Mechanism of osthole inhibition of vascular Cav1.2 current

Fusi, Fabio; Sgaragli, Giampietro; Ha, Le Minh; Cuong, Nguyen Manh; Saponara, Simona

doi:10.1016/j.ejphar.2012.01.038

Cited by 34 publications

(14 citation statements)

References 27 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In addition, the role of vasculature and disturbances in blood flow are thought to be important pathogenic mechanisms in IBD [2] . It was reported that osthole showed vasorelaxant properties due to its Ca 2+ -channel antagonistic effects and the upregulation of cAMP and cGMP levels in vascular smooth muscle cells [30][31][32] . Therefore, it is probable that the anti-inflammatory action of osthole is not the only mechanism that explains its ability to inhibit colitis.…”

Section: Discussionmentioning

confidence: 99%

Osthole pretreatment alleviates TNBS-induced colitis in mice via both cAMP/PKA-dependent and independent pathways

et al. 2017

View full text Add to dashboard Cite

Osthole, a natural coumarin found in traditional Chinese medicinal plants, has shown multiple biological activities. In the present study, we investigated the preventive effects of osthole on inflammatory bowel disease (IBD). Colitis was induced in mice by infusing TNBS into the colonic lumen. Before TNBS treatment, the mice received osthole (100 mg·kg·d, ip) for 3 d. Pretreatment with osthole significantly ameliorated the clinical scores, colon length shortening, colonic histopathological changes and the expression of inflammatory mediators in TNBS-induced colitis. Pretreatment with osthole elevated serum cAMP levels; but treatment with the PKA inhibitor H89 (10 mg·kg·d, ip) did not abolish the beneficial effects of osthole on TNBS-induced colitis. In mouse peritoneal macrophages, pretreatment with osthole (50 μmol/L) significantly attenuated the LPS-induced elevation of cytokines at the mRNA level; inhibition of PKA completely reversed the inhibitory effects of osthole on IL-1β, IL-6, COX2, and MCP-1 but not on TNFα. In Raw264.7 cells, the p38 inhibitor SB203580 markedly suppressed LPS-induced upregulation of the cytokines, whereas the PKA inhibitors H89 or KT5720 did not abolish the inhibitory effects of SB203580. Moreover, in LPS-stimulated mouse peritoneal macrophages, SB203580 strongly inhibited the restored expression of IL-1β, IL-6, COX2, and MCP-1, which was achieved by abolishing the suppressive effects of osthole with the PKA inhibitors. Western blot analysis showed that osthole significantly suppressed the phosphorylation of p38, which was induced by TNBS in mice or by LPS in Raw264.7 cells. Inhibition of PKA partially reversed the suppressive effects of osthole on p38 phosphorylation in LPS-stimulated cells. Collectively, our results suggest that osthole is effective in the prevention of TNBS-induced colitis by reducing the expression of inflammatory mediators and attenuating p38 phosphorylation via both cAMP/PKA-dependent and independent pathways, among which the cAMP/PKA-independent pathway plays a major role.

show abstract

Section: Discussionmentioning

confidence: 99%

Osthole pretreatment alleviates TNBS-induced colitis in mice via both cAMP/PKA-dependent and independent pathways

et al. 2017

View full text Add to dashboard Cite

show abstract

“…Further studies, however, are needed to clarify whether they act as Ca 2+ channel blockers, as it has been recently demonstrated for the coumarin osthole. 9) Finally, these results are important for validating the traditional use of Murraya paniculata and developing novel antihypertensive agents.…”

Section: Resultsmentioning

confidence: 96%

“…9) As part of our search for novel vasoactive agents from selected Vietnamese medicinal plants, we report here the findings of an investigational, screening procedure of Murraya paniculata. The chloroform fraction of the methanol plant extract showed a remarkable vasorelaxing effect on rat aorta rings contracted by K60.…”

mentioning

confidence: 99%

Vasorelaxing Activity of Two Coumarins from <i>Murraya paniculata</i> Leaves

Cuong

Khanh

et al. 2014

Biological & Pharmaceutical Bulletin

Self Cite

View full text Add to dashboard Cite

In the search for novel chemical scaffolds leading to potential antihypertensive agents, the methanol extract of Murraya paniculata leaves was assessed for its effects on isolated rat aorta rings. The vasorelaxing effect of the chloroform fraction of the methanol plant extract was the most potent for its vasorelaxing activity on rat aorta rings contracted by 60 mM K (K60). Two coumarins were isolated from the chloroform fraction: the novel kimcuongin (1) and the known murracarpin (2). Their structures were determined from spectroscopic evidences including 1 H-and 13 C-NMR, correlation spectroscopy (COSY), nuclear Overhauser effect spectroscopy (NOESY), heteronuclear multiple bond correlation (HMBC), heteronuclear single quantum correlation (HSQC), and high resolution mass spectrometry (HR-MS). Kimcuongin and, to a lesser extent, murracarpin, showed vasorelaxing activity with IC 50 values of 37.7 µM and 139.3 µM, respectively. The coumarins kimcuongin and murracarpin may thus represent a novel class of vasodilators of natural source.

show abstract

“…At this point, the various protocols were performed as detailed below. I Ba1.2 and I Ca1.2 did not run down during the following 40 min under these conditions (Fusi et al ., ).…”

Section: Methodsmentioning

confidence: 97%

Functional, electrophysiological and molecular docking analysis of the modulation of Ca_v1.2 channels in rat vascular myocytes by murrayafoline A

Saponara

Spiga

Mugnai

et al. 2015

British J Pharmacology

View full text Add to dashboard Cite

BACKGROUND AND PURPOSEThe carbazole alkaloid murrayafoline A (MuA) enhances contractility and the Ca 2+ currents carried by the Ca v 1.2 channels [I Ca1.2 ] of rat cardiomyocytes. As only few drugs stimulate I Ca1.2 , this study was designed to analyse the effects of MuA on vascular Ca v 1.2 channels. EXPERIMENTAL APPROACHVascular activity was assessed on rat aorta rings mounted in organ baths. Ca v 1.2 Ba 2+ current [I Ba1.2 ] was recorded in single rat aorta and tail artery myocytes by the patch-clamp technique. Docking at a 3D model of the rat, α 1c central pore subunit of the Ca v 1.2 channel was simulated in silico. KEY RESULTSIn rat aorta rings MuA, at concentrations ≤14.2 μM, increased 30 mM K + -induced tone and shifted the concentration-response curve to K + to the left. Conversely, at concentrations >14.2 μM, it relaxed high K + depolarized rings and antagonized Bay K 8644-induced contraction. In single myocytes, MuA stimulated I Ba1.2 in a concentration-dependent, bell-shaped manner; stimulation was stable, incompletely reversible upon drug washout and accompanied by a leftward shift of the voltage-dependent activation curve. MuA docked at the α 1C subunit central pore differently from nifedipine and Bay K 8644, although apparently interacting with the same amino acids of the pocket. Neither Bay K 8644-induced stimulation nor nifedipine-induced block of I Ba1.2 was modified by MuA. CONCLUSIONS AND IMPLICATIONSMurrayafoline A is a naturally occurring vasoactive agent able to modulate Ca v 1.2 channels and dock at the α 1C subunit central pore in a manner that differed from that of dihydropyridines.

show abstract

Mechanism of osthole inhibition of vascular Cav1.2 current

Cited by 34 publications

References 27 publications

Osthole pretreatment alleviates TNBS-induced colitis in mice via both cAMP/PKA-dependent and independent pathways

Osthole pretreatment alleviates TNBS-induced colitis in mice via both cAMP/PKA-dependent and independent pathways

Vasorelaxing Activity of Two Coumarins from <i>Murraya paniculata</i> Leaves

Functional, electrophysiological and molecular docking analysis of the modulation of Ca_v1.2 channels in rat vascular myocytes by murrayafoline A

Contact Info

Product

Resources

About

Mechanism of osthole inhibition of vascular Cav1.2 current

Cited by 34 publications

References 27 publications

Osthole pretreatment alleviates TNBS-induced colitis in mice via both cAMP/PKA-dependent and independent pathways

Osthole pretreatment alleviates TNBS-induced colitis in mice via both cAMP/PKA-dependent and independent pathways

Vasorelaxing Activity of Two Coumarins from <i>Murraya paniculata</i> Leaves

Functional, electrophysiological and molecular docking analysis of the modulation of Cav1.2 channels in rat vascular myocytes by murrayafoline A

Contact Info

Product

Resources

About

Functional, electrophysiological and molecular docking analysis of the modulation of Ca_v1.2 channels in rat vascular myocytes by murrayafoline A