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Toll-Like Receptor 4 Inhibitor TAK-242 Augments Acetylcholine-Induced Relaxation in Superior Mesenteric Arteries of the Streptozotocin-Induced Diabetic Rat
- Source :
- Biologicalpharmaceutical bulletin. 43(8)
- Publication Year :
- 2020
-
Abstract
- Although vascular dysfunction is a key event in the development of diabetic complications, and abnormal toll-like receptor 4 (TLR4) may contribute to the pathophysiology of vascular diseases, the direct relationships between TLR4 and vascular function in diabetic arteries are still poorly understood. Thus, to investigate whether pharmacological blockade of TLR4 affects vascular function in the superior mesenteric artery (SMA) of streptozotocin (STZ)-induced diabetic rats, the SMA was isolated from male Wistar rat injected once with STZ (65 mg/kg, 27-34 weeks) which was treated with TAK-242 (10-6 M), a TLR4 inhibitor, for approximately 1 d using organ culture techniques. After incubation, functional and biochemical studies were performed. In the functional study, treatment with TAK-242 increased acetylcholine (ACh)-induced relaxation of the diabetic SMA in the intact condition. Sodium nitroprusside (SNP)-induced relaxation was also increased in the TAK-242-treated group compared with the vehicle-treated group. Under cyclooxygenase (COX) blockade by indomethacin (10-5 M), ACh-induced relaxation was similar in the vehicle- and TAK-242-treated groups. In addition, ACh-induced relaxation in the combined presence of the nitric oxide (NO) synthase inhibitor, NG-nitro-L-arginine (L-NNA) (10-4 M), and indomethacin (10-5 M) was similar in the vehicle- and TAK-242-treated groups. The productions of thromboxane (TX) B2 in cultured medium in the presence of ACh (10-5 M) were lower in the TAK-242-treated group than in the vehicle-treated group. These data suggested that TAK-242 could augment endothelium-dependent relaxation by partly suppressing vasoconstrictor TXA2 or increasing NO signaling. TLR4 inhibition may be a novel therapeutic strategy to assist in the management of diabetes-associated vascular complications.
- Subjects :
- 0301 basic medicine
Male
Thromboxane
Pharmaceutical Science
Pharmacology
Streptozocin
Nitric oxide
Diabetes Mellitus, Experimental
03 medical and health sciences
chemistry.chemical_compound
Thromboxane A2
0302 clinical medicine
Mesenteric Artery, Superior
medicine.artery
medicine
Animals
Superior mesenteric artery
Rats, Wistar
Mesenteric arteries
Endothelium-Dependent Relaxing Factors
Sulfonamides
biology
General Medicine
Streptozotocin
Acetylcholine
Rats
Toll-Like Receptor 4
Vasodilation
030104 developmental biology
medicine.anatomical_structure
chemistry
030220 oncology & carcinogenesis
biology.protein
Cyclooxygenase
Sodium nitroprusside
Diabetic Angiopathies
medicine.drug
Subjects
Details
- ISSN :
- 13475215
- Volume :
- 43
- Issue :
- 8
- Database :
- OpenAIRE
- Journal :
- Biologicalpharmaceutical bulletin
- Accession number :
- edsair.doi.dedup.....c5c5c71460fd6e3f26230a7372fd1acf