Antihypertensive effect of insulin via nitric oxide production in the Zucker diabetic fatty rat, an animal model for non-insulin-dependent diabetes mellitus

Abstract

It has been reported that insulin treatment improves hypertension in patients with diabetes mellitus. The mechanisms of the antihypertensive effect of insulin, however, remain to be fully elucidated. In the present study, we investigated a possible involvement of nitric oxide (NO) in insulin-induced reduction of blood pressure using the Zucker diabetic fatty (ZDF) rat, an animal model of non-insulin-dependent diabetes mellitus. The animals were divided into three groups and treated for 4 weeks with daily subcutaneous injections of insulin (25 U/kg body weight) with or without oral administration of Lnitro-arginine methyl ester (L-NAME, 50 mg/kg/day body weight as drinking water), an inhibitor of NO synthase (NOS). Saline solution was injected subcutaneously in the control groups. During the experimental period, body weight gain was greater in the insulin-treated groups than in the control groups whereas water intake was considerably decreased in the insulin-treated groups. Insulin treatment resulted in a decrease in plasma glucose and blood pressure, and an increase in both NO metabolites (NOx) in the plasma and NOS activity in the aorta tissue. L-NAME treatment blunted not only the antihypertensive effect of insulin but also the changes in NOx and NOS activity. These findings suggest that insulin reduces blood pressure in the ZDF rat by stimulating NOS activation and NO production.

Effect of insulin on nitric oxide synthase-like immunostaining of arteries in various organs in Zucker diabetic fatty rats

“…Insulin-induced NOS-like immunostaining in the arteries supported our previous observation that insulin-treatment induced NOS in aorta of ZDF rats as studied by NADPH diaphorase staining (2). The present data indicate that improvement of hypertension by insulin treatment was due to induction of NOS in the arteries in ZDF rats.…”

“…We observed that serum levels of NO metabolites were increased by insulin treatment in the ZDF rat (1,2). Furthermore, NO synthase (NOS) activity and NADPH diaphorase staining were enhanced by insulin treatment (2). These data suggest that insulin treatment induces NOS in the ZDF rat.…”

“…Several lines of evidence suggest that insulin stimulates nitric oxide (NO) generation in endothelial cells (12±15). We observed that serum levels of NO metabolites were increased by insulin treatment in the ZDF rat (1,2). Furthermore, NO synthase (NOS) activity and NADPH diaphorase staining were enhanced by insulin treatment (2).…”

“…Recently we have reported that insulin treatment improved hypertension in Zucker diabetic fatty (ZDF) rats (1,2), a model of type 2 diabetes mellitus (3). The antihypertensive effect of insulin was explained either by the secondary action of improved glucose metabolism after insulin treatment or by the direct action on peripheral arterial vessels (4±11).…”

Blood Pressure Characteristics of Female Spontaneously Diabetic Torii-Leprfa Rats

“…Therefore, poor glycemic control is considered to induce hypertension in diabetes mellitus [2,8]. Also, in ZDF rats, insulin reduced the blood pressure [13]. Moreover, an antihyperglycemic effect in male GK rats caused a pronounced suppression of both the systolic and the diastolic blood pressure [12].…”