Troglitazone is a new class of
antidiabetic agent possessing radical scavenging ability similar to
vitamin E. Because of this ability, it is expected to improve decreased nutritive capillary blood flow in diabetes. In the present study, we investigated the effects of
troglitazone on skin blood flow(SBF) in normal and
streptozotocin(STZ)-induced diabetic rats. Effects of
troglitazone on vasodilation, PGI2 and
PGE2 production were also assessed in perfused hindlimb, isolated rat aorta rings and 3T6 fibroblasts, respectively. SBF at the base of the tail was decreased in STZ diabetic rats (2.1+/-0.2 ml/min/100 g) compared with normal rats (3.8+/-0.2 ml/min/100 g). This decrease of SBF was significantly improved (2.9+/-0.2 ml/min/100 g) by
troglitazone treatment (approximately 220 mg/kg/day) for 7 days in STZ diabetic rats without alleviating
hyperglycemia. Similar
troglitazone treatment (approximately 160 mg/kg/day for 7 days) tended to increase SBF (approximately 30%) even in normal rats. In normal rats, subcutaneous administration of
troglitazone (60 mg/kg) acutely increased SBF and, this increase was suppressed by 70% with pretreatment (10 mg/kg s.c.) of
indomethacin,
cyclooxygenase inhibitor, suggesting that
troglitazone increases skin blood flow predominantly by increasing PGI2 and
PGE2 production. In hindlimb perfusion under fixed flow rate,
troglitazone infusion (20 microM) significantly decreased perfusion pressure by 13%, which reflects vasodilation of blood vessels. This decrease of perfusion pressure was inhibited by concomitant infusion of
indomethacin but not N-monomethyl-
L-arginine, inhibitor of
nitric oxide synthase. In vitro studies, using isolated rat aorta rings, revealed that
troglitazone (4.5 to 45 microM) increases PGI2 production by 31 and 70%, respectively. In 3T6 fibroblast (a component of skin tissue),
troglitazone at a low dose of 0.3 microM increased PGI2 and
PGE2 by 200% and 25%, respectively. Overall all, these results suggest that
troglitazone increases nutritive SBF probably by virtue of its radical scavenging thus the resulting in an increase in PGI2 and
PGE2 production in blood vessels and fibroblast.
Troglitazone may alleviate impaired microcirculation in diabetic patients through these effects.