The Vasorelaxing Action of Labedipinedilol-A Involves Endothelial Cell-Derived NO and eNOS Expression Caused by Calcium Influx

Liou, Shu-Fen; Wu, Jiunn‐Ren; Lai, Wen‐Ter; Sheu, Sheng‐Hsiung; Chen, Ing‐Jun; Yeh, Jwu‐Lai

doi:10.1097/01.fjc.0000154375.88283.5c

Cited by 7 publications

(9 citation statements)

References 33 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Because glutamate may increase cytosolic Ca 2ϩ (37) and Ca 2ϩ /calmodulin (CaM)-dependent endothelium NOS (eNOS) increases NO in endothelial cells in response to increased cytosolic Ca 2ϩ (20,32), we examined the effect of CaM inhibition with CzCl on glutamate-induced CO production (Fig. 6).…”

Section: Resultsmentioning

confidence: 99%

“…The predominant NOS is probably eNOS, but the potential inclusion of neuronal NOS (nNOS) cannot be excluded. Because eNOS can be activated to produce NO by an elevation of cytosolic Ca 2ϩ (20,32,39,46), glutamate may increase endothelial cell Ca 2ϩ that would activate eNOS. Conversely, eNOS activity can be increased by elevations of eNOS sensitivity to CaM (reviewed in Ref.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Nitric oxide increases carbon monoxide production by piglet cerebral microvessels

Leffler

Balabanova

Fedinec

et al. 2005

American Journal of Physiology-Heart and Circulatory Physiology

View full text Add to dashboard Cite

Carbon monoxide (CO) and nitric oxide (NO) can be involved in the regulation of cerebral circulation. Inhibition of production of either one of these gaseous intercellular messengers inhibits newborn pig cerebral arteriolar dilation to the excitatory amino acid glutamate. Glutamate can increase NO production. Therefore, the present study tests the hypothesis that NO, which is increased by glutamate, stimulates the production of CO by cerebral microvessels. Experiments used freshly isolated cerebral microvessels from piglets that express only heme oxygenase-2 (HO-2). CO production was measured by gas chromatography-mass spectrometry. Although inhibition of nitric oxide synthase (NOS) with N -nitro-Larginine (L-NNA) did not alter basal HO-2 catalytic activity or CO production, L-NNA blocked glutamate stimulation of HO-2 activity and CO production. Furthermore, the NO donor sodium nitroprusside mimicked the actions of glutamate on HO-2 and CO production. The action of NO appears to be via cGMP because 8-bromo-cGMP mimics and 1H-[1,2,4]oxadiazole-[4,3-a]quinoxalin-1-one (ODQ) blocks glutamate stimulation of CO production and HO-2 catalytic activity. Inhibitors of neither casein kinase nor phosphotidylinositol 3-kinase altered HO-2 catalytic activity. Conversely, inhibition of calmodulin with calmidazolium chloride blocked glutamate stimulation of CO production and reduced HO-2 catalytic activity. These data suggest that glutamate may activate NOS producing NO that leads to CO synthesis via a cGMP-dependent elevation of HO-2 catalytic activity. These results are consistent with the findings in vivo that either HO or NOS inhibition blocks cerebrovascular dilation to glutamate in piglets. heme oxygenase; guanosine 3Ј, 5Ј-cyclic monophosphate; nitric oxide synthase; glutamate BOTH CARBON MONOXIDE (CO) and nitric oxide (NO) are endogenously produced, gaseous, intercellular messengers that can be involved in regulation of cerebral circulation. In neonatal pigs, CO regulation and modulation are involved in cerebrovascular circulatory control in response to neuronal activity, hypoxia, and changing blood pressure (12,18,26,41). Whereas the contributions of NO to cerebral blood flow regulation increase with age (40, 47), NO is important in the newborn as a permissive factor enabling vascular responses to CO (15). In the piglet cerebrovascular circulation, glutamateinduced pial arteriolar dilation can be blocked by either inhibiting nitric oxide synthase (NOS) (14, 24), which produces NO, or heme oxygenase (HO) (18, 30), which produces CO. One possible explanation for these apparently conflicting data is that one gaseous messenger is necessary to allow dilation to the other. Indeed, as noted above, such a permissive contribution of NO to CO-induced dilation has been described. Another possibility is that glutamate receptor activation increases the production of one of the two gases and that gas in turn increases the production of the other, which is the final mediator of the dilatory response.CO has been reported to directly a...

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Nitric oxide increases carbon monoxide production by piglet cerebral microvessels

Leffler

Balabanova

Fedinec

et al. 2005

American Journal of Physiology-Heart and Circulatory Physiology

View full text Add to dashboard Cite

show abstract

“…Labedipinedilol-A, a novel 1, 4-dihydropyridinetype calcium antagonist, has been shown to induce endothelium-dependent vasodilation, which was inhibited by L-N G -nitroarginine methyl ester [Liang et al, 2000], and to inhibit the norepinephrine-induced contraction of the aortic strips by a-adrenoceptor and calcium entry blocking effects [Liou et al, 2005]. The effect of labedipinedilol-A on the heart has also been reported.…”

Section: Discussionmentioning

confidence: 96%

“…Labedipinedilol-A has been suggested to possess calcium entry and a/b-adrenoceptor blocking activities in a single molecule, which is different from conventional calcium antagonists such as nifedipine and amlodipine [Liang et al, 2000[Liang et al, , 2002. Moreover, labedipinedilol-A is also an inhibitor of vascular smooth muscle cell proliferation induced by a broad group of mitogens, such as serum, platelet-derived growth factor, and norepinephrine; thus, it has great potential in the prevention of progressive atherosclerosis [Yeh et al, 2003;Liou et al, 2004Liou et al, , 2005. Our recent evidence indicates that labedipinedilol-A also significantly inhibits cardiomyocyte calcium overload and apoptosis induced by ischemia-reperfusion in rats [Liang et al, 2006].…”

Section: Introductionmentioning

confidence: 98%

Effects of labedipinedilol‐A, third‐generation dihydropyridine‐type calcium blocker, on ouabain‐induced arrhythmia

Liang¹,

Huang²,

Wu³

et al. 2008

Drug Development Research

Self Cite

View full text Add to dashboard Cite

Labedipinedilol-A, a novel dihydropyridine-type calcium antagonist with a/b-adrenoceptor blocking properties, has been reported to produce a cardioprotective effect against ischemia reperfusion injury in rats. We investigated the protective effects of labedipinedilol-A on ouabain-induced tonotropy and arrhythmias in isolated whole atria, and using patch-clamp techniques to study the underlying mechanism of its antiarrhythmic activity on isolated cardiac myocytes. Labedipinedilol-A (10 mM) suppressed the tonotropic effect of ouabain significantly and prolonged the onset time of extrasystole (arrhythmia) induced by ouabain in isolate atria. In the voltage-clamp study, labedipinedilol-A (1-100 mM) reduced the peak amplitude of sodium inward current (I Na ) and L-type calcium current (I Ca-L ), and shifted the current-voltage (I-V) curve upward in a concentration-dependent manner. In contrast, the addition of labedipinedilol-A increased transient outward potassium current (I to ) and inward rectifier potassium current (I K1 ) significantly. Labedipinedilol-A (10 mM) also effectively depressed the isoproterenol-induced increase in the Ca 21 current. These results show that labedipinedilol-A blocks I Ca-L and I Na , and increases I to and I K1 . These findings indicate that labedipinedilol-A produces direct cardiac action, probably due to the inhibition of cardiac Na 1 and Ca 21 channels. Our results suggest that labedipinedilol-A may reduce the membrane conduction through inhibition of ionic channels which decrease ouabaininduced arrhythmia. Drug Dev Res 69: [26][27][28][29][30][31][32][33] 2008 r2008 Wiley-Liss, Inc.

show abstract

“…In our laboratory, a number of synthetic compounds have been prepared and evaluated for the inhibition of VSMC proliferation, one of the causative factors in several vascular diseases, such as atherosclerosis and restenosis after acute vascular injury [12,13]. In previous studies, isoeugenol and its structural isomer, eugenol, the major constituents of clover or nutmeg oil, have been shown to inhibit lipid peroxidation and platelet aggregation [14].…”

Section: Introductionmentioning

confidence: 99%

Isoeugenodilol inhibits smooth muscle cell proliferation and neointimal thickening after balloon injury via inactivation of ERK1/2 pathway

et al. 2008

Self Cite

View full text Add to dashboard Cite

The purpose of this study was to determine the efficacy and the possible mechanism of action of the synthesized drug isoeugenodilol (a new third-generation beta-adrenoceptor blocker) on the growth factor-induced proliferation of cultured rat vascular smooth muscle cells (VSMCs) and neointimal formation in a rat carotid arterial balloon injury model. Isoeugenodilol significantly inhibited 10% FBS, 20 ng/ml PDGF-BB, and 20 ng/ml vascular endothelial growth factor (VEGF)-induced proliferation. In accordance with these findings, isoeugenodilol revealed blocking of the FBS-inducible progression through the G(0)/G(1) to the S phase of the cell cycle in synchronized cells. Neointimal formation, measured 14 days after injury, was reduced by the oral administration of isoeugenodilol (10 mg/kg/day). In an in vitro assay, isoeugenodilol inhibited the migration of VSMCs stimulated by PDGF-BB. These findings indicate that isoeugenodilol shows an inhibitory potency on neointimal formation due to inhibition of both migration and proliferation of VSMCs. In addition, isoeugenodilol in concentration-dependent manner decreased the levels of phosphorylated ERK1/2 in both VSMCs and balloon-injured carotid arteries. The levels of phosphorylated MEK1/2 and Pyk2 as well as intracellular Ca(2+) and reactive oxygen species (ROS) were in concentration-dependent manner reduced by isoeugenodilol. Taken together, these results indicate that isoeugenodilol may suppress mitogen-stimulated proliferation and migration partially through inhibiting cellular ROS and calcium, and hence, through activation of the Pyk2-ERK1/2 signal pathway. This suggests that isoeugenodilol has potential for the prevention of atherosclerosis and restenosis.

show abstract

The Vasorelaxing Action of Labedipinedilol-A Involves Endothelial Cell-Derived NO and eNOS Expression Caused by Calcium Influx

Cited by 7 publications

References 33 publications

Nitric oxide increases carbon monoxide production by piglet cerebral microvessels

Nitric oxide increases carbon monoxide production by piglet cerebral microvessels

Effects of labedipinedilol‐A, third‐generation dihydropyridine‐type calcium blocker, on ouabain‐induced arrhythmia

Isoeugenodilol inhibits smooth muscle cell proliferation and neointimal thickening after balloon injury via inactivation of ERK1/2 pathway

Contact Info

Product

Resources

About