The Role of Massage in Blood Circulation, Pain Relief, and the Recovery Process: Implications of Existing Research I. Basic Physiology of Circulation A. The Vascular Endothelium The endothelium is a complex structure that plays a critical role in regulating vascular wall homeostasis Under normal physiologic conditions, the endothelium modulates vascular smooth muscle tone by secreting a variety of bioactive substances that: o Prevent atherosclerosis (plaque buildup) through anti- proliferative and anticoagulant effects on the vascular wall o Control inflammation by preventing leukocyte activation and adhesion o Maintain oxidative/anti- oxidative balance within the vasculature B. Vascular Structure and the Endothelium The endothelium is composed of a monolayer of endothelial cells that form the inner lining of the vasculature The endothelium is constantly exposed to hemodynamic forces (i.e. hydrostatic pressure, cyclic stretch, and fluid shear stress) induced by both blood pressure and blood flow Increased arterial blood flow (a type of fluid shear stress) stimulates the endothelium to release paracrine substances that mediate vasodilation (widening of blood vessels) through a process called endothelium- dependent vasodilation (EDV) C. Vasodilator and Vasoconstrictor Functions In the context of flow- induced shear stress, the endothelium modulates EDV in addition to vasoconstriction (narrowing) of vessels depending on where increased blood supply is needed. For example: o In a rested state, approximately 20% of the body s cardiac output is directed to the maintenance of skeletal muscle blood flow o During strenuous whole body exercise (i.e. cross- country skiing and running) the cardiac output directed to the skeletal muscles approaches the 80% mark Paradoxical vasoconstriction in response to shear stress and other vasodilator stimuli is a common occurrence in the presence of certain diseases (i.e. cardiovascular disease, high blood pressure, cancer, etc.) D. Nitric Oxide and the Endothelium Nitric oxide (NO) is a chief vasodilator released by the endothelium NO plays a critical role in EDV in response to either shear stress or agonist stimulation (i.e. acetylcholine) Impairment of NO- mediated vasodilation can lead to adverse alterations in blood flow Mechanism of NO- Mediated Vasodilation
Role of Massage in Blood Circulation, Pain Relief, and the Recovery Process Page 2 o Endothelium- derived NO is formed from the guanidine- nitrogen terminal of L- arginine through the action of the enzyme endothelial nitric oxide synthase (enos) upon activation by receptor- dependent agonists (i.e. acetylcholine) or receptor- independent stimuli (i.e. fluid shear stress) o In the context of blood flow- induced shear stress, elevated cytosolic calcium (Ca 2+ ) triggers activation of enos to catalyze the conversion of L- arginine to L- citrulline and NO, with tetrahydrobioterin (BH 4 ) and nicotinamide adenine dinucleotide phosphate (NADPH) as essential cofactors o Once NO is released from the endothelium, it diffuses through the vascular wall and into adjacent smooth muscle cells, where it signals the soluble enzyme guanylate cyclase (sgc) to produce cyclic guanosine monophosphate (cgmp), the second messenger of NO o This signaling cascade ultimately causes smooth muscle cells to relax which results in EDV E. Ultrasonic Determination of Vascular Function Ultrasound assessment of flow- mediated dilation (FMD) serves as a valuable index of EDV and peripheral vascular function High resolution ultrasound is used to evaluate reactivity in peripheral vascular beds at baseline (rest), during reactive hyperemia produced by a brief blood flow occlusion, and during endothelium- independent vasodilation (EIV), typically induced by nitroglycerin (NTG) stimulation of vascular smooth muscle cells The brachial artery is among the most common vessels assessed in response to blood flow occlusion of the forearm during which the percentage increase in diameter is measured and reported 1 Brachial artery FMD is considered both a valid and reliable assessment of NO- mediated EDV with related studies spanning over the course of more than two decades 2-7 II. Vascular Responses to Acute Exertion A. Acute Exertion and Vascular Function Blood flow- related shear stress is a major stimulus to NO release from the endothelium Shear stress induced by acute exertion can also impair vascular function (also referred to as vascular dysfunction/vd) resultant from: o Decreased production of NO o Increased scavenging of NO Acute exertion inherently enhances reactive oxygen species (ROS) production, which can lead to reduced NO bioavailability o A state known as Oxidative Stress
Role of Massage in Blood Circulation, Pain Relief, and the Recovery Process Page 3 Oxidative stress tends to be most pronounced in the presence of unaccustomed strenuous exertion Note: Endothelial cells can adapt to chronic shear stresses (i.e. repeated bouts of exertion) B. Vascular Dysfunction and Oxidative Stress Oxidative stress can result from increased ROS production, impairment of antioxidant defenses, or both Reactive oxygen species are natural by- products of cellular metabolism o At normal physiologic levels ROS have an important role in cellular signaling o When produced in excess ROS can have detrimental effects on cell function Interactions between NO and ROS o Superoxide (O 2 - ), a specific type of ROS, mediates oxidative stress and VD by reducing NO bioavailability o Excess generation of O 2 - can overwhelm the antioxidant capacity of vascular cells leading to increased scavenging of NO and production of the potent oxidant peroxynitrite (ONOO - ) ultimately creating a state of oxidative stress o Increased OONO - can further decrease NO bioavailability by reducing the function of tetrahydrobiopterin (BH 4 ), the critical cofactor for enos o Reduced BH 4 changes the mission of enos from NO production to biosynthesis of ROS which further enhances oxidative stress o Collectively these interactions between NO and ROS can lead to reduced stimulation of soluble guanylate cyclase (sgc) signaling, and consequently, impaired vasodilation C. Exertion- Induced Muscle Injury (EMI): A Potential Culprit EMI most commonly results from muscle damage following unaccustomed and/or strenuous exercise involving high force and/or repetitive eccentric contractions (i.e. resistance training, cycling, and downhill running) Current findings suggest that EMI results primarily from structural muscle damage and subsequent biochemical changes within muscle fibers that trigger acute inflammation Proposed Mechanism of Impaired Vascular Function after EMI o Eccentric exercise- induced muscle damage inherently attracts leukocytes (neutrophils and macrophages) to the site of injury leading to their activation and adhesion to vascular endothelial cells o Collectively, these leukocytes initiate the degradation of damaged muscle tissue by releasing ROS with concomitant production of pro- inflammatory cytokines (tumor necrosis factor α [TNF- α] and interleukin- 6 [IL- 6]) o This physiologic response creates a state of oxidative stress ultimately leading to impairment of vascular function D. Massage Therapy as a Treatment for Exertion- Induced Muscle Injury Massage has been shown to reduce inflammation triggered by damaged muscle fibers in ways that:
Role of Massage in Blood Circulation, Pain Relief, and the Recovery Process Page 4 o Relieve associated pain o Speed up the recovery process When administrated after damage from acute eccentric exercise, massage therapy has specifically been shown to reduce local production of TNF- α and IL- 6 within muscle fibers 8 By influencing inflammatory signaling as well as the production and release of ROS, massage therapy may normalize vascular function thereby improving circulation and boosting recovery from EMI III. Delving into the Process of Research A. Multiple Steps of Research Develop a question or problem Make observations and research the topic of interest Formulate a hypothesis Develop and follow one or more experiments Collect and analyze the results Generate one or more conclusions that accept or reject the hypothesis Communicate the results B. Limitations of Existing Massage- Related Research Inconsistent research designs and methods o Limit experimental repeatability and relevance of research o Make it difficult to formulate any decisive conclusions o Render questionable and inconclusive results Limited randomized controlled trials (RCTs) o The absence of appropriate controls in existing studies has made it difficult to rule out the effects of chance or preference upon outcome measures within existing literature o RCTs are needed in order to compare the results of massage intervention groups with those of carefully chosen control groups Lack of standardization of treatments o Standardization of massage treatment protocols with a consistent classification system is needed in research o Allows practitioners using different styles of massage to employ various treatment protocols using the same terminology o Facilitates more standardized reporting of massage interventions used in research Invalid and/or unreliable measurement tools o Valid tools and instruments are those designed to measured what you are setting out to measure o Reliable tools are those that consistently yield the same results when used
Role of Massage in Blood Circulation, Pain Relief, and the Recovery Process Page 5 C. Structure of Research: The Hourglass Begin with broad questions Narrow down, focus and Operationalize Make observations Analyze data Reach conclusions Generalize back to questions D. Five Steps to Initiating a Research Paradigm for Massage Therapy 1. Determine a research problem/question and define a logical answer 2. Find general background information about the problem/question 3. Use a variety of information sources to find and follow research pertinent to the problem/question 4. Collect data, read, evaluate and write what you have learned as it pertains to the problem/question 5. Cite the information you have found so that others will be able to follow your research trail IV. References Cited 1. Celermajer DS, Sorensen KE, Bull C, Robinson J, Deanfield JE. Endothelium- dependent dilation in the systemic arteries of asymptomatic subjects relates to coronary risk factors and their interaction. Journal of the American College of Cardiology. 1994;24(6):1468-1474 2. Doshi SN, Naka KK, Payne N, et al. Flow- mediated dilatation following wrist and upper arm occlusion in humans: the contribution of nitric oxide. Clin Sci (Lond). 2001;101(6):629-635 3. Franklin NC, Ali M, Goslawski M, Wang E, Phillips S. Reduced Vasodilator Function Following Acute Resistance Exercise in Obese Women. Front. Physiol. 2014;5(253) 4. Franklin NC, Ali MM, Robinson AT, Norkeviciute E, Phillips SA. Massage therapy restores peripheral vascular function after exertion. Archives of physical medicine and rehabilitation. 2014;95(6):1127-1134 5. Phillips SA, Das E, Wang J, Pritchard K, Gutterman DD. Resistance and aerobic exercise protects against acute endothelial impairment induced by a single exposure to hypertension during exertion. Journal of applied physiology. 2011;110(4):1013-1020 6. Phillips SA, Hatoum OA, Gutterman DD. The mechanism of flow- induced dilation in human adipose arterioles involves hydrogen peroxide during CAD. American journal of physiology. Heart and circulatory physiology. 2007;292(1):H93-100 7. Franklin NC, Robinson AT, Bian JT, et al. Circuit Resistance Training Attenuates Acute Exertion- Induced Reductions in Arterial Function but Not Inflammation in Obese Women. Metab Syndr Relat Disord. 2015 8. Crane JD, Ogborn DI, Cupido C, et al. Massage therapy attenuates inflammatory signaling after exercise- induced muscle damage. Science translational medicine. 2012;4(119):119ra113