Vascular L-Type Ca<sup>2+</sup>Channel Blocking Activity of Sulfur-Containing Indole Alkaloids from<i>Glycosmis petelotii</i>

Cuong, Nguyen Manh; Khanh, Pham Ngoc; Huyen, Pham Thu; Ho, Duc Viet; Hương, Trần Thu; Hà, Vũ Thị Thu; Sgaragli, Giampietro; Fusi, Fabio

doi:10.1021/np500076v

Cited by 18 publications

(8 citation statements)

References 23 publications

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“…This effect likely originated from the interaction of zerumbone with the channel in the voltage-inactivated state [22]. This hypothesis is supported by the observation that the potency of zerumbone was lower in single myocytes as compared to depolarised rings where inactivated channels likely predominate, in agreement with what is commonly observed with nifedipine [23]. Findings obtained on aorta rings stimulated with phenylephrine provided important information on the mechanism of action of zerumbone.…”

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confidence: 76%

In Vitro Vasoactivity of Zerumbone from Zingiber zerumbet

et al. 2015

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The sesquiterpene zerumbone, isolated from the rhizome of Zingiber zerumbet Sm., besides its widespread use as a food flavouring and appetiser, is also recommended in traditional medicine for the treatment of several ailments. It has attracted great attention recently for its effective chemopreventive and therapeutic effects observed in various models of cancer. To assess the zerumbone safety profile, a pharmacology study designed to flag any potential adverse effect on vasculature was performed. Zerumbone was tested for vasorelaxing activity on rat aorta rings and for L-type Ba(2+) current blocking activity on single myocytes isolated from the rat-tail artery. The spasmolytic effect of zerumbone was more marked on rings stimulated with 60 mM than with 30 mM K(+) (IC50 values of 16 µM and 102 µM, respectively). In the presence of 60 mM K(+), zerumbone concentration-dependently inhibited the contraction induced by the cumulative additions of Ca(2+), this inhibition being inversely related to the Ca(2+) concentration. Phenylephrine-induced contraction was inhibited by the drug, though less efficiently and independently of the presence of an intact endothelium, without affecting Ca(2+) release from the intracellular stores. Zerumbone inhibited the L-type Ba(2+) current (estimated IC50 value of 458.7 µM) and accelerated the kinetics of current decay. In conclusion, zerumbone showed an overall weak in vitro vasodilating activity, partly attributable to the blocking of the L-type Ca(2+) channel, which does not seem to represent, however, a serious threat to its widespread use.

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confidence: 76%

In Vitro Vasoactivity of Zerumbone from Zingiber zerumbet

et al. 2015

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“…The endothelium was removed by gently rubbing the lumen of the ring with the curved tips of a forceps. Contractile isometric tension was recorded as described elsewhere (Cuong et al , ). Control preparations were challenged with the drug vehicle only.…”

Section: Methodsmentioning

confidence: 99%

“…Cells were continuously superfused with external solution containing 0.1 mM Ca 2+ and 30 mM tetraethylammonium using a peristaltic pump (LKB 2132, Bromma, Sweden ), at a flow rate of 400 μL·min −1 . The conventional whole‐cell patch‐clamp method (Hamill et al , ) was employed to voltage‐clamp smooth muscle cells, as previously described (Cuong et al , ; see also Supporting Information). Electrophysiological responses were assessed at room temperature (20–22°C).…”

Section: Methodsmentioning

confidence: 99%

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

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et al. 2015

British J Pharmacology

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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.

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“…Aorta ring preparation Aorta rings (2.5-3.0 mm wide) were prepared from male Wistar rats (250-350 g; Charles River Italia), anesthetized (i. p.) with a mixture of Zoletil 100 (7.5 mg/kg tiletamine and 7.5 mg/kg zolazepam; Virbac Srl) and Rompun (4 mg/kg xylazine; Bayer), decapitated, and exsanguinated. Contractile isometric tension was recorded as described elsewhere [39]. In rings precontracted with 0.3 µM phenylephrine, an acetylcholine-induced relaxation ≥ 75 % denoted the presence of a functional endothelium.…”

Section: Contractility Experimentsmentioning

confidence: 99%

“…Cells were continuously superfused with external solution using a peristaltic pump (LKB 2132; Bromma) at a flow rate of 400 µL/ min. The conventional whole-cell patch-clamp method was employed to voltage-clamp smooth muscle cells, as previously described [39]. Electrophysiological responses were assessed at room temperature (20-22°C).…”

Section: Whole-cell Patch-clamp I Ba12 Recordingsmentioning

confidence: 99%

Vasorelaxing Activity of R-(−)-3′-Hydroxy-2,4,5-trimethoxydalbergiquinol from Dalbergia tonkinensis: Involvement of Smooth Muscle CaV1.2 Channels

et al. 2020

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Dalbergia species heartwood, widely used in traditional medicine to treat various cardiovascular diseases, might represent a rich source of vasoactive agents. In Vietnam, Dalbergia tonkinensis is an endemic tree. Therefore, the aim of the present work was to investigate the vascular activity of R-(−)-3′-hydroxy-2,4,5-trimethoxydalbergiquinol isolated from the heartwood of D. tonkinensis and to provide circular dichroism features of its R absolute configuration. The vascular effects of R-(−)-3′-hydroxy-2,4,5-trimethoxydalbergiquinol were assessed on the in vitro mechanical activity of rat aorta rings, under isometric conditions, and on whole-cell Ba2+ currents through CaV1.2 channels (IBa1.2) recorded in single, rat tail main artery myocytes by means of the patch-clamp technique. R-(−)-3′-Hydroxy-2,4,5-trimethoxydalbergiquinol showed concentration-dependent, vasorelaxant activity on both endothelium-deprived and endothelium intact rings precontracted with the α 1 receptor agonist phenylephrine. Neither the NO (nitric oxide) synthase inhibitor Nω-nitro-L-arginine methyl ester nor the cyclooxygenase inhibitor indomethacin affected its spasmolytic activity. R-(−)-3′-Hydroxy-2,4,5-trimethoxydalbergiquinol-induced vasorelaxation was antagonized by (S)-(−)-Bay K 8644 and unaffected by tetraethylammonium plus glibenclamide. In patch-clamp experiments, R-(−)-3′-hydroxy-2,4,5-trimethoxydalbergiquinol inhibited IBa1.2 in a concentration-dependent manner and significantly decreased the time constant of current inactivation. R-(−)-3′-Hydroxy-2,4,5-trimethoxydalbergiquinol likely stabilized the channel in its closed state, as suggested by molecular modelling and docking simulation to the CaV1.2 channel α 1c subunit. In conclusion, D. tonkinensis species may represent a source of agents potentially useful for the development of novel antihypertensive drugs.

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Vascular L-Type Ca²⁺Channel Blocking Activity of Sulfur-Containing Indole Alkaloids fromGlycosmis petelotii

Cited by 18 publications

References 23 publications

In Vitro Vasoactivity of Zerumbone from Zingiber zerumbet

In Vitro Vasoactivity of Zerumbone from Zingiber zerumbet

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

Vasorelaxing Activity of R-(−)-3′-Hydroxy-2,4,5-trimethoxydalbergiquinol from Dalbergia tonkinensis: Involvement of Smooth Muscle CaV1.2 Channels

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Vascular L-Type Ca2+Channel Blocking Activity of Sulfur-Containing Indole Alkaloids fromGlycosmis petelotii

Cited by 18 publications

References 23 publications

In Vitro Vasoactivity of Zerumbone from Zingiber zerumbet

In Vitro Vasoactivity of Zerumbone from Zingiber zerumbet

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

Vasorelaxing Activity of R-(−)-3′-Hydroxy-2,4,5-trimethoxydalbergiquinol from Dalbergia tonkinensis: Involvement of Smooth Muscle CaV1.2 Channels

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Vascular L-Type Ca²⁺Channel Blocking Activity of Sulfur-Containing Indole Alkaloids fromGlycosmis petelotii

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