title: 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.
abstract: Thromboxane A(2) (TXA(2)) 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 TXA(2) 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 TXA(2) was increased. Chronic treatment with ozagrel (100mg/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.
authors.affiliation: Department of Physiology and Morphology, Institute of Medicinal Chemistry, Hoshi University, Tokyo, Japan.
authors.forename: Takayuki
authors.initials: T
authors.lastname: Matsumoto
authors.forename: Eri
authors.initials: E
authors.lastname: Takaoka
authors.forename: Keiko
authors.initials: K
authors.lastname: Ishida
authors.forename: Naoaki
authors.initials: N
authors.lastname: Nakayama
authors.forename: Eri
authors.initials: E
authors.lastname: Noguchi
authors.forename: Tsuneo
authors.initials: T
authors.lastname: Kobayashi
authors.forename: Katsuo
authors.initials: K
authors.lastname: Kamata
mesh_terms: D000109:Acetylcholine / Q000378:metabolism; D000818:Animals; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000378:metabolism / Q000473:pathology*; D008297:Male; D008638:Mesenteric Arteries / Q000378:metabolism* / Q000473:pathology; D008689:Methacrylates / Q000494:pharmacology; D009566:Nitrates / Q000737:chemistry; D009573:Nitrites / Q000737:chemistry; D011453:Prostaglandins / Q000378:metabolism; D051381:Rats; D020334:Rats, Inbred OLETF; D015398:Signal Transduction; D013928:Thromboxane A2 / Q000737:chemistry*; D013930:Thromboxane-A Synthase / Q000037:antagonists & inhibitors*
chemical_list: D008689:Methacrylates; D009566:Nitrates; D009573:Nitrites; D011453:Prostaglandins; D013928:Thromboxane A2; D013930:Thromboxane-A Synthase; C034364:ozagrel; D000109:Acetylcholine