Aldose reductase inhibition restores endothelial cell function in diabetic rabbit aorta.
A possible relationship between increased aldose reductase activity and abnormal endothelium-dependent relaxation was examined in aorta from alloxan-induced diabetic rabbits. Isolated aorta of diabetic rabbits, contracted submaximally with phenylephrine, showed significantly decreased endothelium-dependent relaxations induced by acetylcholine or adenosine diphosphate compared to those from normal rabbits. Basal and acetylcholine-stimulated levels of cyclic GMP and the relaxations in response to an endothelium-independent vasodilator, sodium nitroprusside, were not significantly different between diabetic and normal rabbits, indicating that nitric oxide release and action on the vascular smooth muscle were unchanged. The release of thromboxane A2 from diabetic vessels was increased, as previously demonstrated. Treatment with an aldose reductase inhibitor, zopolrestat, normalized the elevated red blood cell sorbitol levels in diabetic rabbits. Zopolrestat also restored the abnormal acetylcholine- and adenosine diphosphate-induced relaxations of the aorta. The aldose reductase inhibitor had no effect on the levels of cyclic GMP or on the increased release of thromboxane A2 in diabetic aorta. These findings suggest that increased activity of the aldose reductase pathway in hyperglycemia is responsible for the abnormal endothelium-dependent relaxation in diabetic blood vessels. Significant alterations in endothelial production of neither nitric oxide nor vasoconstrictor prostanoids could be directly implicated in the improvement caused by the drug, suggesting another mechanism of action.
Tesfamariam
B
B
Robert Dawson Evans Department of Clinical Research, Boston University School of Medicine, Massachusetts.
Palacino
J J
JJ
Weisbrod
R M
RM
Cohen
R A
RA
D000109:Acetylcholine / Q000494:pharmacology; D000244:Adenosine Diphosphate / Q000494:pharmacology; D000449:Aldehyde Reductase / Q000037:antagonists & inhibitors*; D000818:Animals; D001011:Aorta / Q000503:physiopathology*; D001786:Blood Glucose / Q000378:metabolism; D001835:Body Weight / Q000187:drug effects; D006152:Cyclic GMP / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000503:physiopathology*; D004730:Endothelium, Vascular / Q000187:drug effects / Q000503:physiopathology*; D007093:Imidazoles / Q000494:pharmacology; D048289:Imidazolidines; D066298:In Vitro Techniques; D008297:Male; D009126:Muscle Relaxation / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D010656:Phenylephrine / Q000494:pharmacology; D011453:Prostaglandins / Q000378:metabolism; D011817:Rabbits; D013012:Sorbitol / Q000097:blood
D001786:Blood Glucose; D007093:Imidazoles; D048289:Imidazolidines; D011453:Prostaglandins; D010656:Phenylephrine; D013012:Sorbitol; D000244:Adenosine Diphosphate; D000449:Aldehyde Reductase; C026411:sorbinil; D006152:Cyclic GMP; D000109:Acetylcholine