Imperatorin induces vasodilatation possibly via inhibiting voltage dependent calcium channel and receptor-mediated Ca2+ influx and release

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Abstract

The purpose of the present study was to investigate the effect of imperatorin on vasodilatation and its possible mechanisms. Isometric tension of rat mesenteric arterial rings was recorded by a myograph system in vitro. The results showed that imperatorin at more than 10 μM concentration-dependently relaxed rat mesenteric arteries pre-contracted by potassium chloride (KCl) and endothelin-1, and human omental arteries pre-contracted by noradrenaline and U46619. Removal of the endothelium did not affect imperatorin-induced relaxant responses, suggesting that the vasodilatation effect is independent of the endothelium. Co-incubation with imperatorin resulted in rightward shift of concentration–response curves of KCl, calcium chloride (CaCl2) and noradrenaline in a non-parallel manner; 5-hydroxytryptamine (5-HT) concentration–response curves were shifted towards right in a parallel manner by imperatorin 10 and 30 μM, but markedly suppressed by imperatorin 100 μM. These results suggest that the inhibitory effect of imperatorin is mainly via voltage dependent calcium channel and possibly receptor operated calcium channel. β-adrenoceptor, ATP-sensitive potassium channel and inwardly rectifying potassium channel were not involved in the vasodilatation, whereas blockage of calcium-activated potassium channel with tetraethylammonium had effect. Furthermore, in Ca2+-free medium, imperatorin concentration-dependently depressed the vasoconstrictions derived from noradrenaline and CaCl2, and resulted in a decreased contractile response induced by caffeine, indicating a role of inhibiting extracellular Ca2+ influx and intracellular Ca2+ release from Ca2+ store. Taken together, our results suggest that imperatorin induces vasodilatation by possible mechanisms inhibiting voltage dependent calcium channel and receptor-mediated Ca2+influx and Ca2+release. Opening calcium-activated potassium channel and competitive antagonism of 5-HT receptors may also contribute to this vasodilatation effect.

Introduction

Imperatorin, the dietary furanocoumarin, is abundant in citrus fruits, umbelliferous vegetables, in culinary herbs such as parsnip, parsley, and fennel (Ceska et al., 1987, Murray et al., 1982), and in some herbal medicines (Murray et al., 1982) such as Angelica dahurica (Baek et al., 2000, Wang et al., 2005), Peucedanum praeruptorum (Zhang et al., 2006), Cnidium monnieri (Li et al., 2006, Mi et al., 2005), Heracleum rapula (Liu et al., 2006), Radix Glehniae (Li and Shi, 2005), Archangelica brevicaulis (Rupr.) Rchb (Zhang et al., 1999), Aegle marmelos (Yang et al., 1996), the roots of Angelica amurensis, A. anomala, A. dahurica and A. gigas (Yang et al., 1994). As an effective component extracted from traditional Chinese medicines, imperatorin has been extensively studied and shown potent pharmacological activities such as anti-inflammatory and antitumoral effects (Ban et al., 2003, Garcia-Argaez et al., 2000, Kawaii et al., 2001, Sigurdsson et al., 2004). It can inhibit γ-aminobutyric acid degradative enzyme and elevate the neurotransmitter γ-aminobutyric acid levels in the central nervous system (Choi et al., 2005). It inhibits either vesicular stomatitis virus-pseudotyped or gp160-enveloped recombinant HIV-1 infection (Sancho et al., 2004). It can also inhibit oxidized-low density lipoprotein-induced enhanced intercellular adhesion molecule-1 expression in U937 foam cells (Yang et al., 2002) and antagonize proliferation of bovine cerebral microvascular smooth muscle cells induced by tumor necrosis factor (Yang et al., 1994). In lipopolysaccharide-activated mouse macrophages models, imperatorin inhibited nitric oxide and prostaglandin E2 production, inhibited inducible nitric oxide synthase protein expression, cyclooxygenase-2 and microsomal prostaglandin E synthase expression (Ban et al., 2003, Matsuda et al., 2005, Zhang et al., 1999). Imperatorin can inhibit bacterial growth, and exhibit a significant antitumoral property and anticoagulant activity (Kim et al., 2007, Rosselli et al., 2007). It relaxes rabbit corpus cavernosum arteries pre-contracted by phenylephrine (Chiou et al., 2001).

However, the vasodilatation effect of imperatorin on resistance vessels has not been reported yet. The present study was to investigate vasodilatation effect of imperatorin and the possible mechanisms behind, emphasizing on the role of calcium channels inhibition.

Section snippets

Tissue preparation

Sprague–Dawley rats weighing 250–300 g were anesthetized and sacrificed by decapitation. The superior mesenteric arteries were gently removed. The branches of human omental arteries were obtained from patients undergoing tumor resections. The arteries were immersed in cold oxygenated Kreb's solution and dissected free of adhering tissue under a microscope. In endothelium-denuded experiments the endothelium was denuded by perfusion of the vessel for 10 s with 0.1% Triton X-100 followed by

Vasodilation effect of imperatorin on arteries pre-contracted by agonists

60 mM KCl or endothelin-1 (0.3 μM) was added to the baths to induce pre-contraction of rat mesenteric artery segments, while noradrenaline (10 μM) or U46619 (1 μM) was used for human omental artery segments. After the sustained tension was obtained, imperatorin (1 μM to 1 mM) was added cumulatively to the baths, and the concentration–response curves to imperatorin were constructed. Imperatorin concentration-dependently relaxed the mesenteric artery segments pre-contracted by KCl or endothelin-1

Discussion

The present study is the first to demonstrate that imperatorin relaxes rat mesenteric artery pre-contracted by KCl and endothelin-1, and human omental artery pre-contracted by noradrenaline and U46619. The removal of the endothelium did not affect imperatorin-induced relaxant responses, indicating that the vasodilatation was independent of the endothelium.

Propranolol (a general β-adrenoceptor antagonist), glibenclamide (an ATP sensitive potassium channel inhibitor), tetraethylammonium (a

Acknowledgment

This work is one part of the National Nature Science Foundation of China (30371734 and 20075020).

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    These authors contributed equally to this work.

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