Hyperglycemia increases
glucose metabolism via the
polyol pathway, which results in elevations of intracellular
sorbitol concentration. Thus we hypothesized that elevated level of
sorbitol contributes to the development of
hyperglycemia-induced dysfunction of microvessels. In isolated, pressurized (80 mmHg) rat gracilis muscle arterioles (approximately 150 microm), high
glucose treatment (25 mM) induced reduction in flow-dependent dilation (from maximum of 39 +/- 2% to 15 +/- 1%), which was significantly mitigated by an
aldose reductase inhibitor,
zopolrestat (maximum 27 +/- 2%). Increasing doses of
sorbitol (10(-10)-10(-4) M) elicited dose-dependent constrictions (maximum 22 +/- 3%), which were abolished by endothelium removal, a
prostaglandin H(2)/
thromboxane A(2) (
PGH(2)/TXA(2))
receptor (TP) antagonist
SQ-29548, or
superoxide dismutase (SOD) plus
catalase (CAT). Incubation of arterioles with
sorbitol (10(-7) M) reduced flow-dependent dilations (from maximum of 39 +/- 2% to 20 +/- 1.5%), which was not further affected by inhibition of
nitric oxide synthase by
N(omega)-nitro-l-arginine methyl ester but was prevented by SOD plus CAT and mitigated by
SQ-29548.
Nitric oxide donor sodium nitroprusside-induced (10(-9)-10(-6) M) dilations were also decreased in a
SQ-29548 and SOD plus CAT-reversible manner, whereas
adenosine dilations were not affected by
sorbitol exposure.
Sorbitol significantly increased arterial
superoxide production detected by
lucigenin-enhanced chemiluminescence, which was inhibited by SOD plus CAT.
Sorbitol treatment also increased arterial formation of
3-nitrotyrosine. We suggest that
hyperglycemia by elevating intracellular
sorbitol induces oxidative stress, which interferes with
nitric oxide bioavailability and promotes
PGH(2)/TXA(2) release, both of which affect regulation of vasomotor responses of arterioles. Thus increased activity of the
polyol pathway may contribute to the development of microvascular dysfunction in
diabetes mellitus.