Mechanisms underlying the losartan treatment-induced improvement in the endothelial dysfunction seen in mesenteric arteries from type 2 diabetic rats

Matsumoto, Takayuki; Ishida, Keiko; Nakayama, Naoaki; Taguchi, Kumiko; Kobayashi, Tsuneo; Kamata, Katsuo

doi:10.1016/j.phrs.2010.03.003

Cited by 31 publications

(35 citation statements)

References 69 publications

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“…Vascular isometric force was measured as in our previous papers [24,[36][37][38][39]. After euthanasia, the superior mesenteric artery was rapidly removed and immersed in oxygenated, modified Krebs-Henseleit solution (KHS).…”

Section: Vascular Functional Studymentioning

confidence: 99%

“…The artery was carefully cleaned of all fat and connective tissue and ring segments 2 mm in length were suspended by a pair of stainless steel pins in a well-oxygenated (95% O 2 -5% CO 2 ) bath containing 10 ml of KHS at 37°C. The rings were stretched until the optimal resting tension (1.0 g) was reached, which value was derived from preliminary length-active tension curves [24,[36][37][38][39]. They were then allowed to equilibrate for at least 1 h. Force generation was monitored by means of an isometric transducer (model TB-611 T; Nihon Kohden, Tokyo, Japan).…”

Section: Vascular Functional Studymentioning

confidence: 99%

“…We proposed that upregulation of the ET A receptor, a defect in ET B receptor-mediated NO signaling, and activation of the MEK/ERK pathway together represent a likely mechanism underlying the hyperreactivity to ET-1 that exists at the chronic stage of type 2 diabetes in GK rats [36]. In addition, we recently reported that the release of vasoconstrictor prostanoids including PGE 2 that occurs upon agonist stimulation was increased in superior mesenteric arteries from type 2 diabetic rats [24,37].…”

Section: Introductionmentioning

confidence: 99%

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Protein kinase C delta contributes to increase in EP3 agonist-induced contraction in mesenteric arteries from type 2 diabetic Goto-Kakizaki rats

Ishida

Matsumoto

Taguchi

et al. 2012

Pflugers Arch - Eur J Physiol

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Prostaglandin E(2) (PGE(2)), an important and ubiquitously present vasoactive eicosanoid, may either constrict or dilate systemic vascular beds. However, little is known about the vascular contractile responsiveness to and signaling pathways for PGE(2) at the chronic stage of type 2 diabetes. We hypothesized that PGE(2)-induced arterial contraction is augmented in type 2 diabetic Goto-Kakizaki (GK) rats via the protein kinase Cδ (PKCδ) pathway. Here, we investigated the vasoconstrictor effects of PGE(2) and of sulprostone (EP1-/EP3-receptor agonist) in rings cut from superior mesenteric arteries isolated from GK rats (37-44 weeks old). In arteries from GK rats (vs. those from age-matched Wistar rats), examined in the presence of a nitric oxide synthase inhibitor: 1) the PGE(2)- and sulprostone-induced vasocontractions (which were not blocked by the selective EP1 receptor antagonist sc19220) were enhanced, and these enhancements were suppressed by rottlerin (selective PKCδ inhibitor) but not by Gö6976 (selective PKCα/β inhibitor); 2) the sulprostone-stimulated phosphorylation of PKCδ (at Thr(505)), which yields an active form, was increased and 3) sulprostone-stimulated caldesmon phosphorylations, which are related to isometric force generation in smooth muscle, were increased. The protein expression of EP3 receptor in superior mesenteric arteries was similar between the two groups of rats. Our data suggest that the diabetes-related enhancement of EP3 receptor-mediated vasocontraction results from activation of the PKCδ pathway. Alterations in EP3 receptor-mediated vasocontraction may be important factors in the pathophysiological influences over arterial tone that are present in diabetic states.

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Section: Vascular Functional Studymentioning

confidence: 99%

Section: Vascular Functional Studymentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Protein kinase C delta contributes to increase in EP3 agonist-induced contraction in mesenteric arteries from type 2 diabetic Goto-Kakizaki rats

Ishida

Matsumoto

Taguchi

et al. 2012

Pflugers Arch - Eur J Physiol

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“…[26][27][28][29][30][31][32][33] The arterial rings were stretched until an optimal resting tension of 9.8 mN was loaded and then allowed to equilibrate; subsequently, the high-K + (80 mM)-induced contraction was measured. For the relaxation studies, mesenteric arterial rings were pre-contracted with an equi-effective concentration of phenylephrine (PE) (0.6-50 µM; the contractile force was similar between vehicle-and tunicamycin-treated groups).…”

Section: )mentioning

confidence: 99%

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

Matsumoto

Ando

Watanabe

et al. 2016

Biological & Pharmaceutical Bulletin

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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 ( Key words endoplasmic reticulum stress; mesenteric artery; relaxation; tunicamycin Organelle dysfunction, including endoplasmic reticulum (ER) stress, has an important role in the development of various diseases, such as cancer, and neuronal, metabolic, and cardiovascular diseases.1-10) ER stress is caused by various conditions, including glucose deprivation or glucose overload, calcium depletion or overload, hypoxia or oxidative stress, fatty acid overload, protein aggregation, and exposure to chemicals, such as tunicamycin or thapsigargin. 10,11) Recent evidence has shown a relationship between ER stress and vascular function in various disease states. 8,11,12) For instance, inhibition of ER stress could decrease blood pressure, aortic apoptosis, and fibrosis, and normalize vascular dysfunction in the aorta and mesenteric resistance artery of angiotensin II (Ang II)-treated hypertensive animals. 13,14) Spitler et al. found that increased ER stress was present in the aorta of spontaneously hypertensive rats (SHR) and that the suppression of ER stress reduced acetylcholine (ACh)-induced endothelium-dependent contraction in the aorta of SHR.15) Moreover, we recently suggested that a relationship existed between ER stress and renal arterial function in type 2 diabetic rats.16) Therefore, ER stress is a key intracellular event in the pathogenesis of vascular dysfunction and is an important target against such vasculopathies. However, the direct linkage between ER stress and vascular function especially vasorelaxation, remains unclear.Tunicamycin, an antibiotic, is known to inhibit N-linked glycosylation.17,18) Moreover, tunicamycin is also a major ER stress inducer in vitro and in vivo. 13,14,[19][20][21] In vivo treatment with tunicamycin for several weeks reduced ACh-induced endothelium-dependent relaxation in large and small arteries. 13,14) Moreover, in vitro acute treatment with tunicamycin (for 1 h) impaired insulin-mediated vasomotor activity, such as by causing contraction but no relaxation in the aorta through endothelin-1 (ET-1) release. 22) However, there are no reports regarding the in vitro effect of short-term treatment with tunicamycin on relaxations induced by various types of mechanisms in the superior mesenteric artery of rats.The aim of this study was to investigate the effect of short-term tunicamycin treatment on vasorelaxant responses induced by various vasodilator...

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“…The halflife (t 1/2 ) of E3174 is 10 to 40 times longer than that of losartan. The varied metablism could be induced by interaction of the enzyme activity and different losartan plasma concentration profiles due to different CYP2C9 genotypes [3][4][5][6][7].…”

Section: Introductionmentioning

confidence: 99%

Pharmacokinetics of Hydrochlorothiazide, Losartan and E3174 after Oral Doses of Losartan and Losartan/Hydrochlorothiazide in Healthy Chinese Male Volunteers

Li¹,

Bu²,

Wei³

et al. 2012

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Aims: A simple and highly sensitive LC-MS method was used to determine the concentrations of losartan, its major active metabolite E3174 and hydrochlorothiazide in human plasma and pharmacokinetic characteristics and metabolism phenotype observation after administration of losartan tablets and losartan/hydrochlorothiazide combination tablets.Methods: An open, randomized cross-over single-dose study was designed in forty healthy male volunteers, A single-dose of 50 mg losartan tablets or 50 mg losartan/12.5 mg hydrochlorothiazide combination tablets was orally given and blood samples were collected at scheduled time. A LC-MS method was established and evaluated for determining the plasma concentrations of losartan, E3174 and hydrochlorothiazide. The pharmacokinetic parameters and characteristic of metabolism phenotypes were calculated and compared via this test. Results: The elimination rate of E3174 (t 1/2 ) was significantly shorter (P < 0.05) and the AUC 0-t was lower (P < 0.05) for administration of combination tablets. The rest of pharmacokinetic parameters of losartan and E3174 have no significant differences. Among all subjects, three phenotypes were observed: the poor, the intermediate and the extensive metabolism. Conclusion: It is indicated that the test and reference tablets were bioequivalent, and that hydrochlorothiazide could significantly alter the t 1/2 , AUC 0-t and AUC 0-inf of E3174.

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Mechanisms underlying the losartan treatment-induced improvement in the endothelial dysfunction seen in mesenteric arteries from type 2 diabetic rats

Cited by 31 publications

References 69 publications

Protein kinase C delta contributes to increase in EP3 agonist-induced contraction in mesenteric arteries from type 2 diabetic Goto-Kakizaki rats

Protein kinase C delta contributes to increase in EP3 agonist-induced contraction in mesenteric arteries from type 2 diabetic Goto-Kakizaki rats

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

Pharmacokinetics of Hydrochlorothiazide, Losartan and E3174 after Oral Doses of Losartan and Losartan/Hydrochlorothiazide in Healthy Chinese Male Volunteers

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