Abnormalities of endothelium-dependent responses in mesenteric arteries from Otsuka Long-Evans Tokushima Fatty (OLETF) rats are improved by chronic treatment with thromboxane A2 synthase inhibitor

Thromboxane A2 (TXA2) is thought to contribute to the development of diabetic complications. We tested the hypothesis that the impaired endothelial function seen in Otsuka Long-Evans Tokushima Fatty (OLETF) rats (a type 2 diabetic model) might be improved by chronic treatment with ozagrel, a TXA2 synthase inhibitor. In mesenteric arteries from OLETF rats (40-46 weeks old) [vs. those from age-matched Long-Evans Tokushima Otsuka (LETO) rats]: (1) ACh-induced endothelium-dependent relaxation, NO-mediated relaxation, and endothelium-derived hyperpolarizing factor (EDHF)-type relaxation were all reduced; (2) ACh-induced cyclooxygenase-dependent contraction was enhanced; (3) endothelium-derived contracting factor (EDCF)-mediated contraction was enhanced; (4) ACh-stimulated nitrite production was reduced but the nitrate/nitrite ratio was increased; and (5) ACh-stimulated production of TXA2 was increased. Chronic treatment with ozagrel (100 mg/kg/day for 4 weeks, starting when they were 36-42 weeks of age) partly corrected the above abnormalities. These results suggest that ozagrel has normalizing effects on endothelial functions in OLETF mesenteric arteries, at least partly by increasing endothelium-derived relaxing factors (i.e., NO and EDHF) signaling and reducing EDCF signaling.