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©2008 Korean Pharmacopuncture Institute
 J Acupunct Meridian Stud 
*Corresponding author. National Research Institute of Chinese Medicine, No. 155-1, Section 2, Linong Street, Beitou District,Taipei 112, Taiwan.E-mail: leohsiao@nricm.edu.tw
Acupuncture is the practice of inserting needles into the body to reduce pain orinduce anesthesia. More broadly, acupuncture is a family of procedures involvingthe stimulation of anatomical locations on or in the skin by a variety of techniques.Employing acupuncture to treat human disease or maintain bodily condition hasbeen practiced for thousands of years. However, the mechanism(s) of action of acu-puncture at the various meridians are poorly understood. Most studies have indi-cated that acupuncture is able to increase blood flow. The acupuncture points havehigh electrical conductance and a relationship of the acupuncture points and merid-ians with the connective tissue planes and the perivascular space has also beensuggested. Several studies employing the human and animal models have shownthat acupuncture enhances the generation of nitric oxide (NO) and increases localcirculation. Specifically, electroacupuncture (EA) seems to prevent the reductionin NO production from endothelial NO synthetase (eNOS) and neuronal NO synthase(nNOS) that is associated with hypertension and this process involves a stomach-meridian organ but not a non-stomach-meridian organ such as the liver. How can weexplain the phenomena of EA and meridian effect? Here, we proposed a neurovas-cular transmission model for acupuncture induced NO. In this proposed model, theacupuncture stimulus is able to influence connective tissue via mechanical forcetransfer to the extracellular matrix (ECM). Through the ECM, the mechanotransduc-tion stimulus can be translated or travel from the acupuncture points, which involvelocal tissue and cells. Cells in the local tissue that have received mechanotransduc-tion induce different types of NO production that can induce changes in blood flowand local circulation. The local mechanical stress produced is coupled to a cyclicstrain of the blood vessels and this could then change the frequency of resonance.According to the resonance theory, an oscillatory pattern of NO formation mightoccur in that specific organ. Therefore, the artery tree would then change the blooddistribution and microcirculation of various organs and as a result further affectthe production of NO.
A Neurovascular Transmission Model forAcupuncture-induced Nitric Oxide
Sheng-Hsiung Hsiao
*, Li-Jen Tsai
Division of Informatics, National Research Institute of Chinese Medicine, Taipei, Taiwan
Institute of Molecular Biology, Academia Sinica, Taipei, Taiwan
Received: Feb 29, 2008Accepted: Apr 14, 2008
acupuncture point;mechanotransduction;meridian;neurovasculartransmission;nitric oxide;resonance theory
Neurovascular transmission model for acupuncture-induced NO 43
1. Introduction
Acupuncture is the practice of inserting needlesinto the body to reduce pain or induce anesthesia.More broadly, acupuncture is a family of proceduresinvolving the stimulation of anatomical locations onor in the skin by a variety of techniques. Employingacupuncture to treat human disease or to maintainbodily condition has been practiced for thousandsof years. Recently, models able to describe the modeof action of acupuncture have aroused scientists’curiosity. Scientific interest in acupuncture has lednumerous investigators to conduct clinical trials thathave tested the efficacy of acupuncture using vari-ous acupuncture points; however, the mechanism(s)of action of acupuncture at the various meridiansare still poorly understood.Previous studies have provided a variety of in-formation regarding the physiological effects of acupuncture on animal and human bodies. Most of them have indicated that acupuncture is able toincrease blood flow [1] and that the acupuncturepoints and meridians have a high electrical con-ductance [2,3]. A relationship has also been sug-gested between acupuncture points and meridianswith connective tissue planes [4] and the perivas-cular space [5]. A number of possible mechanismsby which acupuncture acts have been reviewed [6]and these results are available at the site of theNational Center for Complementary and Alternativemedicine (NCCAM) [7]. A Question and Answer pageon “How might acupuncture work?” is also availa-ble on the website of the NCCAM at the NationalInstitutes of Health where it states: “It is proposedthat acupuncture produces its effects through reg-ulating the nervous system, thus aiding the activ-ity of pain killing biochemicals such as endorphinsand immune system cells at specific sites in the body.In addition, studies have shown that acupuncturemay alter brain chemistry by changing the releaseof neurotransmitters and neurohormones and, thus,affecting the parts of the central nervous systemrelated to sensation and involuntary body functions,such as immune reactions and processes that regu-late a person’s blood pressure, blood flow and bodytemperature.”The results obtained from human and animalstudies have also shown that acupuncture enhancesthe generation of nitric oxide (NO) and increaseslocal circulation [8]. Kim et al demonstrated thatemploying acupuncture on stomach 36 point (ST-36) is able to reduce blood pressure by activatingNO signaling mechanisms [9]. Ma showed that NOcontent and NO synthase (NOS) expression were con-sistently higher at skin acupuncture points/meridians[10]. Chen et al showed that L-arginine-derived NOsynthesis appears to mediate the noradrenergicfunction of skin sympathetic nerve activation andthat this contributes to skin electrical resistanceof the acupuncture points and meridians [11].NO is known to exert an effect on a number of functions including the regulation of blood pressure,contributing to the immune response, the controlof neurotransmission and participation in cell dif-ferentiation and other physiological functions [12].NO, a diffusible signaling gas, is synthesized by threeNOS isoforms, namely a neuronal NOS (nNOS), aninducible NOS (iNOS) [13] and an endothelial NOS(eNOS) [14,15]. Using BH4 (tetrahydrobiopterin),Ca
-calmodulin, Heme, flavin adenine dinucleotide,riboflavin monophosphate and NADPH [16] as co-factors and coupled with electron transfer, theseenzymes are able to convert L-arginine to L-citrulineand NO.Chinese acupuncture theory maintains that thereare twelve main meridians or energy channels thatrelate to the internal organs. These include thelungs, large intestine, stomach, spleen, heart, thepericardium (the sac around the heart), etc. Elec-troacupuncture (EA) prevents the reduction of NOproduction from eNOS and nNOS associated withhypertension and has been shown to even increaseeNOS and nNOS expression in stomach and cheekpouch tissue (which are also part of the stomachmeridian) compared with a sham control. This ef-fect was found not to occur on liver tissue, a non-stomach-meridian organ [9]. A question arises fromthe results of this study and this is how to explainthe phenomena whereby EA was able to prevent thereduction of NO production from eNOS and nNOSassociated with hypertension in a stomach-meridianorgan but did not affect a non-stomach-meridianorgan. Our hypothesis involves a neurovascular trans-mission model. Briefly, the acupuncture stimulus isable to induce a burst of NO production throughmechanotransduction at the local acupuncture pointand this NO diffuses and changes the blood floweither at the local and/or organ microcirculationlevel. The result of acupuncture is differential pro-duction of NO in various meridian organs, whichare connected via tissue/cells coupled to the cycli-cally strained blood vessel; this is able to changethe frequency of resonance.
2. A Neurovascular Transmission Modelof Acupuncture
In the vascular wall, most of the bioavailable NOis believed to be derived from eNOS and diffusesinto vascular smooth muscle and the blood stream,where it rapidly reacts with the hemoglobin (Hb)of the red blood cells. Hb, of course, is also ableto transport oxygen and carbon dioxide. The blood
44 S.H. Hsiao, L.J. Tsaicarries the oxygen complexed with Hb to all partsof the body where it is required for metabolismand also returns carrying carbon dioxide back tothe lungs, where gaseous exchange occurs withthe atmosphere. The peripheral chemoreceptorslocated in the carotid bodies respond primarily tohypoxemia. Central chemoreceptors located in theregion of the brainstem respond to hypercapnia.Activation of either the hypoxic or hypercapnicchemoreflex elicits both hyperventilation and sym-pathetic activation [17]. There is evidence fromanimal and human studies that NO may play a role inhypercapnia induced vasodilation [18,19]. Recently,nNOS has been identified as a source of NO in thevicinity of microvessels and has been shown toparticipate in vascular function. Thus, NO can beproduced and transported to the vascular smoothmuscle cells from endothelial cells and perivascularnerve fibers, mast cells and other NOS-containingsources [20].In Chinese terms, “acupuncture is a healing artof inserting a needle into an acupuncture point in themeridian to correct an imbalance of Qi. The aim of acupuncture is to stimulate the flow of Qi throughthat meridian.” To explain the meridian pheno-menon, we proposed a neurovascular transmissionmodel for acupuncture induced NO.
2.1. Acupuncture inducedmechanotransduction
Immediately after a needle is inserted into connec-tive tissue, the mechanical force is transferred tothe extracellular matrix (ECM). The ECM is a multi-component tissue that is able to transduce internaland external mechanical signals into changes inthe tissue structure and function through a processtermed mechanochemical transduction [21,22].
2.2. Mechanical force is able to changeNO production, the blood vessels’local circulation and skin sympatheticnerve activation
Through the ECM, the mechanical force stimuluscan travel across the acupuncture point into thelocal tissue cells. The local tissue cells includingarterioles, nerve terminals and mast cells can stim-ulate vascular nerve fibers; this will trigger nNOSand eNOS induced NO production [10]. Other tis-sues that may be involved include smooth musclecells and endothelium cells; this is because theacupuncture is able to produce NO and this in-creases the blood flow, which change the local cir-culation [8,23]. Thus, mechanotransduction is ableto trigger these cells to produce a burst of NO pro-duction, which diffuses into the vascular smoothmuscle and change blood flow and local circulation.L-arginine-derived NO synthesis appears to medi-ate the noradrenergic function that is part of skinsympathetic nerve activation and this contributesto the skin electrical resistance at acupuncturepoints and meridians [11].
2.3. The mechanical force of the needlecoupled with cyclic strain of bloodvessels changes the hemodynamicbalance of the artery tree
Blood vessels are permanently subjected to mechan-ical forces in the form of stretching, which includecyclic mechanical strain. When acupunctured at aspecific acupuncture point, the local mechanicalstress produced is coupled with a cyclic strain of the blood vessel and this may change the resonancefrequency.According to the resonance theory [24], a merid-ian can be classified according to its effects on thepulse spectrum and all meridian related effects,including those caused by acupuncture, are fre-quency specific. Therefore, the artery tree wouldchange the blood distribution and microcirculationof various organs and further affect the productionof NO by eNOS.
2.4. An oscillatory pattern of NO formationin a specific organ
For both agonist and hemodynamic stimuli, an oscil-latory pattern of NO formation might occur with aburst of duration of a few seconds and a stimuli-dependent frequency in the order of tens of secondsto a few minutes [25]. Thus, by changing the hemo-dynamic state of the organ, an oscillatory patternof NO formation might be created at a particularfrequency in a specific organ [26]. In such a case,the frequency in the stomach ought to be differentto that of the liver and therefore the NO productionwill also be different.
3. Evaluation of the NeurovascularTransmission Model of Acupuncture
Over the past 30 years, studies aimed at understand-ing the acupuncture point/meridian system havemainly looked for distinct histological features thatmight differentiate acupuncture points from thesurrounding tissue. Several structures, such as neu-rovascular bundles [27
29], neuromuscular attach-ments [30
32] and various types of sensory nerveendings [33,34], have been described at acupuncturepoints.

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