Fx. Dai et al., DIABETES-INDUCED ENDOTHELIAL DYSFUNCTION IN STREPTOZOTOCIN-TREATED RATS - ROLE OF PROSTAGLANDIN ENDOPEROXIDES AND FREE-RADICALS, Journal of the American Society of Nephrology, 4(6), 1993, pp. 1327-1336
The vasoactive responses of renal arteries from diabetic and control r
ats were compared in vitro in arteriograph assemblies. Diabetes was es
tablished by an iv injection of streptozotocin (55 mg/kg) in Wistar-Ky
oto rats. Endothelium-dependent relaxations mediated by nitric oxide (
EDNO) were impaired in arteries from the diabetic rats; the impairment
in endothelial function increased with duration of the diabetic state
. After 6 and 16 wk, the concentrations of acetylcholine required to p
roduce 50% relaxation of norepinephrine preconstriction were 3.2 and 2
5 muM for arteries from diabetic rats and 0.4 muM in control arteries,
representing 8- and 62-fold decreases in sensitivity to the endotheli
um-dependent vasodilator in the diabetic arteries. After 6 wk of diabe
tes, renal arteries also became 20-fold less sensitive to relaxation i
nduced by histamine, another agonist that induces EDNO-mediated relaxa
tions. The inhibition of EDNO production with L-N(G)-nitroarginine pro
duced greater impairments in acetylcholine relaxations in arteries fro
m diabetic rats than from control rats. Relaxations in response to ace
tylcholine were impaired in arteries from diabetic rats because of inc
reased production of factors that opposed the vasorelaxant effects of
EDNO, rather than from decreased production of EDNO. Pretreatment of t
he diabetic arteries with the hydroxyl radical scavenger dimethylthiou
rea normalized relaxations in response to acetylcholine. The blockade
of prostaglandin H-2-thromboxane A2 receptors with SQ 29548 also impro
ved relaxations in response to acetylcholine in diabetic arteries. The
se data indicate that endothelial dysfunction in the renal arteries of
diabetic rats may be mediated by the increased production of tree rad
icals and of prostaglandin endoperoxides, which oppose the vasorelaxan
t effects of EDNO.