabetic macroangiopathy.Various hypotheses including increased polyol pathway activity, protein kinase C (PKC) activation, increased oxidative stress and enhanced non-enzymatic glycation have been implicated in the pathogenesis of diabetic microangiopathy such as retinopathy, nephropathy and neuropathy [5,6]. Hyperglycaemia-induced metabolic alterations could also contribute to the development of diabetic macroangiopathy. Although the importance of the latter three metabolic deficits in the pathogenesis of diabetic macroangiopathy have been investigated precisely [7±12], the relation between polyol pathway hyperactivity and diabetic macroangiopathy remains unclear. Diabetologia (1999) Abstract Aims/hypothesis. Although increased polyol pathway activity has been implicated in the pathogenesis of diabetic microangiopathy, the relation with diabetic macroangiopathy remains unclear. Galactose feeding is known to stimulate the polyol pathway and to develop abnormalites similar to those in diabetic microangiopathy. Our study was conducted to investigate whether an activation of polyol pathway by long-term treatment with galactose produced morphological changes in coronary arteries of dogs and the effect of an aldose reductase inhibitor, epalrestat, was also studied. Methods. Dogs received either normal chow or chow containing 30 % galactose with or without epalrestat given orally (20 or 50 mg × kg ±1 ). After 44 months, morphometric analyses of coronary arteries were carried out and the galactitol contents in aortas were measured.Results. The ratio of areas of the intimal layer to those of the medial layer, an indicator of intimal thickening, was statistically significantly increased in galactosefed dogs compared with control dogs. Galactose-fed dogs had a remarkable accumulation of galactitol in their aortas. These morphological and biochemical deficits were reduced by treatment with epalrestat. Conclusion/interpretation. This report morphologically shows diabetes-like macrovascular abnormalities in galactosaemic animals, suggesting that polyol pathway hyperactivity is closely related to the development of diabetic macroangiopathy, which could be prevented by aldose reductase inhibition. [Diabetologia (1999

Glucose-induced hyperproliferation of cultured rat aortic smooth muscle cells through polyol pathway hyperactivity

“…In our previous study [7] an aldose reductase inhibitor (ARI) prevented intimal thickening in coronary arteries of galactose-fed beagle dogs, suggesting that polyol pathway hyperactivity plays an important part in the development of diabetic macroangiopathy. We also reported that epalrestat prevented the glucose-induced increase in the proliferation activities and PDGF-b receptor expression in cultured smooth muscle cells [8].…”

Enhanced oxidative stress impairs cAMP-mediated dilation by reducing Kv channel function in small coronary arteries of diabetic rats

“…To this end, DM has been associated with widespread vascular dysfunction (6,11,14). There has been substantial evidence illustrating enhanced reactive oxygen species (ROS) as crucial pathological factors responsible for the impaired vasomotor function in DM patients (20,27,28) and animals (15,18,19). It has been well characterized that in conduit arteries, the decreased vasodilator response is largely due to the reduced nitric oxide (NO) bioavailability resulting from overproduction of superoxide (O 2 Ϫ ⅐) that quenches NO (7,9).…”

Role of PKC and TGF-β Receptor in Glucose-Induced Proliferation of Smooth Muscle Cells

“…Several theories including polyol pathway hyperactivity (8), enhanced non-enzymatic glycation (9), increased oxidative stress (5), and activation of protein kinase C (PKC) (10) have been proposed to explain the adverse effects of hyperglycemia on the macrovasculature as well as the microvasculature. Among these, glucose-induced PKC activation has recently drawn much attention.…”