Imbalance between endothelium-derived relaxing and contracting factors in mesenteric arteries from aged OLETF rats, a model of Type 2 diabetes

Abstract

We investigated whether the balance between endothelium-derived relaxing factors (EDRFs) and endothelium-derived contracting factors (EDCFs) might be altered in mesenteric arteries from aged Otsuka Long-Evans Tokushima Fatty (OLETF) rats (a Type 2 diabetic model) [vs. age-matched control Long-Evans Tokushima Otsuka (LETO) rats]. ACh-induced relaxation was impaired in the OLETF group, and a tendency for the relaxation to reverse at high ACh concentrations was observed in both groups. This tendency was abolished by indomethacin. Nitric oxide- and/or endothelium-derived hypolarizing factor-mediated relaxation and the protein expressions of phospho-endothelial nitric oxide synthase (Ser1177) and extracellular superoxide dismutase were also reduced in OLETF. An ACh-induced contraction was observed at higher ACh concentrations in the presence of N(G)-nitro-L-arginine (L-NNA) but was greater in OLETF rats. This contraction in OLETF rats was reduced by cyclooxygenase (COX) inhibitors and by prostanoid-receptor antagonists. The ACh-induced productions of thromboxane A(2) and PGE(2) were greater in OLETF than LETO rats, as were the mesenteric artery COX-1 and COX-2 protein expressions. Moreover, tert-butyl hydroperoxide (t-BOOH) (membrane-permeant oxidant) induced a concentration-dependent contraction that was greater in OLETF rats. The t-BOOH-mediated contraction was increased both by L-NNA and by endothelium removal in LETO but not OLETF rats, suggesting that a negative modulatory role of the endothelium was lost in OLETF rats. These results suggest that an imbalance between EDRFs and EDCFs may be implicated in the endothelial dysfunction seen in aged OLETF mesenteric arteries, and may be attributable to increased oxidative stress.

Effect of Short-term Polyphenol Treatment on Endothelial Dysfunction and Thromboxane A₂ Levels in Streptozotocin-Induced Diabetic Mice

“…2,10,11,37) Moreover, we found that endothelium-dependent vasorelaxation of isolated aortas in response to ACh was improved by MO in diabetic mice and showed a marked tendency to improve by CA and RV; because the polyphenols reduced TXA 2 levels in the aorta, the subsequent reduction of contraction factors may, at least in part, account for the observed improvement of endothelium-dependent vasorelaxation. That is, the polyphenols did not modify ACh-stimulated NO production, but suppressed TXA 2 levels in the diabetic aorta.…”

“…[8][9][10][11][12][13][14][15][16]27,28) Plasma samples were stored at −20°C until analysis. Briefly, plasma glucose, cholesterol, high-density lipoprotein (HDL) cholesterol, triglyceride, and serum non-esterified fatty acid (NEFA) levels were each determined with a commercially available enzyme kit (Wako Pure Chemical Industries, Ltd., Osaka, Japan).…”

“…The endothelium plays a central role in physiological maintenance of the vascular function by regulating vascular tone, leukocyte adhesion, and platelet activation, as a result of the release of vasoactive substances such as nitric oxide (NO), prostacyclin, and thromboxane A 2 (TXA 2 ). 1,[6][7][8][9][10][11][12][13][14][15][16] Several natural polyphenols have been evaluated for their ability to protect against endothelial dysfunction and, thus, for their effectiveness in preventing cardiovascular disease. 17) Indeed, we have also shown that long-term chlorogenic acid (CA) treatment (2 months) can normalize the impaired endothelium-dependent relaxation seen in diabetic rats.…”

Reduced EDHF responses and connexin activity in mesenteric arteries from the insulin-resistant obese Zucker rat

“…Furthermore, the EDHF component of acetylcholine-induced relaxation was impaired in epineurial arterioles [19] and small mesenteric arteries [20] from Zucker fatty rats, a model of type 2 diabetes. EDHF-mediated responses have also been shown to be reduced in mesenteric arteries from aged Otsuka Long-Evans Tokushima fatty rats, another model of type 2 diabetes [21].…”

Cyclooxygenase-2-Derived Prostaglandin F 2α

“…EDCFmediated vasoconstriction might prevail with increasing age, as well as disturbed endothelial function, for example, in hypertension 1,2 or type 2 diabetes. 3 In addition to reduced generation of vasodilator prostaglandins (PGs), such as PGI 2 , enhanced production of vasoconstrictor prostanoids has been described. 4,5 Oxygen-derived free radicals and isoprostanes, generated by exaggerated oxidative stress, are further members of the EDCF family.…”