Changes of endothelin in streptozotocin-induced diabetic rats: effects of an angiotensin converting enzyme inhibitor, enalapril maleate

Abstract

Endothelin-1 (ET-1) concentrations are increased in patients with diabetes mellitus, particularly those with diabetic retinopathy, or essential hypertension. We hypothesized that ET-1 might participate in the development and progression of diabetic microangiopathy. In this study, the effects of the angiotensin converting enzyme (ACE) inhibitor, enalapril maleate, on diabetic angiopathy were examined in streptozotocin (STZ)-induced diabetic (STZ-DM) rats by monitoring variations in renal function and ET-1 concentrations in blood and organ tissues.Significant increases in kidney weight and in concentrations of urinary albumin, N-acetyl-fl--glucosamidase (NAG) and serum ET-1 were observed in the STZ-DM rats as compared with the non-diabetic rats, and the concentration of ET-1 in the kidneys tended to be increased. Microscopic and electron microscopic analyses showed increased mesangial cell proliferation, matrix expansion and enlarged mesangial area in the kidney of the diabetic rats. After administration of the ACE inhibitor, increased concentrations of urinary albumin and NAG in the STZ-DM rats were reduced to the control values with a slight improvement in the electron microscopic changes.These data suggest that ET-1 may be involved in the development and progression of diabetic nephropathy and may explain, in part, why diabetes is liable to complicate hypertension. ACE inhibitor may help to restore diabetic nephropathy in the STZ-induced diabetic rats.

Angiotensin AT 1 receptor antagonism normalizes retinal blood flow and acetylcholine-induced vasodiliation in normotensive diabetic rats

“…The mechanisms that mediate these chronic effects of the AT 1 pathway on RBF likely involve the local production of factors that cause microvascular vasoconstriction. The AngII/AT 1 pathway has been shown to up-regulate a number of pathways that induced vasoconstriction, including endothelin-1 expression, superoxide ion production, and the DAG/PKC activation in a number of vascular tissues in diabetes [33,34,35,36,37]. Retinal DAG levels are increased in STZ-induced diabetic rats and elevation of DAG levels by treatment of NDM rats with a DAG kinase inhibitor reduces RBF in a manner similar to that observed in diabetes [28].…”

Microvascular basement membranes in diabetes mellitus

“…Basement membranes of retinal vessels in diabetic rats contain increased amounts of the α1 (IV) chain of collagen, as well as of the β1 and γ chains of laminin and of fibronectin, as early as 8 weeks after induction of diabetes, indicating increased expression of matrix components [67]. In parallel, increased plasma concentrations of the vasoactive peptide endothelin have been found [68]. Blocking of the effects of endothelin by bosentan, a general endothelin receptor blocker, prevented thickening of retinal capillary basement membranes ( Figure 6), and also the increased expression of the α1 (IV) chain and fibronectin, in streptozotocin-diabetic rats [69,70].…”

B2-receptor modulation of the reactivity to phenylephrine and angiotensin II in the carotid artery of normotensive rats after trandolapril treatment

“…ACEI increase BK-induced relaxation (Gohlkeet et al, 1995), increase the release of endothelium-derived nitric oxide (NO) (AuchSchwelk et al, 1993), decrease the production of endothelin-1 (Itoh et al, 2002) and can have a free radical scavenging action (Chopra et al, 1992). The acute and chronic administration of ACEI can attenuate the contraction responses of aortic rings of renal hypertensive rats to alphaadrenergic agonists in vitro (Kikta et al, 1983) and prevent functional changes in vascular reactivity in diabetic rats (Baluchnejadmojarad et al, 2004).…”