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.
INTRODUCTION
Cigarette smoke is a significant risk factor of stroke1-3. Both active smoking and passive smoking pose a risk. The population-attributable risk for and stroke associated with smoking4 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 smoking5. 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 stroke6-10. Cigarette smoking may be a risk factor for recurrent hemorrhagic stroke after aneurysm repair9 and it has also been associated with symptomatic vasospasm after hemorrhagic stroke11. 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-smokers11-13. However, it was reported that 37% of patients resume smoking after hemorrhagic stroke6. Cerebral vasospasm after subarachnoid hemorrhage (SAH) is the leading cause of delayed morbidity and mortality following aneurysmal SAH14. Cerebral vasospasm is a multi factorial disease process characterized by a combination of endothelial and smooth muscle cell dysfunction and inflammation15-17.
Cigarette smoke is a highly complex mixture containing thousands of different compounds18 and nicotine is considered to be the major pathogenic compound in cigarette smoke19. 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 content20,21. This present studies have specifically studied effects of nicotine on the cerebral vascular after hemorrhagic stroke22-24. 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 circulation25.
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. Toda26 reported that nicotine caused a transient relaxation in the canine basilar artery which pre-contracted with prostaglandin F2α (PGF2α). It has been reported that nicotine induced endothelium-dependent contraction in the basilar artery of rat22-24,27 and canine28. It has been reported that nicotine induced endothelium-dependent rexalation in the basilar artery of porcine29, guinea pig30 and canine26 (Table 1).
Recently, we have reported that the nicotine-induced contractions of the rat basilar artery are mostly endothelium-dependent at nicotine concentrations (3×10–5 to 3×10–3 mol L–1). At higher nicotine concentrations (10–3 to 10–2 mol L–1), nicotine-induced contraction is about 90% endothelium-dependent in the rat basilar artery27.
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 artery31. Nicotine-induced contraction appeared to be mediated by activation of nicotinic acetylcholine receptors (nAChRs), Rho-kinase and cyclooxygenase pathways in the rabbit corpus cavernosum32. Acute exposure to nicotine impaired NOS-dependent dilation of the rat basilar artery33.
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 (α1β1δε and α1β1δγ-nAChRs), (2) Ganglion-type nAChRs (α3β2-nAChRs) and (3) Central nervous system (CNS)-type nAChRs (α4β2, α3β2 and α7-nAChRs)34,35 (Table 2).
| Table 1: | Effects of nicotine on the basilar artery |
| Table 2: | Subtype of nAChRs |
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 pigs36 and endothelial cells of the rat coronary microvascular37. The muscle-type nAChRs are present exclusively in the cell membranes of skeletal muscle38.
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 nAChRs26. Wu et al.29 have been reported that nicotine-induced relaxation in the porcine basilar artery were in relation to α3β239,40 and α7-nAChRs36,41-48.
Mecamylamine was an antagonistof neuronal nAChRs49-51. Hexamethonium was an antagonist of ganglion-type nAChRs, which was one of the first compounds used to discriminate the ganglionic and muscle nAChRs50. Gallamine was an antagonist of the muscle-type nAChRs.
In this previous study24, 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 1/100th) 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 nAChRs52. 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 (3×10–5 to 3×10–3 mol L–1). At higher nicotine concentrations (10–3 to 10–2 moL L–1), nicotine-induced contraction is about 90% endothelium-dependent in the rat basilar artery27. Neuronal nAChRs are expressed in vascular smooth muscle cells38 and endothelial cells37. In contrast to this, skeletal muscle nAChRs are only present exclusively in skeletal muscle38.
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 cells36 and norepinephrine-induced contraction in the pial arteries of cat and rabbit53,54.
The Ca2+ was one of the effectors of nAChR34,55,56. The nAChR activation could cause a significant elevation of the cytosolic concentrationsof Ca2+ in rat endothelium57. Nicotine does not induce a transient increase in the intracellular free Ca2+ concentration in rat microvascular endothelial cells37. It also have been reported that nicotine induced a significant Ca2+ influx in cultured superior cervical ganglionic cells but failed to affect calcium influx in cultured sphenopalatine ganglionic cells in the porcine basilar artery41. Stimulation of nAChR causes the depolarization and activation of L-type Ca2+ channel in rat pineal ocytes58. The nAChRs are inhibited by several drugs that are commonly thought to be specific for L-type Ca2+ channel59,60. It also have been reported that the sympathetic neuronal calcium influx through L-type Ca2+ channel was modulated by α3β2-nAChRs29. It have been considered that L-type Ca2+ channel played an important role in the regulation of functions, especially in the synthesis and release of vasoactiveendothelium-derived factors61,62. The global Ca2+ signals that activate smooth muscle cell contractionare largely due to the activation of L-type Ca2+ channels61. The L-type Ca2+ channels are present not only in vascular smooth muscle cells63-66 but also in endothelium cells62,67,68 in the arterial system. Nifedipine is an L-type Ca2+ channel blocker and selectively inhibited the nicotine-induced contractions of intracranial arteries but not of peripheral arteries69. This study also indicated that nicotine-induced contraction involved L-type Ca2+ channels and contraction of the rat basilar artery was inhibited by nifedipine (10–9 to 10–8 mol L–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 states70,71. The levels of arachidonic acid metabolites are enhanced in the cerebrospinal fluid of SAH patients22,23,72,73.
Phospholipase C (PLC) and phospholipase A2 (PLA2) 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) H2, 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 pathways24 and nAChRs signaling is involved in the PLC pathway74,75.
| 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 A2 (TXA2) in the canine basilar artery28. In the rat coronary artery, nicotine-induced contraction involves endothelial COX-1 metabolites of arachidonic acid76. This present studies reported that the PLC (or calcium-independent PLA2), COX-2, 5-LOX and BLT2 pathways may be the main signaling pathways involved in nicotine-induced contraction in the rat basilar artery (Fig. 1)21,30. The PGF2α could induce endothelium-dependent contraction in the porcine77 and canine78 basilar arteries. Nicotine could cause a transient relaxation in the canine basilar artery which pre-contracted26,29 with PGF2α.
The PLA2 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, PLA2 is known to be present in several isoforms79. There are three broad classes of PLA2 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–1 order), have been termed sPLA2. A second form, cPLA2 is activated by low concentrations (μmoL L–1) of calcium80. A third form, iPLA2 is Ca2+-independent and shares some characteristics with sPLA2 and others81 with cPLA2. It has been reported that iPLA2 represents about 80% of the total PLA2 activity82. The iPLA2 was present in the endothelial cells, but weak signals were also detected in the smooth muscle cells83. The iPLA2 played a key role in the endothelium-dependent contractions to acetylcholine in the aorta of the spontaneously hypertensive rat83. Our group also reported that iPLA2 was an important isoform among the three PLA2 isoforms regarding contraction induced by nicotine. Nicotine-induced contraction in the rat basilar artery is partially due to PLC and iPLA2 activation.
In the basilar artery, COX catalyses the production of prostanoids from arachidonic acid84,85. 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 inflammation86-88. 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.
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 vivo89. 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 contraction90. 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 aneurysms91. 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) synthesis92. The levels of leukotriene B4 (LTB4) and leukotriene E4 (LTE4) were 4 times higher in the blood of cigarette smokers than in that of the controls93. Moreover, the urinary excretion of thromboxane A2 (TXA2) metabolite was higher in cigarette smokers than in the controls94. The TXA2 is a cyclooxygenase metabolite of arachidonic acid, whereas LTB4 and CysLTs are the 5-lipoxygenase (5-LOX) metabolites of arachidonic acid.
The LTB4, an endothelium-derived contracting factor, was found in the rat coronary artery95 and the guinea pig aorta96. Neither LTC4 nor LTD4 lead to the contraction or relaxation of the isolated human cerebral artery strips97. Physiological concentrations of nicotine do not affect thromboxane production in the human umbilical vein98.
In the previous study, we observed that the antagonists of the TXA2 and CysLT receptors did not affect nicotine-induced contraction. In contrast, the antagonists of LTB4 receptor (BLT1 and BLT2) significantly attenuated nicotine-induced contraction in the rat basilar artery. The concentration of LY255283 (a BLT2 receptor antagonist) that produced attenuation was significantly lower than that of CP105696 (a BLT1 receptor antagonist), in order to obtain the same inhibitory effect on nicotine-induced contraction. These results suggest that LTB4 is involved in nicotine-induced contraction in the rat basilar artery, whereas, TXA2 and CysLTs are not involved. Moreover, nicotine in the rat basilar artery exhibits a higher affinity for BLT2 receptor than BLT1 receptor. The study found that blockade LTB4 receptors, BLT1 and BLT2, abrogate nicotine-induced cerebrovascular vasoconstriction in a dose-dependent manner whereas blockade of cysteinyl LT (CysLT, collectively LTC4, LTD4 and LTE4) and TXA2 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 (2014FB170 ), the Research Programs of State Key Laboratory of Phytochemistry and Plant Resources in West China (Y3728211Z1), the Research Programs of Youth Innovation Promotion Association in the Chinese Academy of Sciences, Technology project of Yunnan Tobacco Industry Co., Ltd., Yunnan tabacoo 1st and 2nd kinds of low tar cigarette products research and development (2013CP02).