Involvement of Arachidonic Acid Metabolites Pathway and Nicotinic...

[Full title: Involvement of Arachidonic Acid Metabolites Pathway and Nicotinic Acetylcholine Receptors (nAChRs) on Nicotine-induced Contractions (or Relaxations) in the Basilar Artery]

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OPEN ACCESS International Journal of Pharmacology ISSN 1811-7775 DOI: 10.3923/ijp.2017.1.10 Review Article Involvement of Arachidonic Acid Metabolites Pathway and Nicotinic Acetylcholine Receptors (nAChRs) on Nicotine-induced Contractions (or Relaxations) in the Basilar Artery 1 Yifan Li, 2 Dan Luo, 2 Xuejiao Chen, 2 Jie Li, 1 Liang Yan, 1 Tong Li, 3 Yingliang Zhao, 4 Hui Liu, 2 Xu Ji and 1 Xiao Ma 1 Key Laboratory of Pu-erh Tea Science of Ministry of Education, Yunnan Research Center for Advanced Tea Processing, Yunnan Agricultural University, No. 452 FengYuan Street, Kunming, 650201 Yunnan, China 2 State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, 650201 Yunnan, China 3 Technology center of China Tobacco Yunnan Industry Co., Ltd, Kunming, Yunnan, China 4 Urology, The Second Hospital of Dalian Medical University, Dalian, 116021 Liaoning, China Abstract Smoking is one of the most important risk factors for cerebral circulatory disorders and nicotine is considered to be the major pathogenic compound in cigarette smoke. Amelioration of nicotine-induced vasoconstrictions (or vasodilations) may provide a therapeutic target for the treatment of stroke. This study will review the involvement of arachidonic acid metabolites pathway and nicotinic acetylcholine receptors (nAChRs) on nicotine-induced contractions (or relaxations) in the basilar artery. Arachidonic acid metabolites pathway and nAChRs may be new drug targets and their selectivity antagonists (or agonists) may be new therapeutic drugs for the treatment of stroke Key words: Basilar artery, nicotine, vasoconstriction, vasorelaxation, arachidinic acid, nicotinic acetylcholine receptors (nAChRs), endothelium Received: March 24, 2016 Accepted: October 19, 2016 Published: December 15, 2016 Citation: Yifan Li, Dan Luo, Xuejiao Chen, Jie Li, Liang Yan, Tong Li, Yingliang Zhao, Hui Liu, Xu Ji and Xiao Ma, 2017. Involvement of arachidonic acid metabolites pathway and nicotinic acetylcholine receptors (nAChRs) on nicotine-induced contractions (or relaxations) in the basilar artery. Int. J. Pharmacol., 13: 1-10 Corresponding Authors: Xiao Ma, Key Laboratory of Pu-erh Tea Science of Ministry of Education, Yunnan Research Center for Advanced Tea Processing, Yunnan Agricultural University, No. 452 FengYuan Street, Kunming, 650210 Yunnan, China Tel: +86-871-65229853 Fax: +81-871-65216611 Xu Ji, State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, 650201 Yunnan, China Copyright : © 2017 Yifan Li et al. This is an open access article distributed under the terms of the creative commons attribution License, which permits unrestricted use, distribution and reproduction in any medium, provided the original author and source are credited. Competing Interest: The authors have declared that no competing interest exists Data Availability: All relevant data are within the paper and its supporting information files.

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Int. J. Pharmacol., 13 (1): 1-10, 2017 INTRODUCTION Cigarette smoke is a significant risk factor of stroke 1-3 . Both active smoking and passive smoking pose a risk. The population-attributable risk for and stroke associated with smoking 4 is about 18.9%. Smoking is a chronic disease that tends to recur because of nicotine dependency, many patients continue smoking even after an attack of stroke. At one year after and stroke, 22% of patients are still smoking 5 Therefore, support measures to enforce nonsmoking are required in this high-risk population. The risk after smoking cessation for 5-10 years is equal to that faced by a non-smoker There are two main types of stroke: Ischemic stroke due to lack of blood flow and hemorrhagic stroke due to bleeding. Cigarette smoking is also one of the most important risk factors of hemorrhagic stroke 6-10 . Cigarette smoking may be a risk factor for recurrent hemorrhagic stroke after aneurysm repair 9 and it has also been associated with symptomatic vasospasm after hemorrhagic stroke 11 . In recent studies, cigarette smoking has been shown to increase the risk of vasospasm following hemorrhagic stroke and smokers are 2.5 times more likely to experience a ruptured aneurysm than non-smokers 11-13 . However, it was reported that 37% of patients resume smoking after hemorrhagic stroke 6 . Cerebral vasospasm after subarachnoid hemorrhage (SAH) is the leading cause of delayed morbidity and mortality following aneurysmal SAH 14 . Cerebral vasospasm is a multi factorial disease process characterized by a combination of endothelial and smooth muscle cell dysfunction and inflammation 15-17 Cigarette smoke is a highly complex mixture containing thousands of different compounds 18 and nicotine is considered to be the major pathogenic compound in cigarette smoke 19 . Nicotine is a chiral molecule and the S(-)-isomer is predominant in cigarette smoke, with the R(+)-isomer representing only 3-12% of total nicotine content 20,21 . This present studies have specifically studied effects of nicotine on the cerebral vascular after hemorrhagic stroke 22-24 . Therefore, amelioration of nicotine-induced vasoconstrictions (or vasodilations) may provide a therapeutic target for the treatment of stroke Nicotine is considered to most significantly affect cerebral arterial tone in the brain. Large arteries such as the basilar artery, make an important contribution to the total cerebral vascular resistance and are major determinants of local micro vascular pressure in the cerebral circulation 25 Undoubtedly, understanding the mechanism of nicotine-induce contractions (or relaxations) in the basilar artery will be a crucial step for designing a more effective treatment plan. Although, the pharmacology of nicotine-induced vasocontractions (or vasodilations) was well studied, nicotine-induced vasoconstriction (or vasodilation) in the basilar artery was not well summarized in the basilar artery. In the present study, we will review the involvement of arachidonic acid metabolites pathway and nicotinic acetylcholine receptors (nAChRs) on nicotine-induced contractions (or relaxations) in the basilar artery. Arachidonic acid metabolites pathway and nAChRs may be new drug targets and their selectivity antagonists (or agonists) may be new therapeutic drugs for the treatment of stroke EFFECTS OF NICOTINE IN THE BASILAR ARTERY Nicotine could induce contraction or relaxation of the basilar artery. Toda 26 reported that nicotine caused a transient relaxation in the canine basilar artery which pre-contracted with prostaglandin F 2 " (PGF 2 " ). It has been reported that nicotine induced endothelium-dependent contraction in the basilar artery of rat 22-24,27 and canine 28 . It has been reported that nicotine induced endothelium-dependent rexalation in the basilar artery of porcine 29 , guinea pig 30 and canine 26 (Table 1) Recently, we have reported that the nicotine-induced contractions of the rat basilar artery are mostly endothelium-dependent at nicotine concentrations (3×10 G 5 to 3×10 G 3 mol L G 1 ). At higher nicotine concentrations (10 G 3 to 10 G 2 mol L G 1 ), nicotine-induced contraction is about 90% endothelium-dependent in the rat basilar artery 27 In addition, nicotine not only induced contraction or rexalationin the basilar artery but also affect other pharmacological nature of the artery. For example, nicotine potentiated 5'-triphosphate (UTP)-induced contraction response through protein kinase C (PKC) activation in the canine basilar artery 31 . Nicotine-induced contraction appeared to be mediated by activation of nicotinic acetylcholine receptors (nAChRs), Rho-kinase and cyclooxygenase pathways in the rabbit corpus cavernosum 32 . Acute exposure to nicotine impaired NOS-dependent dilation of the rat basilar artery 33 EFFICACY OF nAChRs IN THE BASILAR ARTERY The effects of nicotine are mediated by the interaction of the alkaloid with a number of nAChRs. According to specific pattern of distribution, three different types of nAChRs exist: (1) Muscle-type nAChRs ( " 1 $ 1 δ , and " 1 $ 1 δγ -nAChRs), (2) Ganglion-type nAChRs ( " 3 $ 2-nAChRs) and (3) Central nervous system (CNS)-type nAChRs ( " 4 $ 2, " 3 $ 2 and " 7-nAChRs) 34,35 (Table 2) 2

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Int. J. Pharmacol., 13 (1): 1-10, 2017 Table 1: Effects of nicotine on the basilar artery Year Specimen of basilar artery Dose of nicotine (µmol L G 1 ) Effects Mechanism References 1975 Canine 5-10000 Contraction and relaxation nAChR, Na + pump Toda 26 1988 Canine 10000 Contraction Endothelium-dependent, TXA 2 Shirahase et al 28 1997 Guinea-pig 100 Relaxation Endothelium-dependent, NO Jiang et al 30 1998 Porcine 100 Relaxation NO, nAChR Nguyen et al 32 1999 Guinea-pig 100 Relaxation 5-HT 1 receptor, NO Mayhan et al 33 2000 Porcine 100 Relaxation NO Domino 34 2001 Porcine 1-100 Relaxation nAChR Rang and Dale 35 2002 Porcine 100 NO, nAChR Li et al 36 2006 Porcine 100 Relaxation " 7-nAChR, NO Moccia et al 37 and Devillers-Thiery et al 38 2007 Rat 30-3000 Contraction Endothelium-dependent, Ji et al 27 Arachidonic acid metabolites 2009 Porcine 100 Relaxation PGE 2 , EP 1 receptor Lee et al 39 2011 Porcine 100 Relaxation " 7-nAChR, NO Lee et al 40 2012 Monkey Relaxation NO Si and Lee 41 2012 Porcine 100 Relaxation " 3 $ 2-nAChR Si and Lee 42 2013 Rat 3000 Contraction Arachidonic acid metabolites, nAChR Ji et al 22-24 2014 Porcine 100 Relaxation L-type calcium channel, Wu et al 29 " 3 $ 2-nAChR Table 2: Subtype of nAChRs Receptor-type Location Effect and functions Nicotinic agonists Nicotinic antagonists Muscle-type: Neuromuscular junction EPSP, mainly by increased Acetylcholine " -bungarotoxin ( " 1 ) 2 $ 1 δ , or Na + and K + permeability Carbachol " -conotoxin ( " 1 )2 $ 1 δ ( Suxamethonium Tubocurarine Pancuronium Atracurium Ganglion-type: Autonomic gangila EPSP, mainly by increased Acetylcholine Burropion ( " 3 ) 2 ( $ 4 ) 3 Na + and K + permeability Carbachol 18-methoxycoronaridine Nicotine Dextromethorphan Epibatidine Hexamethonium Dimethylphenylpiperazinium Ibogaine Mecamylamine Trimetaphan Heteromeric Brain Post and presynaptic excitation Acetylcholine " -conotoxin CNS-type: mainly by increase Na + and K + Cytisine Dextromethorphan ( " 4 ) 2 ( $ 2 ) 3 permeability Epibatidine Dihydro- $ -erythroidine Major subtype involved in the Nicotine Mecamylamine rewarding effect of nicotine Nifene Varenicline Further Brain Post and presynaptic excitation Acetylcholine Dextromethopphan CNS-type: Cytisine Hexamethonium ( " 3 ) 2 ( $ 4 ) 3 Epibatidine Mecamylamine Nicotine Tubocurarine Homomeric Brain Post and presynaptic excitation mainly Cytisine " -bungarotoxin CNS-type by increase Ca 2+ permeability. Major Epibatidine Amantadine ( " 7 ) 5 subtype involve in the pro-cognitive Dimethylphenylpiperazinium Dextromethorphan effects of nicotine. Also involved in the Varenicile Mecamylamine pro-angiogenic effects of nicotine Memantine and accelerate the progression of Methylcaconitine chronic kindly disease in smokers Ganglion-type and CNS-type nAChRs belong to the neuronal nAChR. These receptors were originally discovered in the nervous system but are also expressed in a variety of non-neuronal cells, for example, vascular smooth muscle cells from the basilar artery of the guinea pigs 36 and endothelial cells of the rat coronary microvascular 37 . The muscle-type nAChRs are present exclusively in the cell membranes of skeletal muscle 38 Various nAChRs play different biological roles in the basilar artery. It has been reported that nicotine-induced relaxation in the canine basilar artery and nicotine-induced contraction in the canine mesenteric artery were the result of a specific action on nAChRs 26 . Wu et al 29 have been reported that nicotine-induced relaxation in the porcine basilar artery were in relation to " 3 $ 2 39,40 and " 7-nAChRs 36,41-48 3

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Int. J. Pharmacol., 13 (1): 1-10, 2017 Mecamylamine was an antagonistof neuronal nAChRs 49-51 Hexamethonium was an antagonist of ganglion-type nAChRs, which was one of the first compounds used to discriminate the ganglionic and muscle nAChRs 50 . Gallamine was an antagonist of the muscle-type nAChRs In this previous study 24 , in the rat basilar artery, mecamylamine (CNS and ganglion-type nAChRs antagonist) and gallamine (muscle-type nAChR antagonist) attenuated the nicotine-induced contraction in a concentration-dependent manner but hexamethonium (ganglion-type nAChR antagonist) did not affect nicotine-induced contraction. These results suggested that nicotine-induced contraction involved the CNS nAChR subfamily and skeletal muscle nAChR subfamily pathways. The concentration of mecamylamine leading to attenuation was significantly lower (over 1/100 th) than the concentration of gallamine, to obtain the same inhibitory effect on nicotine-induced contraction. In addition, it have been reported that nicotine is a very weak agonist of muscle nAChRs 52 . These results indicated that nicotine in the rat basilar artery showed a high affinity to the CNS-type nAChRs and low affinity to the muscle-type nAChRs Our group has also reported the nicotine-induced contractions of the rat basilar artery are mostly endothelium-dependent at nicotine concentrations (3×10 G 5 to 3×10 G 3 mol L G 1 ). At higher nicotine concentrations (10 G 3 to 10 G 2 moL L G 1 ), nicotine-induced contraction is about 90% endothelium-dependent in the rat basilar artery 27 Neuronal nAChRs are expressed in vascular smooth muscle cells 38 and endothelial cells 37 . In contrast to this, skeletal muscle nAChRs are only present exclusively in skeletal muscle 38 . Taken together with our preview reports, nicotine-induced contraction in the rat basilar artery involved the CNS nAChR and skeletal muscle nAChR subfamily pathways. Nicotine has a lower agonistic potency for the muscle-type nAChRs and is a much more potent agonist for the neuronal nAChRs. Our group assumed that the CNS-type nAChRs in the endothelium play a key role to nicotine-induced contraction in the rat basilar artery The nAChRs played a significant role to nicotine-induced contraction (or rexalation) in the basilar artery. Furthermore, the nAChRs were also mediated nicotine-induced migration of vascular smooth muscle cells 36 and norepinephrine-induced contraction in the pial arteries of cat and rabbit 53,54 The Ca 2+ was one of the effectors of nAChR 34,55,56 . The nAChR activation could cause a significant elevation of the cytosolic concentrationsof Ca 2+ in rat endothelium 57 . Nicotine does not induce a transient increase in the intracellular free Ca 2+ concentration in rat microvascular endothelial cells 37 . It also have been reported that nicotine induced a significant Ca 2+ influx in cultured superior cervical ganglionic cells but failed to affect calcium influx in cultured sphenopalatine ganglionic cells in the porcine basilar artery 41 . Stimulation of nAChR causes the depolarization and activation of L-type Ca 2+ channel in rat pineal ocytes 58 . The nAChRs are inhibited by several drugs that are commonly thought to be specific for L-type Ca 2+ channel 59,60 . It also have been reported that the sympathetic neuronal calcium influx through L-type Ca 2+ channel was modulated by " 3 $ 2-nAChRs 29 . It have been considered that L-type Ca 2+ channel played an important role in the regulation of functions, especially in the synthesis and release of vasoactiveendothelium-derived factors 61,62 . The global Ca 2+ signals that activate smooth muscle cell contractionare largely due to the activation of L-type Ca 2+ channels 61 . The L-type Ca 2+ channels are present not only in vascular smooth muscle cells 63-66 but also in endothelium cells 62,67,68 in the arterial system. Nifedipine is an L-type Ca 2+ channel blocker and selectively inhibited the nicotine-induced contractions of intracranial arteries but not of peripheral arteries 69 . This study also indicated that nicotine-induced contraction involved L-type Ca 2+ channels and contraction of the rat basilar artery was inhibited by nifedipine (10 G 9 to 10 G 8 mol L G 1 ) 24 INVOLVEMENT OF ARACHIDONIC ACID METABOLITES PATHWAY ON NICOTINE-INDUCED CONTRACTIONS (OR RELAXATIONS) IN THE BASILAR ARTERY Arachidonic acid is a key inflammatory intermediate factor and inflammation play a central role in tissue injury and many diseased states 70,71 . The levels of arachidonic acid metabolites are enhanced in the cerebrospinal fluid of SAH patients 22,23,72,73 Phospholipase C (PLC) and phospholipase A 2 (PLA 2 ) catalyze the production of arachidonic acid from membrane phospholids during cellular stimulation. Arachidonic acid is metabolized mainly by 2 pathways: (1) The cyclooxygenase (COX) pathway generates the unstable intermediary endoperoxide prostaglandin (PG) H 2 , which gives rise to prostaglandins, thromboxanes and prostacyclin, (2) The lipoxygenase (LOX) pathway generates 5(S)-hydroperoxy- 6-trans-8,11,14-cis-eicosatetraenoic acid, which gives rise to 5(S)-hydroxy-6-trans-8, 11, 14-cis-eicosatetraenoic acid and leukotrienes It is also reported that nicotine-induced contraction of the rat basilar artery via the CNS-type nAChRs and muscle-type nAChRs pathways 24 and nAChRs signaling is involved in the PLC pathway 74,75 4

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Int. J. Pharmacol., 13 (1): 1-10, 2017  7-nAChRs PLC   3 2-nAChRs iPLA 2 COX-2 5-LOX AA TXA 2 LTB 4 Nicotine L-type Ca 2+ channel N N H Endothelium cells Smooth muscle cells Contraction or relaxation of basilar artery Fig. 1: Involvement of arachidonic acid metabolites nicotine-induced contractions (or relaxations) in the basilar artery It has been reported that nicotine-induced contraction involves thromboxane A 2 (TXA 2 ) in the canine basilar artery 28 In the rat coronary artery, nicotine-induced contraction involves endothelial COX-1 metabolites of arachidonic acid 76 . This present studies reported that the PLC (or calcium-independent PLA 2 ), COX-2, 5-LOX and BLT 2 pathways may be the main signaling pathways involved in nicotine-induced contraction in the rat basilar artery (Fig. 1) 21,30 . The PGF 2 " could induce endothelium-dependent contraction in the porcine 77 and canine 78 basilar arteries Nicotine could cause a transient relaxation in the canine basilar artery which pre-contracted 26,29 with PGF 2 " The PLA 2 is a family of enzymes that is ubiquitous in mammalian cells and plays an important role in the maintenance of membrane phospholipids, as well as the production of inflammatory lipid mediators that regulate cellular activity. In mammalian cells, PLA 2 is known to be present in several isoforms 79 . There are three broad classes of PLA 2 based on the cellular disposition and calcium dependence. A family of low molecular mass (14 kDa) enzymes, depending on high calcium concentrations (of the mmol L G 1 order), have been termed sPLA 2 . A second form, cPLA 2 is activated by low concentrations ( : moL L G 1 ) of calcium 80 . A third form, iPLA 2 is Ca 2+ -independent and shares some characteristics with sPLA 2 and others 81 with cPLA 2 . It has been reported that iPLA 2 represents about 80% of the total PLA 2 activity 82 . The iPLA 2 was present in the endothelial cells, but weak signals were also detected in the smooth muscle cells 83 . The iPLA 2 played a key role in the endothelium-dependent contractions to acetylcholine in the aorta of the spontaneously hypertensive rat 83 . Our group also reported that iPLA 2 was an important isoform among the three PLA 2 isoforms regarding contraction induced by nicotine. Nicotine-induced contraction in the rat basilar artery is partially due to PLC and iPLA 2 activation In the basilar artery, COX catalyses the production of prostanoids from arachidonic acid 84,85 . Two distinct COX isoforms have been identified and both perform the same catalytic reaction and inhibit the conversion of arachidonic acid to prostanoids. The COX-1 is expressed constitutively in most tissues throughout the body, including the gastrointestinal tract, kidneys and platelets. The COX-2 is normally expressed at low levels in normal tissue, but it is stimulated to express strongly by inflammatory mediators at sites of inflammation 86-88 . Our group indicates that COX-2 but not COX-1, is involved in nicotine-induced contraction in the rat basilar artery, suggesting that nicotine may play a role as a pro-inflammatory mediator 5

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Int. J. Pharmacol., 13 (1): 1-10, 2017 The ZM-230487 (5-LOX inhibitor) attenuated the contraction of the rat basilar artery in a concentration-dependent manner. The 5-LOX is the key enzyme involved in leukotriene biosynthesis and catalyzes the initial steps in the conversion of arachidonic acid to these biologically active lipid mediators, which are known to exert proinflammatory effects in vivo 89 . In this present study concerning the effects of the 5-LOX inhibitor (ZM-230487) on vasopressin-induced contraction in the rat basilar artery, ZM-230487 attenuated the contraction 90 . As far as nicotine-induced contraction in the rat basilar artery is concerned, the activation of 5-LOX may play a role in promoting the formation of not only atherosclerotic lesions, but also aortic aneurysms 91 . These studies suggest that smoking and particularly nicotine, may activate the 5-LOX pathways in the cerebrovascular system Cigarette smoke is related to enhanced cysteinyl leukotriene (CysLT) synthesis 92 . The levels of leukotriene B 4 (LTB 4 ) and leukotriene E 4 (LTE 4 ) were 4 times higher in the blood of cigarette smokers than in that of the controls 93 Moreover, the urinary excretion of thromboxane A 2 (TXA 2 ) metabolite was higher in cigarette smokers than in the controls 94 . The TXA 2 is a cyclooxygenase metabolite of arachidonic acid, whereas LTB 4 and CysLTs are the 5-lipoxygenase (5-LOX) metabolites of arachidonic acid The LTB 4 , an endothelium-derived contracting factor, was found in the rat coronary artery 95 and the guinea pig aorta 96 Neither LTC 4 nor LTD 4 lead to the contraction or relaxation of the isolated human cerebral artery strips 97 . Physiological concentrations of nicotine do not affect thromboxane production in the human umbilical vein 98 . In the previous study, we observed that the antagonists of the TXA 2 and CysLT receptors did not affect nicotine-induced contraction. In contrast, the antagonists of LTB 4 receptor (BLT 1 and BLT 2 ) significantly attenuated nicotine-induced contraction in the rat basilar artery. The concentration of LY 255283 (a BLT 2 receptor antagonist) that produced attenuation was significantly lower than that of CP 105696 (a BLT 1 receptor antagonist), in order to obtain the same inhibitory effect on nicotine-induced contraction. These results suggest that LTB 4 is involved in nicotine-induced contraction in the rat basilar artery, whereas, TXA 2 and CysLTs are not involved. Moreover, nicotine in the rat basilar artery exhibits a higher affinity for BLT 2 receptor than BLT 1 receptor. The study found that blockade LTB 4 receptors, BLT 1 and BLT 2 , abrogate nicotine-induced cerebrovascular vasoconstriction in a dose-dependent manner whereas blockade of cysteinyl LT (CysLT, collectively LTC 4 , LTD 4 and LTE 4 ) and TXA 2 receptors does not affect contractility. PERSPECTIVES Taken together with preview reports and this studies, nicotine-induced contractions (or relaxations) in the basilar artery is concentration-dependent and endothelium-dependent. This study provides novel pharmacological evidence for the first time that nicotine-induced vasoconstrictions (or vasorelaxations) is about 90% endothelium-dependent in the basilar artery and nicotine in the basilar artery showed a high affinity to the neuronal nAChR subfamily and low affinity to the skeletal muscle nAChR subfamily. The nAChRs signaling is involved in the arachidonic acid metabolites. Nicotine-induced contractions (or relaxations) might be due to the products of membrane phospholipids involving arachidonic acid metabolites pathway in the basilar artery (Fig. 1). This review elucidates the arachidonic acid metabolites pathways and nAChRs involved in nicotine-induced contractions (or relaxations). This study may represent a new cerebrovascular pathology and play critical roles in fatal cerebral circulatory disorders. Arachidonic acid metabolites pathway and nAChRs maybe new drug targets and their selectivity antagonists (or agonists) may be new therapeutic drugs for the treatment of stroke ACKNOWLEDGMENTS This review was supported by the grants from the National Natural Science Foundation of China (No. 81300609), the Applied Basic Research Programs of Science and Technology Department of Yunnan province (2014 FB 170 ), the Research Programs of State Key Laboratory of Phytochemistry and Plant Resources in West China (Y 3728211 Z 1), the Research Programs of Youth Innovation Promotion Association in the Chinese Academy of Sciences, Technology project of Yunnan Tobacco Industry Co., Ltd., Yunnan tabacoo 1 st and 2 nd kinds of low tar cigarette products research and development (2013 CP 02) REFERENCES 1 Bejot, Y., A. Jacquin, B. Daubail, C. Lainay and S. Janoura et al ., 2014. Smoking status and severity of ischemic stroke A population-based study. Eur. Neurol., 71: 59-64 2 Nordahl, H., M. Osler, B.L. 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