Tunicamycin-Induced Alterations in the Vasorelaxant Response in Organ-Cultured Superior Mesenteric Arteries of Rats.

In cellular events, endoplasmic reticulum (ER) stress has an important role in the development of various diseases including cardiovascular diseases. Tunicamycin, an inhibitor of N-linked glycosylation, is known to be an inducer of ER stress. However, the extent to which tunicamycin affects the vasorelaxant function is not completely understood. Thus, we investigated the effect of tunicamycin on relaxations induced by various vasorelaxant agents, including acetylcholine (ACh; endothelium-dependent vasodilator), sodium nitroprusside (SNP; endothelium-independent vasodilator), isoprenaline (ISO; beta-adrenoceptor agonist), forskolin (FSK; adenylyl cyclase activator), and cromakalim [ATP-sensitive K(+) (KATP) channel activator] in organ-cultured superior mesenteric arteries of rats, which are treated with either a vehicle [dimethyl sulfoxide (DMSO)] or tunicamycin (20 µg/mL for 22-24 h). Protein levels of the ER stress marker binding immunoglobulin protein (BiP) were determined by Western blotting. Tunicamycin increased the expression of BiP in organ-cultured arteries. Tunicamycin impaired ACh-induced relaxation, but did not alter SNP-induced relaxation. Tunicamycin also impaired vasorelaxation induced by ISO, FSK, and cromakalim; moreover, it reduced basal nitric oxide (NO) formation. In conclusion, short-term treatment with tunicamycin not only caused endothelial dysfunction but also impaired cAMP- and KATP-mediated responses in the superior mesenteric arteries of rats. These alterations in tunicamycin-treated arteries may be due to reduced basal NO formation. This work provides new insight into ER stress in vascular dysfunction.

Mechanisms Underlying Enhanced Noradrenaline-Induced Femoral Arterial Contractions of Spontaneously Hypertensive Rats: Involvement of Endothelium-Derived Factors and Cyclooxygenase-Derived Prostanoids.

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)F1α (a metabolite of prostacyclin (PGI2), PGE2, and PGF2α] and COX-2 protein were increased compared with that in WKY rats. By contrast, contractions induced by beraprost (a stable PGI2 analogue), PGE2, and U46619 (thromboxane/prostanoid receptor agonist) were similar between the SHR and WKY groups. Thus, NAd-induced femoral arterial contractions are augmented in SHR resulting from endothelial dysfunction and increased COX-derived vasoconstrictor prostanoid levels.