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Praeruptorin a Enantiomers Exert Distinct Relaxant Effects on Isolated Rat Aorta Rings Dependent on Endothelium and Nitric Oxide Synthesis

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Praeruptorin a Enantiomers Exert Distinct Relaxant Effects on Isolated Rat Aorta Rings Dependent on Endothelium and Nitric Oxide Synthesis Chemico-Biological Interactions 186 (2010) 239–246 Contents lists available at ScienceDirect Chemico-Biological Interactions journal homepage: www.elsevier.com/locate/chembioint (±)-Praeruptorin A enantiomers exert distinct relaxant effects on isolated rat aorta rings dependent on endothelium and nitric oxide synthesis Zhao Xu a,1, Xiaobing Wang b,1, Yue Dai a,∗, Lingyi Kong b,∗, Fengyun Wang a, Huan Xu a, Dan Lu a, Jie Song a, Zhiguo Hou b a Department of Pharmacology of Chinese Materia Medica, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, Jiangsu, China b Department of Natural Medicinal Chemistry, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, Jiangsu, China article info abstract Article history: Praeruptorin A is a coumarin compound naturally occurring in the roots of Peucedanum praeruptorum Received 6 February 2010 Dunn., a commonly used traditional Chinese medicine for the treatment of certain respiratory dis- Received in revised form 16 April 2010 eases and hypertension. Although previous studies indicated the relaxant effects of (±)-praeruptorin Accepted 19 April 2010 A on tracheal and arterial preparations, little is known about the functional characteristics of the enan- Available online 28 April 2010 tiomers. In the present study, the two enantiomers were successfully isolated and identified by using a preparative Daicel Chiralpak AD-H column, and their relaxant effects on aorta rings were observed Keywords: and compared. (+)-Praeruptorin A showed more potent relaxation than (−)-praeruptorin A against KCl- (±)-Praeruptorin A Aorta and phenylephrine-induced contraction of rat isolated aortic rings with intact endothelium. Removal − Relaxation of the endothelium remarkably reduced the relaxant effect of (+)-praeruptorin A but not that of ( )- ␻ Endothelium praeruptorin A. Pretreatment of aortic rings with N -nitro-l-arginine methyl ester (l-NAME, an inhibitor Nitric oxide of nitric oxide synthase) or methylene blue (MB, a soluble guanylyl cyclase inhibitor) resulted in simi- lar changes of the relaxant effects of the two enantiomers to endothelium removal. Molecular docking studies also demonstrated that (+)-praeruptorin A was in more agreement to nitric oxide synthase phar- macophores than (−)-praeruptorin A. On the other hand, the two enantiomers of praeruptorin A could slightly attenuate the contraction of rat aortic rings induced by internal Ca2+ release from sarcoplasmic reticulum (SR). These findings indicated that (+)-praeruptorin A and (−)-praeruptorin A exerted distinct relaxant effects on isolated rat aorta rings, which might be mainly attributed to nitric oxide synthesis catalyzed by endothelial nitric oxide synthase. © 2010 Elsevier Ireland Ltd. All rights reserved. 1. Introduction muscles [3]. (+)-Praeruptorin A can improve the vascular hypertro- phy by decreasing the area of smooth muscle cells (SMCs), collagen 2+ The dry roots of Peucedanum praeruptorum Dunn. (Baihua content and [Ca ]i in SMCs, and by increasing nitric oxide (NO) pro- Qianhu) have long been used in traditional Chinese medicine for duction in renovascular and spontaneously hypertensive rats [4]. the treatments of certain respiratory diseases such as cough and It is also able to decrease the blood pressure, the amount of colla- asthma, and pulmonary hypertension. The decoctions of the roots gen in the left ventricular and ameliorate the systolic and diastolic are able to relax tracheal and pulmonary arterial preparations [1]. functions of the heart in renal hypertensive rats [5], and decrease P. praeruptorum contains various angular-type pyranocoumarins, the maximum contractile effect of Ca2+ in potassium-depolarized such as (±)-praeruptorin A and B and (+)-praeruptorin A and B [2]. swine coronary strips and shift the concentration–responses curve (±)-Praeruptorin A can effectively relax ileum and tracheal smooth to right in a non-parallel manner [6]. These findings suggest that praeruptorin A is the main bioactive constituent of P. praeruptorum roots for vascular smooth muscle relaxation. Given that the enantiomers of many compounds show distinct Abbreviations: l-NAME, N␻-nitro-l-arginine methyl ester; MB, methylene blue; SMCs, smooth muscle cells; NO, nitric oxide; PE, phenylephrine; ACh, acetylcholine and even adverse pharmacological action, a comparative study of chloride; TEA, tetraethylammonium; EDTA, ethylenediamine tetraacetic acid; sGC, bioactivities of praeruptorin A enantiomers is essential for under- soluble guanylate cyclase; cGMP, cyclic guanosine monophosphate; PKG, cGMP- standing the action characteristics of the two compounds. In the dependent protein kinase; IP3, inositol-1,4,5-triphosphate. ± ∗ present study, we separated ( )-praeruptorin A from the dried Corresponding authors. roots of P. praeruptorum Dunn. by preparative HPLC, and success- E-mail addresses: [email protected] (Y. Dai), cpu [email protected] (L. Kong). fully isolated the two enantiomers by using a preparative Daicel 1 These authors equally contributed to this paper. Chiralpak AD-H column. The differences of the relaxant effects on 0009-2797/$ – see front matter © 2010 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.cbi.2010.04.024 240 Z. Xu et al. / Chemico-Biological Interactions 186 (2010) 239–246 Fig. 3. The molecular structures of (±)-praeruptorin A. spectra of (±)-praeruptorin A in CDCl3 were obtained on a 500 MHz and 125 MHz NMR spectrometer. 1H NMR 6.23 (1H, d, J = 9.5 Hz, C3- H), 7.60 (1H, d, J = 9.5 Hz, C4-H), 7.35 (1H, d, J = 8.6 Hz, C5-H), 6.80 (1H, d, J = 8.6 Hz, C6-H), 5.41 (1H, d, J = 4.8 Hz, C3-H), 6.60 (1H, d, Fig. 1. UV–vis spectra of the (±)-praeruptorin A stereoisomers. J = 4.8 Hz, C4 -H), 1.43 (3H, s, C2 -CH3), 1.47 (3H, s, C2 -CH3), 6.13 (1H, br q, J = 7.3 Hz, C3-H), 1.96 (1H, br d, J = 7.3 Hz, C4-H), 1.88 (1H, br s, C5-H), 2.11 (3H, s, C2-H). 13C NMR 159.91 (C-2), 113.18 rat aorta rings between the two enantiomers and related mecha- (C-3), 143.30 (C-4), 129.15 (C-5), 114.34 (C-6), 129.15 (C-7), 156.73 nisms were addressed in vitro. (C-8), 153.99 (C-9), 112.53 (C-10), 77.71 (C-2), 69.75 (C-3), 61.02 (C-4 ), 24.89 (C-2 -CH3), 22.98 (C-2 -CH3), 166.46 (C-1 ), 126.95 2. Materials and methods (C-2 ), 139.81 (C-3 ), 15.77 (C-4 ), 20.51 (C-5 ), 169.81 (C-1 ), 20.66 (C-2). There are two chiral carbon atoms in the molecular 2.1. Preparation of (±)-praeruptorin A structures of (±)-praeruptorin A. It was reported that the relative configuration of the type of compounds can be determined by its 1 13 Fifty grams of dried roots of P. praeruptorum Dunn. were pulver- H NMR and C NMR. The relative configuration at C-3 and C-4 ized and extracted with 100 mL of light petroleum (boiling range in the pyrane ring was cis form based on the coupling constants of 60–90 ◦C) three times (2 h, 1 h and 1 h, respectively). Then, the light C-3 -H (ı 5.41, d, J = 4.8 Hz) and C-4 -H (ı 6.60, d, J = 4.8 Hz), and in 1 petroleum solutions were combined and concentrated by rotary H NMR, the difference between the methyl proton signals at ı 1.43 13 vaporization at 65 ◦C. The residual liquid was frozen under −4 ◦C for and ı 1.47 of the 2 -gem-dimethyl group was 0.04 ppm; in C NMR, 48 h. The precipitate (2 g) was collected by filtration and separated the difference between the methyl carbon signals at ı 22.98 and ı by preparative HPLC to afford (±)-praeruptorin A 300 mg. 24.89 of the 2 -gem-dimethyl group was 1.91 ppm. Their absolute UV–vis spectra of the (±)-praeruptorin A stereoisomers in configurations were elucidated by chemical correlation with khel- MeOH were taken on Shimadzu UV-2450 spectrophotometer, and lactones. Single-crystal X-ray diffraction analysis (Fig. 2) affirmed 1 13 ± showed Kmax at 322 nm and 220 nm (Fig. 1). H NMR and CNMR the structures of ( )-praeruptorin A (Fig. 3). Fig. 2. The single-crystal X-ray diffraction diagram of (±)-praeruptorin A. Z. Xu et al. / Chemico-Biological Interactions 186 (2010) 239–246 241 Fig. 4. (A) The HPLC chromatogram of the enantiomers of (±)-praeruptorin A. (B) The CD spectra of the enantiomers. 2.2. Isolation of the (±)-praeruptorin A stereoisomers isometrically via a force–displacement transducer connected to a MedLab BL-410 Polygraph (Tai Meng Technology, Chengdu, China). (±)-Praeruptorin A was further separated by using a prepar- ative Daicel Chiralpak AD-H column, with 90:10 ratio of hexane/isopropanol solvent system. CD spectra of the enantiomer 2.6. Measurement of isometric vascular tone in MeOH were obtained on J-810 CD spectrometer. It showed that the isolated enantiomers had classical Cotton effect (Fig. 4). Each aortic ring was allowed to equilibrate for 30 min under a basal resting tension of 1.5 g. Before each experiment, the rings were first contracted with a single concentration of KCl (60 mM) or 2.3. Drugs and reagents PE (1 ␮M) to test their contractility. After which, they were rinsed with Krebs–Henseleit solution for several times until the basal level Phenylephrine (PE), acetylcholine chloride (ACh), N␻-nitro- of tension was restored. The rings were then allowed to equili- l-arginine methyl ester (l-NAME, an inhibitor of nitric oxide brate further for 30 min. To confirm intact endothelium, each ring synthase), methylene blue (MB, a soluble guanylyl cyclase was contracted with PE (1 ␮M) and then exposed to ACh (10 ␮M), inhibitor), tetraethylammonium (TEA, a nonselective K+ channel endothelium-dependent vasodilator, at the peak of the contrac- blocker) and heparin (a selective IP R inhibitor) were purchased 3 tion.
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