To study the time-course relationship between vascular functions and endoplasmic reticulum (ER) stress in type 2 diabetes, we investigated vascular function and associated protein expression, including cyclo-oxygenase (COX), ER stress, and apoptotic markers, in renal arteries (RA) from type 2 diabetic Otsuka Long-Evans Tokushima fatty (OLETF) rats at the young adult (4 months old) and aged (18 months old) stages. In the RA of aged OLETF (vs. young OLETF), we found: (1) Increased contractions induced by uridine adenosine tetraphosphate (Up4A) and phenylephrine, (2) decreased relaxation and increased contraction induced by acetylcholine (ACh) at lower and higher concentrations, respectively, and (3) increased expression of COX-1 and C/EBP-homologous protein (CHOP, a pro-apoptotic protein). In aged rats, the expression of COX-1, COX-2, PDI (an ER protein disulfide isomerase), Bax (a proapoptotic marker), and CHOP were increased in RA from OLETF rats (vs. age-matched control Long-Evans Tokushima Otsuka [LETO] rats). Up-regulation of PDI and Bax were seen in the RA from young OLETF (vs. young LETO) rats. No age-related alterations were apparent in the above changes in RA from LETO rats, excluding ACh-induced contraction. Short-term treatment with the ER stress inhibitor tauroursodeoxycholic acid (TUDCA, 100 mg/kg per day, intraperitoneally for 1 week) to OLETF rats at the chronic stage of the disease (12 months old) could suppress renal arterial contractions induced by Up4A and ACh. These results suggest that a long-term duration of disease may be important for the development of vascular dysfunction rather than aging per se. The early regulation of ER stress may be important against the development of diabetes-associated vascular dysfunction.

We investigated the relationship between noradrenaline (NAd)-induced contractions, endothelial function, and hypertension in femoral arteries isolated from spontaneously hypertensive rats (SHR). In the femoral arteries of SHR, vs. age-matched control Wistar Kyoto (WKY) rats, contractions induced by NAd were increased. These effects were enhanced by endothelial denudation, which abolished the differences between the two groups. NAd-induced contractions were enhanced by nitric oxide (NO) synthase inhibition, and further increased by the blockade of endothelium-derived hyperpolarizing factor (EDHF). Conversely, NAd-induced contractions were inhibited by cyclooxygenase (COX) inhibition. In addition, in SHR arteries, acetylcholine-induced relaxation was reduced, and components of endothelium-derived factors were altered, such as increased COX-derived vasoconstrictor prostanoids, reduced EDHF, and preserved NO-mediated relaxation. In the femoral arteries of SHR, the production of prostanoids [6-keto prostaglandin (PG)F 1α (a metabolite of prostacyclin (PGI 2 ), PGE 2 , and PGF 2α ] and COX-2 protein were increased compared with that in WKY rats. By contrast, contractions induced by beraprost (a stable PGI 2 analogue), PGE 2 , and U46619 (thromboxane/prostanoid receptor agonist) were similar between the SHR and WKY groups. Thus, NAdinduced femoral arterial contractions are augmented in SHR resulting from endothelial dysfunction and increased COX-derived vasoconstrictor prostanoid levels.Key words cyclooxygenase; endothelium; femoral artery; hypertension; contraction Hypertension is one of the most common chronic diseases in humans, 1) and hypertension-associated vascular complications such as stroke, heart failure, kidney diseases and peripheral arterial diseases are major sources of morbidity and mortality that exacerbate the quality of life.1-3) Because dysfunction and abnormal signaling in the main structural elements of the vasculature, such as endothelial cells and smooth muscle cells, are characteristic hypertension-associated vascular complications, [4][5][6][7][8][9] and functional impairments in these cells are observed in hypertensive patients and animal models of the disease, 10-19) a comprehensive understanding of the underlying mechanisms is indispensable for preventing and treating such complications.Among endothelium-derived factors, nitric oxide (NO) is of the greatest importance for modulating vascular function. 20,21) However, other factors including endothelium-derived hyperpolarizing factor (EDHF) and cyclooxygenase (COX)-derived prostanoids can also modulate vascular tone. [22][23][24][25] Indeed, there are several reports suggesting that contraction induced by various substances including alpha-adrenoceptor ligands is enhanced by the inhibition of EDHF signaling 26) and enhanced 27) or suppressed 11,28,29) by COX signaling in various arteries under a (patho) physiological state. Because prostacyclin (PGI 2 ) serves as an endothelium-derived vasodilator and vasoconstrictor depending on the vessel t...

We investigated whether responsiveness to dinucleotide uridine adenosine tetraphosphate (Up4A) was altered in aortas from type 2 diabetic Otsuka Long-Evans Tokushima Fatty (OLETF) rats compared with those from age-matched control Long-Evans Tokushima Otsuka (LETO) rats at the chronic stage of disease. In OLETF aortas, we observed the following: (1) Up4A-induced contractions were lower than those in the LETO aortas under basal conditions, (2) slight relaxation occurred due to Up4A, but this was not observed in phenylephrine-precontracted LETO aortas, (3) acetylcholine-induced relaxation was reduced (vs. LETO), and (4) prostanoid release (prostaglandin (PG)F2α, thromboxane (Tx)A2 metabolite, and PGE2) due to Up4A was decreased (vs. LETO). Endothelial denudation suppressed Up4A-induced contractions in the LETO group, but increased the contractions in the OLETF group. Under nitric oxide synthase (NOS) inhibition, Up4A induced contractions in phenylephrine-precontracted aortas; this effect was greater in the LETO group (vs. the OLETF group). The relaxation response induced by Up4A was unmasked by cyclooxygenase inhibitors, especially in the LETO group, but this effect was abolished by NOS inhibition. These results suggest that the relaxant component of the Up4A-mediated response was masked by prostanoids in the LETO aortas and that the LETO and OLETF rats presented different contributions of the endothelium to the response.

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