scholarly journals Alloxan inhibits ligand binding to adrenoceptors of vascular smooth muscle microsomes

1990 ◽  
Vol 270 (1) ◽  
pp. 137-140 ◽  
Author(s):  
C Y Kwan ◽  
S Sipos ◽  
V Gaspar
Keyword(s):  
Smooth Muscle ◽  
Plasma Membrane ◽  
Vascular Smooth Muscle ◽  
Radioligand Binding ◽  
Mesenteric Arteries ◽  
Dependent Manner ◽  
Inhibitory Effects ◽  
Experimental Conditions ◽  
Concentration Dependent Manner ◽  
Number Of Binding Sites

We have examined the effects of alloxan on the binding of [3H]prazosin and [125I]monoiodocyanopindolol (ICYP) to plasma-membrane-enriched microsomes isolated from dog aortas and dog mesenteric arteries respectively. Preincubation of the vascular smooth muscle membranes with alloxan reduced the number of binding sites of the alpha- and β-adrenoceptors in a concentration-dependent manner, whereas the affinity of the radioligands for the adrenoceptors was not affected by alloxan. Streptozotocin, which is also a diabetogenic agent like alloxan, had no effect on the radioligand binding to these adrenoceptors under similar experimental conditions. The inhibitory effects of alloxan on binding to β-adrenoceptors were found to be highly pH-dependent. These results indicate that alloxan exerts adverse effects on cell membrane adrenoceptors in addition to those on the ion-transport function of vascular smooth muscle cell [Kwan (1988) Biochem. J. 254, 293-296], and also suggest that the primary site of action of alloxan is the plasma membrane.

Ca2+- and Myosin Phosphorylation–independent Relaxation by Halothane in K+-depolarized Rat Mesenteric Arteries

2003 ◽  
Vol 99 (3) ◽  
pp. 656-666 ◽  
Author(s):  
Isao Tsuneyoshi ◽  
Dongya Zhang ◽  
Walter A. Boyle
Keyword(s):  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Mesenteric Arteries ◽  
Dependent Manner ◽  
Resistance Arteries ◽  
Concentration Dependent Manner ◽  
Myosin Phosphorylation ◽  
High K ◽  
Mlc Phosphorylation ◽  
Depolarized Smooth Muscle

Background Volatile anesthetics inhibit vascular smooth muscle contraction, but the mechanisms responsible are uncertain. In this study, the effects of halothane on Ca2+ signaling and Ca2+ activation of contractile proteins were examined in high K+-depolarized smooth muscle from rat mesenteric resistance arteries. Methods Vessels were cannulated and held at a constant transmural pressure (40 mmHg). Image analysis and microfluorimetry were used to simultaneously measure vessel diameter and smooth muscle intracellular [Ca2+] concentration ([Ca2+]i). Myosin light chain (MLC) phosphorylation was measured using the Western blotting technique. Results Step increases in extracellular [Ca2+] concentration (0-10 mM) in high K+ (40 mM)-depolarized smooth muscle produced incremental increases in [Ca2+]i, MLC phosphorylation, and contraction. Halothane (0.5-4.5%) inhibited contraction in a concentration-dependent manner, but the decrease in [Ca2+]i was small, and there was a marked shift in the [Ca2+]i-contraction relationship to the right, indicating an important Ca2+ desensitizing effect. Halothane (0.5-4.5%) did not affect MLC phosphorylation or the [Ca2+]-MLC phosphorylation relationship, but the MLC phosphorylation-contraction relationship was also shifted rightward, indicating an "MLC phosphorylation" desensitizing effect. In contrast, control relaxations produced by the Ca2+ channel blocker nifedipine were accompanied by decreases in both [Ca2+]i and MLC phosphorylation, and nifedipine had no affect on the [Ca2+]i-contraction, [Ca2+]i-MLC phosphorylation, and MLC phosphorylation-contraction relationships. Conclusions In high K+-depolarized vascular smooth muscle, halothane relaxation is largely mediated by a Ca2+ and MLC phosphorylation desensitizing effect. These results suggest that the relaxing action of halothane is independent of the classic Ca2+-induced myosin phosphorylation contraction mechanism.

Heterogeneous distribution of endothelium-dependent relaxations resistant to NG-nitro-L-arginine in rats

1992 ◽  
Vol 263 (4) ◽  
pp. H1090-H1094 ◽  
Author(s):  
T. Nagao ◽  
S. Illiano ◽  
P. M. Vanhoutte
Keyword(s):  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Calcium Ionophore ◽  
Renal Arteries ◽  
Mesenteric Arteries ◽  
K Channel ◽  
Ionophore A23187 ◽  
Dependent Manner ◽  
Arterial Tree ◽  
Heterogeneous Distribution

Endothelium-dependent relaxations that are resistant to inhibitors of nitric oxide synthase probably are mediated by endothelium-dependent hyperpolarization of the vascular smooth muscle. Experiments were performed to examine the distribution of this type of relaxation along the arterial tree of the rat by measuring changes in isometric force. Acetylcholine induced concentration- and endothelium-dependent relaxations in aortas and in pulmonary, common iliac, femoral, mesenteric, and renal arteries contracted with phenylephrine. In the presence of NG-nitro-L-arginine, the cumulative administration of acetylcholine induced relaxations only in the femoral, mesenteric, and renal arteries. The calcium ionophore A23187 relaxed mesenteric arteries contracted with phenylephrine in a concentration- and endothelium-dependent manner. The concentration-relaxation curve to A23187 was shifted to the right in the presence of NG-nitro-L-arginine. The maximal relaxations induced by lemakalim, a K+ channel opener, were smaller in those arteries that did not exhibit NG-nitro-L-arginine-resistant relaxations. These results suggest that NG-nitro-L-arginine-resistant relaxations are more frequently observed in smaller arteries. The arteries that exhibit NG-nitro-L-arginine-resistant relaxations may be more sensitive to an endothelium-derived substance that causes hyperpolarization of vascular smooth muscle cells.

Norepinephrine and endothelin activate diacylglycerol kinases in caveolae/rafts of rat mesenteric arteries: agonist-specific role of PI3-kinase

2007 ◽  
Vol 292 (5) ◽  
pp. H2248-H2256 ◽  
Author(s):  
Christopher J. Clarke ◽  
Vasken Ohanian ◽  
Jacqueline Ohanian
Keyword(s):  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Muscle Contraction ◽  
Smooth Muscle Contraction ◽  
Pi3 Kinase ◽  
Mesenteric Arteries ◽  
Dependent Manner ◽  
Kinase Inhibition ◽  
Small Arteries ◽  
Vascular Smooth Muscle Contraction

The phosphatidylinositol (PI) signaling pathway mediates norepinephrine (NE)- and endothelin-1 (ET-1)-stimulated vascular smooth muscle contraction through an inositol-trisphosphate-induced rise in intracellular calcium and diacylglycerol (DG) activation of protein kinase C (PKC). Subsequent activation of DG kinases (DGKs) metabolizes DG to phosphatidic acid (PA), potentially regulating PKC activity. Because precise regulation and spatial restriction of the PI pathway is necessary for specificity, we have investigated whether this occurs within caveolae/rafts, specialized plasma membrane microdomains implicated in vascular smooth muscle contraction. We show that components of the PI signaling cascade-phosphatidylinositol 4,5-bisphosphate (PIP2), PA, and DGK-θ are present in caveolae/rafts prepared from rat mesenteric small arteries. Stimulation with NE or ET-1 induced [33P]PIP2 hydrolysis solely within caveolae/rafts. NE stimulated an increase in DGK activity in caveolae/rafts alone, whereas ET-1 activated DGK in caveolae/rafts and noncaveolae/rafts; however, [33P]PA increased in all fractions with both agonists. Previously, we reported that NE activated DGK-θ in a phosphatidylinositol 3-kinase (PI3-kinase)-dependent manner; here, we describe PI3-kinase-dependent DGK activation and [33P]PA production in caveolae/rafts in response to NE but not ET-1. Additionally, PKB, a potential activator of DGK-θ, translocated to caveolae/rafts in response to NE but not ET-1, and PI3-kinase inhibition prevented this. Furthermore, PI3-kinase inhibition reduced the sensitivity of contraction to NE but not ET-1. Our study shows that caveolae/rafts are major sites of vasoconstrictor hormone activation of the PI pathway in intact small arteries and suggest a link between lipid signaling events within caveolae/rafts and contraction.

Cocaine Induces Apoptosis in Primary Cultured Rat Aortic Vascular Smooth Muscle Cells: Possible Relationship to Aortic Dissection, Atherosclerosis, and Hypertension

2004 ◽  
Vol 23 (4) ◽  
pp. 233-237 ◽  
Author(s):  
Jialin Su ◽  
Jianfeng Li ◽  
Wenyan Li ◽  
Bella T. Altura ◽  
Burton M. Altura
Keyword(s):  
Smooth Muscle ◽  
Aortic Dissection ◽  
Vascular Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Vascular Smooth Muscle Cells ◽  
Cocaine Abuse ◽  
Cardiovascular Effects ◽  
Muscle Cells ◽  
Dependent Manner ◽  
Concentration Dependent Manner

Cocaine abuse is known to induce many adverse cardiovascular effects, including hypertension, atherosclerosis, and aortic dissection. A major physiological event leading to these pathophysiological actions of cocaine could be apoptosis. This study was designed to investigate if primary cultured rat aortic vascular smooth muscle cells (VSMCs) can undergo apoptosis when treated with cocaine. After treatment with cocaine (10−6 to 10−4 M), morphological analysis of aortic VSMCs using confocal fluoresence microscopy showed that the percentage of apoptotic aortic VSMCs increased after cocaine (10−6 to 10−4 M) treatment for 12, 24, and 48 h. These results demonstrate that aortic VSMCs can undergo rapid apoptosis in response to cocaine in a concentration-dependent manner. Cocaine-induced apoptosis may thus play a major role in cocaine abuse-induced aortic dissection, atherosclerosis, and hypertension.

scholarly journals Homocysteine promotes vascular smooth muscle cell migration by induction of the adipokine resistin

2009 ◽  
Vol 297 (6) ◽  
pp. C1466-C1476 ◽  
Author(s):  
Changtao Jiang ◽  
Heng Zhang ◽  
Weizhen Zhang ◽  
Wei Kong ◽  
Yi Zhu ◽  
...  
Keyword(s):  
Cardiovascular Disease ◽  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Smooth Muscle Cell ◽  
Muscle Cell ◽  
Vascular Smooth Muscle Cell ◽  
Focal Adhesions ◽  
Diabetic Patients ◽  
Dependent Manner ◽  
Concentration Dependent Manner

Adipokines may represent a mechanism linking insulin resistance to cardiovascular disease. We showed previously that homocysteine (Hcy), an independent risk factor for cardiovascular disease, can induce the expression and secretion of resistin, a novel adipokine, in vivo and in vitro. Since vascular smooth muscle cell (VSMC) migration is a key event in vascular disease, we hypothesized that adipocyte-derived resistin is involved in Hcy-induced VSMC migration. To confirm our hypothesis, Sprague-Dawley rat aortic SMCs were cocultured with Hcy-stimulated primary rat epididymal adipocytes or treated directly with increasing concentrations of resistin for up to 24 h. Migration of VSMCs was investigated. Cytoskeletal structure and cytoskeleton-related proteins were also detected. The results showed that Hcy (300–500 μM) increased migration significantly in VSMCs cocultured with adipocytes but not in VSMC cultured alone. Resistin alone also significantly increased VSMC migration in a time- and concentration-dependent manner. Resistin small interfering RNA (siRNA) significantly attenuated VSMC migration in the coculture system, which indicated that adipocyte-derived resistin mediates Hcy-induced VSMC migration. On cell spreading assay, resistin induced the formation of focal adhesions near the plasma membrane, which suggests cytoskeletal rearrangement via an α5β1-integrin-focal adhesion kinase/paxillin-Ras-related C3 botulinum toxin substrate 1 (Rac1) pathway. Our data demonstrate that Hcy promotes VSMC migration through a paracrine or endocrine effect of adipocyte-derived resistin, which provides further evidence of the adipose-vascular interaction in metabolic disorders. The migratory action exerted by resistin on VSMCs may account in part for the increased incidence of restenosis in diabetic patients.

Darusentan is a potent inhibitor of endothelin signaling and function in both large and small arteriesThis article is one of a selection of papers published in the two-part special issue entitled 20 Years of Endothelin Research.

2010 ◽  
Vol 88 (8) ◽  
pp. 840-849 ◽  
Author(s):  
Faquan Liang ◽  
Christopher B. Glascock ◽  
Denise L. Schafer ◽  
Jennifer Sandoval ◽  
LouAnn Cable ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Potent Inhibitor ◽  
Inositol Phosphate ◽  
Contractile Activity ◽  
Binding Activity ◽  
Dependent Manner ◽  
Endothelin Receptor ◽  
Resistance Arteries ◽  
Concentration Dependent Manner

Endothelin is a potent vasoconstrictor often up-regulated in hypertension. Endothelin vasoconstriction is mediated via the G-protein coupled endothelin A (ETA) receptor present on vascular smooth muscle. Endothelin receptor antagonists (ERAs) have been shown to antagonize ET-induced vasoconstriction. We describe the primary pharmacology of darusentan, a propanoic acid based ERA currently in phase 3 clinical trials for resistant hypertension. Darusentan was tested in membrane-, cell-, and tissue-based assays to determine its biochemical and functional potency. Rat aortic vascular smooth muscle cells (RAVSMs) were characterized using flow cytometry. RAVSM membrane fractions tested in saturation experiments exhibited moderate endothelin receptor density. Receptor counting revealed that >95% of the endothelin receptors in these fractions were the ETA subtype. (S)-Darusentan competed for radiolabeled endothelin binding in RAVSM membranes with single-site kinetics, exhibiting a Ki = 13 nmol/L. (R)-Darusentan exhibited no binding activity. In cultured RAVSMs, endothelin induced increases in inositol phosphate and Ca2+ signaling, both of which were attenuated by (S)-darusentan in a concentration-dependent manner. In isolated endothelium-denuded rat aortic rings, (S)-darusentan inhibited endothelin-induced vascular contractility with a pA2 = 8.1 ± 0.14 (n = 4 animals; mean ± SD). (R)-Darusentan had no effect. The vasorelaxant potency of (S)-darusentan did not change when determined in isolated denuded rat mesenteric arterioles, suggesting a similar mode of action in both conductance and resistance arteries. In vascular smooth muscle, (S)-darusentan is an ERA with high affinity for the ET receptor, which in this preparation is predominantly ETA receptors. (S)-Darusentan inhibits endothelin-induced signaling related to pro-contractile activity and is a potent inhibitor of vasoconstriction in large and small arteries.

scholarly journals Effects of dexmedetomidine on porcine pulmonary artery vascular smooth muscle

2019 ◽  
Author(s):  
Mami Chikuda ◽  
Kenichi Sato
Keyword(s):  
Smooth Muscle ◽  
Pulmonary Artery ◽  
Vascular Smooth Muscle ◽  
Local Anesthetics ◽  
Pulmonary Arteries ◽  
Dependent Manner ◽  
Concentration Dependent Manner ◽  
Duration Of Action ◽  
Porcine Pulmonary Artery ◽  
Ca2 Channels

Abstract Background Dexmedetomidine is added to local anesthetics to increase their potency and extend their duration of action, thus providing postoperative analgesia with a single administration. However, the effects and mechanism of action of dexmedetomidine on pulmonary arteries have not been determined. The aim of this study was to investigate the effect of dexmedetomidine on pulmonary artery vascular smooth muscle, evaluating changes in contraction tension. Methods Endothelium-denuded porcine pulmonary arteries were sliced into 2- to 3-mm rings. Changes in isometric contraction tension were measured with the addition of various substances at various concentrations, under different conditions of baseline stimulation (with KCl, Adrenaline, caffeine, or histamine) and different conditions of Ca2+ depletion with intracellular reservoirs or extracellular stores depleted. Results Dexmedetomidine increased the contraction tension induced by high-KCl depolarization in a concentration-dependent manner. Dexmedetomidine inhibited receptor-activated Ca2+ channels (RACCs) and phosphatidylinositol-1,4,5-triphosphate-induced Ca2+ release (IICR), but not Ca2+-induced Ca2+ release (CICR). Conclusions Dex increased the contraction tension resulting from depolarization stimulation by high KCl in a concentration-dependent manner in porcine pulmonary artery vascular smooth muscle. The enhancement of high KCl-induced contraction with Dex addition was mediated by α2 receptors. Dex suppressed increases in contraction tension induced by receptor stimulation with adrenaline, also in a concentration-dependent manner. Dex inhibited RACC and IICR, but not CICR. Elucidating the effects and mechanisms of action of Dex in the central arteries is likely to be useful as basic data for creating Dex-containing local anesthetics.

Catecholamines Abrogate the Anti-Mitogenic Effects of 2-Hydroxy Metabolite of Estradiol on Vascular Smooth Muscle Cells by Inhibiting Catechol-O-Methyltransferase (COMT) Activity and 2-Methoxyestradiol Formation

Hypertension ◽  
2000 ◽  
Vol 36 (suppl_1) ◽  
pp. 705-706
Author(s):  
Lefteris C Zacharia ◽  
Edwin K Jackson ◽  
Delbert G Gillespie ◽  
Raghvendra K Dubey
Keyword(s):  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Dna Synthesis ◽  
Angiogenesis Inhibitor ◽  
Inhibitory Effect ◽  
Cell Number ◽  
Dependent Manner ◽  
Concentration Dependent Manner ◽  
Local Synthesis ◽  
The Right

P70 Methylation of 2-hydroxyestradiol(2OHE; endogenous estradiol metabolite) to 2-methoxyestradiol (2MeOE; angiogenesis inhibitor)by COMT plays a key role in mediating the anti-mitogenic effects of 2OHE on vascular smooth muscle cell (SMC)growth. Catecholamines such as norepinephrine (NE) are also substrates for COMT and increased levels of NE are associated with vasoocclusive disorders. We hypothesize that increased endogenous synthesis/levels of NE under pathophysiological conditions may abrogate the vasoprotective effects of 2OHE by competing for COMT and inhibiting 2MeOE formation. To test this hypothesis we investigated the anti-mitogenic effects of .001-10μM 2OHE on 2.5% FCS-induced SMC growth (cell number, DNA synthesis [thymidine incorporation], collagen synthesis [proline incorporatio])in rat and human aortic SMCs in the presence and absence of NE (0.1-40μM). NE concentration-dependently abrogated the inhibitory effects of 2OHE on SMC growth and in the presence of 10μM NE the inhibitory curve of 2OHE on SMC growth was shifted to the right(P<.05). In the presence of 10μM NE, the inhibitory effect of 1μM 2OHE on DNA synthesis was reduced from 70±3% to 24±2% (P<.05), and this effect of NE was mimicked by isoproterenol (ISO) and epinephrine (EPI). Additionally, NE (0.5-2.5mM) inhibited the metabolism of 10μM 2OHE to 2MeOE in a concentration-dependent manner and the effects of NE were mimicked by ISO, EPI, metanephrine, normetanephrine and 3,4-dihydroxymandelic acid. At 0.5 mM ISO, NE and EPI inhibited 2MeoE formation by 70±4%,20±2% and 40±2%, respectively. Our findings suggest that increases in local synthesis of catecholamines within the vasculature may abrogate the anti-vasoocclusive effects of estradiol and 2OHE by blocking 2MeOE formation. In conclusion, the interaction between catecholamines and 2OHE may play a key role in the biology of vascular SMC growth.

The indazole derivative YD-3 inhibits thrombin-induced vascular smooth muscle cell proliferation and attenuates intimal thickening after balloon injury

2004 ◽  
Vol 92 (12) ◽  
pp. 1232-1239 ◽  
Author(s):  
Jih-Hwa Guh ◽  
Yi-Nan Liu ◽  
Ya-Ling Chang ◽  
Sheng-Chu Kuo ◽  
Fang-Yu Lee ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Dependent Manner ◽  
Concentration Dependent Manner ◽  
Developmental Potential ◽  
Vsmc Proliferation ◽  
Neointimal Thickness ◽  
Immunochemical Detection

SummaryProliferation of vascular smooth muscle cells (VSMCs) is postulated to be one of the key events in the pathogenesis of atherosclerosis and restenosis. We investigated whether YD-3, a lowmolecular weight, non-peptide compound, could modulate proliferation of VSMCs in vitro and restenosis after balloon angioplasty in vivo. We examined the effect of YD-3 on thrombininduced VSMC proliferation by [3H]thymidine incorporation assay. The data demonstrated that YD-3 inhibited VSMC proliferation in a concentration-dependent manner. To define the mechanisms of YD-3 action, we found that YD-3 showed a profound inhibition on thrombin-induced Ras and ERK1/2 activities by using Western blotting analysis. Furthermore, oral administration of YD-3 exhibited a marked reduction in neointimal thickness using the carotid injury model in rats. Using immunochemical detection, our experiments also revealed that YD-3 significantly suppressed expression of the PAR-1 receptor, and markedly inhibited PAR-1-activating peptide (SFLLRN)-induced VSMC proliferation in a concentration-dependent manner. These results suggest that YD-3 inhibits thrombin-induced VSMC growth via the Rasand ERK1/2-mediated signaling pathway. Moreover, YD-3 also shows a developmental potential in the treatment of atherosclerosis and restenosis after vascular injury.

scholarly journals Ca2+ channels involved in endothelin-induced mitogenic response in carotid artery vascular smooth muscle cells

2002 ◽  
Vol 282 (2) ◽  
pp. C330-C337 ◽  
Author(s):  
Yoshifumi Kawanabe ◽  
Nobuo Hashimoto ◽  
Tomoh Masaki
Keyword(s):  
Smooth Muscle ◽  
Carotid Artery ◽  
Vascular Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Vascular Smooth Muscle Cells ◽  
Muscle Cells ◽  
Minor Role ◽  
Channel Blockers ◽  
Dependent Manner ◽  
Concentration Dependent Manner

Endothelin (ET)-1 activates two types of Ca2+-permeable nonselective cation channels (NSCC-1 and NSCC-2) and a store-operated Ca2+ channel (SOCC) in rabbit internal carotid artery (ICA) vascular smooth muscle cells (VSMCs) in addition to the voltage-operated Ca2+channel (VOCC). These channels can be discriminated using the Ca2+ channel blockers SK&F-96365 and LOE-908. SK&F-96365 is sensitive to NSCC-2 and SOCC, and LOE-908 is sensitive to NSCC-1 and NSCC-2. On the basis of sensitivity to nifedipine, a specific blocker of the L-type VOCC, VOCCs have a minor role in ET-1-induced mitogenesis. Both LOE-908 and SK&F-96365 inhibited ET-1-induced mitogenesis in a concentration-dependent manner, and the combination of LOE-908 and SK&F-96365 abolished it. The IC50 values of these blockers for ET-1-induced mitogenesis correlated well with those of the ET-1-induced intracellular free Ca2+concentration responses. These results indicate that the inhibitory action of these blockers on ET-1-induced mitogenesis may be mediated by blockade of NSCC-1, NSCC-2, and SOCC. Collectively, extracellular Ca2+ influx through NSCC-1, NSCC-2, and SOCC may be essential for ET-1-induced mitogenesis in ICA VSMCs.

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