Enhanced 5-HT&lt;sub&gt;2&lt;/sub&gt; Receptor Mediated Contractions in Diabetic Rat Aorta: Participation of Ca&lt;sup&gt;2+&lt;/sup&gt;Channels Associated with Protein Kinase C Activity

Hattori, Yoshiyuki; Kawasaki, Hisao; Kanno, Morio; Fukao, Mitsuhiro

doi:10.1159/000159096

Cited by 13 publications

(18 citation statements)

References 22 publications

(27 reference statements)

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“…This finding supports previous reports using aorta and other vessels from diabetic animals [4][5][6][7][8]10]. Recently, we have demonstrated that the contractile response to 5-HT is also enhanced in diabetic rat aorta [19], It seems likely that the enhanced responsiveness of diabetic aorta to noradrenaline and 5-HT is due to a greater Ca2+ influx through Ca2+ channels as a consequence of increased PKC-activated process. First, the contractions induced by phorbol esters are greater in diabetic aortas compared to controls [12,19].…”

Section: Discussionsupporting

confidence: 92%

“…rats. Diabetic rats also manifested other symptoms of the disease including polyuria, polydipsia and cataracts, as previously reported [19].…”

Section: General Features O F Animalssupporting

confidence: 83%

“…Recently, we have also shown that high K+-evoked depolarization results in the reduced contraction in diabetic aorta, despite the en hanced contractile responses to 5-hydroxytryptamine (5-HT) and phorbol-12,13-dibutyrate through nifedipinesensitive pathway [19], Thus, it is possible that activation of vascular Ca2+ channels by membrane depolarization may be specifically impaired in diabetes.…”

Section: Introductionmentioning

confidence: 99%

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Diminishment of Contractions Associated with Depolarization-Evoked Activation of Ca<sup>2+</sup> Channels in Diabetic Rat Aorta

Hattori

Kawasaki²,

Fukao³

et al. 1996

J Vasc Res

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Alterations in contractile responses of aortic rings mediated by activation of Ca²⁺ channels were investigated in rats with streptozotocin-induced diabetes. Eight to 12 weeks of diabetes resulted in a marked decrease in the contractile response of aortic rings to high K⁺. In contrast, diabetic aortas exhibited significantly greater contractions in response to noradrenaline compared to age-matched controls. In the presence of 15 ml K⁺, the Ca²⁺ channel agonist Bay K 8644 consistently produced concentration-dependent contractions in control aortas. On the other hand, the half of diabetic aortas did not respond to Bay K 8644. As a result, the contractile response to Bay K 8644 was significantly less in diabetic aortas compared to controls. There was no significant difference in basal ⁴⁵Ca²⁺ uptake between control and diabetic aortas. However, the uptake of ⁴⁵Ca²⁺ induced by high K⁺ was significantly less in diabetic aortas than in controls, and pretreatment with the Ca²⁺ channel antagonist nifedipine abolished both responses. The resting membrane potentials were not significantly different between control and diabetic aortas. Furthermore, no difference was found in the magnitude of depolarization evoked by increasing K⁺ concentrations between the two groups of tissues. There were no significant differences in the density and the dissociation constant for [³H]-(+)-PN200-110, a radiolabeled Ca²⁺ channel antagonist, between aortic membranes from control and diabetic rats. These data indicate that the contractile responses to high K⁺ and Bay K 8644 are specifically diminished in diabetic aortas. These diminished responses are not due to a difference in the number of Ca²⁺ channels, but may be related to an alteration in activation of the channels by membrane depolarization.

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Section: Discussionsupporting

confidence: 92%

“…rats. Diabetic rats also manifested other symptoms of the disease including polyuria, polydipsia and cataracts, as previously reported [19].…”

Section: General Features O F Animalssupporting

confidence: 83%

Section: Introductionmentioning

confidence: 99%

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Diminishment of Contractions Associated with Depolarization-Evoked Activation of Ca<sup>2+</sup> Channels in Diabetic Rat Aorta

Hattori

Kawasaki²,

Fukao³

et al. 1996

J Vasc Res

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“…33 Ca 2ϩ causes muscle contraction. 34 We have confirmed that 5-HT 2A receptor mRNA is expressed in cultured human VSMCs by RT-PCR (data not shown). Using these cells, we revealed that 5-HT enhances IL-6 synthesis in VSMCs via the 5-HT 2A receptor.…”

Section: Discussionsupporting

confidence: 56%

Serotonin Increases Interleukin-6 Synthesis in Human Vascular Smooth Muscle Cells

et al. 2000

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Background-Interleukin-6 (IL-6) is a key molecule in chronic inflammation and has been implicated in the progression of atherosclerosis. Serotonin (5-hydroxytryptamine; 5-HT) causes vascular contraction and proliferation, but its role in atherogenesis has not been clarified. We investigated the effects of 5-HT on IL-6 synthesis in human vascular smooth muscle cells (VSMCs). Methods and Results-IL-6 levels in the culture medium of VSMCs were determined by ELISA. IL-6 mRNA accumulation was determined by use of a Quantikine mRNA colorimetric quantification kit. NF-B activation was tested by gel retardation assay. 5-HT induced IL-6 production by VSMCs in a time-and dose-dependent manner, with increased IL-6 mRNA accumulation and nuclear factor-B activation. The effect of 5-HT on IL-6 production was significantly inhibited by the 5-HT 2 receptor antagonist ketanserin and the selective 5-HT 2A receptor antagonist sarpogrelate. Conversely, the 5-HT 2 receptor agonist ␣-methyl-5-HT increased IL-6 production. The protein kinase C (PKC) inhibitor calphostin C, but not the protein kinase A inhibitor KT5720, suppressed 5-HT-induced IL-6 production.The effect of 5-HT was also abolished in PKC-depleted VSMCs after pretreatment with phorbol 12-myristate 13-acetate for 24 hours. Conclusions-5-HT acts on 5-HT 2A receptors and increases IL-6 synthesis in human VSMCs at least partially through a PKC-dependent pathway. These results suggested that 5-HT may contribute to inflammatory activation of the vessels during atherogenesis.

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“…The increased contractility to both agents in diabetes without any change in the sensitivity indicates an impairment in postreceptor events, other than an impairment in receptor activation. Enhanced 5-HT contractility in diabetic rat aorta has been reported to be a consequence of increased protein kinase C-activated processes [47]. It has been well reviewed that activation of protein kinase C pathway could lead to vascular dysfunction in diabetes and that high doses of vitamin E could decrease the enhanced diacylglycerol and protein kinase C activity in diabetic vasculature processes [48].…”

Section: Discussionmentioning

confidence: 99%

Effect of Dietary Vitamin E Supplementationon Vascular Reactivity of Thoracic Aorta in Streptozotocin-Diabetic Rats

Çınar¹,

Ülker²,

Alper

et al. 2001

Pharmacology

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The present study evaluated the effect of dietary vitamin E supplementation (1,000 mg/kg chow) on the alterations in vascular reactivity of streptozotocin-diabetic aorta of Wistar rats. After 12 weeks of treatment, thoracic aortic rings of rats were mounted in organ baths and contractile responses to phenylephrine and 5-hydroxytryptamine and relaxant responses to acetylcholine, calcium ionophore and sodium nitroprusside were assessed. Plasma vitamin E concentration as measured by HPLC was markedly decreased in diabetic rats and increased with dietary vitamin E supplementation. Induction of diabetes significantly impaired endothelium-dependent relaxations to acetylcholine and calcium ionophore in aortic rings, but did not change endothelium-independent relaxation to sodium nitroprusside. Vitamin E significantly improved the impaired endothelium-dependent relaxations, further it decreased the enhanced contractile response to phenylephrine and 5-hydroxytryptamine in diabetic rings. The mechanical denudation of endothelium or the chemical inhibition of endothelium-dependent relaxation with N^ω-nitro-L-arginine methyl ester (100 µmol/l) significantly increased phenylephrine contractility in control rings and the rings of diabetic rats treated with vitamin E; such a difference was not observed in diabetic rats fed with normal diet. Liver and lung malondialdehyde concentrations, as an index of lipid peroxidation, were increased in diabetic rats and significantly decreased with vitamin E supplementation. It is concluded that dietary supplementation of vitamin E improved endothelial dysfunction in insulin-dependent model of uncontrolled diabetes, probably decreasing membranal lipid peroxidation.

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Enhanced 5-HT<sub>2</sub> Receptor Mediated Contractions in Diabetic Rat Aorta: Participation of Ca<sup>2+</sup>Channels Associated with Protein Kinase C Activity

Cited by 13 publications

References 22 publications

Diminishment of Contractions Associated with Depolarization-Evoked Activation of Ca<sup>2+</sup> Channels in Diabetic Rat Aorta

Diminishment of Contractions Associated with Depolarization-Evoked Activation of Ca<sup>2+</sup> Channels in Diabetic Rat Aorta

Serotonin Increases Interleukin-6 Synthesis in Human Vascular Smooth Muscle Cells

Effect of Dietary Vitamin E Supplementationon Vascular Reactivity of Thoracic Aorta in Streptozotocin-Diabetic Rats

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