1. We investigated the roles of
nitric oxide (NO) and
endothelin-1 (ET-1) in organ dysfunction in diabetic mice with normal genotype (wild-type, WT) or myocyte-specific overexpression of endothelial
NO synthase (eNOS) (transgenic, TG) after chronic oral treatment with the
endothelin-A (ETA) receptor antagonist
atrasentan. 2. Mice were rendered diabetic by injection of 200 mg kg-1
streptozotocin (STZ). Experimental groups were: untreated WT diabetic (n=9), untreated TG diabetic (n=9),
atrasentan-treated WT diabetic (n=9),
atrasentan-treated TG diabetic (n=8) and the four corresponding nondiabetic groups (n=5).
Atrasentan was administered orally via
drinking water at 3 mg kg-1 per day over 28 days. All diabetic mice developed similar hyperglycaemia (27-30 mmol l-1). 3.
Atrasentan treatment significantly improved left ventricular systolic and diastolic function in response to exogenous
norepinephrine, but there were no differences between genotypes. 4.
Atrasentan antagonized the diabetic impairments in endothelium-dependent coronary relaxation and
thromboxane-receptor mediated aortic constriction. Further, it improved cardiac and renal
oxidant status as evident from reduced tissue
malondialdehyde levels. 5.
Atrasentan reduced diabetic urine flow,
proteinuria and plasma
creatinine levels, but
creatinine clearance was not significantly altered. 6. These results suggest that in experimental
type 1 diabetes, blocking ETA receptors ameliorates myocardial, coronary and renal function and improves tissue
oxidant status, whereas raising myocardial NO levels has neither beneficial nor deleterious effects on
diabetic cardiomyopathy in this transgenic model.