Diabetes-related changes in cAMP-dependent protein kinase activity and decrease in relaxation response in rat mesenteric artery

et al. 2006

J. Smooth Muscle Res.

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Using perfused kidneys isolated from age-matched controls and streptozotocin (STZ)-induced diabetic rats, we investigated the effects of arachidonic acid (AA) on perfusion pressure in the presence of methoxamine. AA elicited a transient contraction followed by a sustained relaxation in each group. The amplitude of contraction was smaller in the diabetic group than in the control group, whereas the amplitude of the sustained relaxation was greater in the former than in the latter group. In the diabetic group, the AA-induced sustained relaxation was completely inhibited by indomethacin [cyclooxygenase (COX) inhibitor], SKF525A [cytochrome P450 (CYP450) inhibitor], or clotrimazole (epoxygenase inhibitor), but not by furegrelate [thromboxane A2 (TXA2)-synthase inhibitor], SQ29548 (TXA2-receptor antagonist), or baicalein [lipoxygenase (LOX) inhibitor]. In the diabetic kidney, more-or-less additive inhibitions of the AAinduced relaxation were seen when indomethacin was given with either SKF525A or clotrimazole. These results suggest that in the STZ-induced diabetic perfused kidney, vasorelaxant metabolites derived from AA (probably COX and/or CYP450 metabolites) are increased, and may serve to regulate vascular tone.

Section: Introductionmentioning

confidence: 99%

Altered arachidonic acid-mediated responses in the perfused kidney of the streptozotocin-induced diabetic rat

Kamata

Hosokawa

et al. 2006

J. Smooth Muscle Res.

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“…[39][40][41][42][43][44][45][46][47][48][49][50] So far, few studies have investigated the direct effect of tunicamycin on vascular relaxation. In vivo treatment with tunicamycin for several weeks increased ER stress and reduced ACh-induced relaxation in the arteries of rats 14) and mice.…”

Section: Discussionmentioning

confidence: 99%

“…40,44,46) It is well known that activation of beta-adrenoceptors in arteries leads to AC activation, which subsequently causes intracellular cAMP accumulation and activation of protein kinase A (PKA). 39,43) Therefore, relaxation of vascular smooth muscle by non-selective betaadrenoceptor ISO involves cAMP-dependent mechanisms because the beta-adrenoceptors are coupled to AC through G s proteins.…”

Section: 28-32)mentioning

confidence: 99%

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

Biological & Pharmaceutical Bulletin

Ando

Watanabe

et al. 2016

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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...

“…[13][14][15][16][17][18] Rats were anesthetized with diethyl ether and then euthanized by decapitation. The superior mesenteric artery was rapidly removed and immersed in oxygenated, modified Krebs-Henseleit solution (KHS).…”

Section: Drugs and Chemicals Phenylephrine Indomethacin Nmentioning

confidence: 99%

Vasodilator Effect of Cassiarin A, a Novel Antiplasmodial Alkaloid from Cassia siamea, in Rat Isolated Mesenteric Artery

Biological & Pharmaceutical Bulletin

Kobayashi

Ishida

et al. 2010

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Cassia siamea (Leguminosae), a small-to medium-sized tree, is one of the most commonly cultivated trees in Southeast Asia. Different parts of this plant can be used for a variety of medical purposes, giving the plant considerable medicinal potential. In traditional folk medicine, its stem bark is used as a mild, pleasant, safe purgative; a decoction of the bark is given to treat diabetes; a paste is used as a dressing for ringworm and chilblains; the roots are used as an antipyretic; and the leaves are used for the treatment of constipation, hypertension, and insomnia.1,2) A number of compounds, including barakol, emodin, b-and g-sitosterol, lupeol, luteolin, D-pinitol, chromone alkaloids, flavonoid glycosides, and a number of anthraquinones and bianthraquinones, have been isolated from Cassia siamea. 1,3,4) Although members of the genus Cassia are widely distributed in tropical and subtropical regions, where they have long been used in traditional folk medicine, particularly for the treatment of periodic fever and malaria, 5) we only recently have isolated the novel heteroaromatic alkaloid cassiarin A (Fig. 1) from the leaves of Cassia siamea. 6) This was followed a year later by the first total synthesis of cassiarin A, a process completed in eight steps from a known compound, methyl 2,4-dihydroxybenzoate.7) This alkaloid possesses an unprecedented tricyclic skeleton and exhibits potent antiplasmodial activity. 6,8,9) Although we have recently reported that some alkaloids and peptides exhibit not only antiplasmodial activity, but also vasorelaxant activity in the rat aorta, 10-12) the effect of cassiarin A on vascular tone remains unclear. We have very recently found that cassiarin A induces relaxation in the rat thoracic aorta and this was largely due to endotheliumderived nitric oxide (NO).9) However, no study has investigated the effects of cassiarin A on vascular tone in other, smaller arteries. The primary purpose of this study was therefore to test the hypothesis that cassiarin A induces in vitro vascular relaxation in rat mesenteric arteries precontracted with phenylephrine. In addition, we wanted to determine whether the vascular relaxation is endothelium dependent or whether cassiarin A acts directly upon vascular smooth muscle. MATERIALS AND METHODS Drugs and Chemicals, glibenclamide, 4-aminopyridine (4-AP), and tetraethylammonium (TEA) were all purchased from Sigma Chemical Co. (St. Louis, MO, U.S.A.). Acetylcholine chloride was from Daiichi-Sankyo Pharmaceuticals (Tokyo, Japan), 1H-[1,2,4]oxadiazolo[4,3-a]-quinoxalin-1-one (ODQ) was from Wako (Osaka, Japan), and iberiotoxin was from the Peptide Institute Inc. (Osaka, Japan). Drugs were dissolved in saline, except for glibenclamide [dissolved in dimethyl sulfoxide (DMSO)] and indomethacin (dissolved first in a small amount of Na 2 CO 3 0.1 M solution, then made up to the final volume with distilled water).Cassiarin A was prepared as previously reported. 6) Briefly, leaves of Cassia siamea (collected at the Purwodadi Botanical Garden, Pasuruan, Indon...