Animal Models for the Study of Autonomic Cardiovascular Control Scott Alan Smith, PhD
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UTSW Collaborators Mexico USA USA Jianhau Li, PhD (China) Michel Baum, MD (USA) Orson Moe, MD (China) Chou-Long Huang, MD (Taiwan) Naim Maalouf, MD (Egypt) Research Interns (USA) USA USA China USA Thailand USA USA Japan USA Richard Newcomb Jack Squiers Kate Squiers Brandon Cherry Sterling Wiedemann Lisa Varghese Sydney Kapp Will Squiers Elissa Dunlap Travis Allen Philip Brown Scott Crawford Sam Rosengarden Cooper Carnahan
AUTONOMIC CONTROL OF CARDIOVASCULAR FUNCTION
Camilla Martin Christian Eriksen Eskild Ebbesen Thomas Bjorn
Advantages of Using Animal Models Increased control of experimental conditions Enhanced isolation of system or process of interest Mechanistic studies at the cellular & molecular level available Disease models readily available and/or inducible Genetic manipulation of models available in some species
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mm Hg The Pressor Response to Static Exercise is Exaggerated in Hypertensive Patients Isometric Handgrip (30% MVC) 100 80 * NT (119/79) HT (162/112) 60 40 * 20 0 D SBP D DBP Kazatani et al. Am J Ther 2: 165-169, 1995
Risks Associated with Abnormal Blood Pressure Control During Exercise in Hypertension Stroke Arrhythmia Acute Myocardial Infarction Cardiac Arrest
Question What could be causing these abnormally exaggerated blood pressure responses to exercise in hypertension?
Neural Control of the Cardiovascular System During Exercise
Question Is the exercise pressor reflex responsible for the abnormal blood pressure response to exercise in hypertension?
Tension (Kg) MAP (mmhg) HR (beats min -1 ) ABP (mmhg) 1.5 0 110 50 200 0 425 375 30 s 1. Preferentially Activates the Exercise Pressor Reflex 2. Eliminates Central Command input 3. Option to Eliminate Baroreflex input Smith et al. J Physiol 537: 961-970, 2001
The Exercise Pressor Reflex is Overactive in Hypertension D MAP (mm Hg) 60 40 20 WKY SHR * D MAP (mmhg) 60 50 40 30 20 WKY (r=0.65) SHR (r=0.70) 0 10 D HR (beats min -1 ) D Tension (kg) 20 15 10 5 0 2.0 1.5 1.0 0.5 * D MAP (mmhg) 0 0 25 50 75 100 Percent Maximal Tension (%) 50 WKY SHR 40 30 20 10 * * 0.0 Smith et al. J Physiol 577: 1009-1020, 2006 0 1-33 34-67 68-100 Percent Maximal Tension (%)
Question Which component of the exercise pressor reflex mediates its overactivity in hypertension?
What Drives Exercise Pressor Reflex Overactivity in Hypertension?? Group III (A- fibers) Mechanically Sensitive Afferents Vagal and Sympathetic Efferents Contracting Muscle Group IV (C fibers) Metabolically Sensitive Afferents? Blood Pressure Heart Rate
D HR (beats min -1 ) D MAP (mmhg) The Cardiovascular Response to Activation of Mechanically Sensitive Muscle Afferent Fibers is Enhanced in Hypertensive Rats 60 50 40 WKY SHR * 30 20 * 10 0 1-33 34-67 68-100 Percent Maximal Tension (%) 20 15 10 * * 5 Leal et al. Am J Physiol 295: H1429-H1438, 2008 0 1-33 34-67 68-100 Percent Maximal Tension (%)
The Pressor Response to Ischemic Muscle Contraction is Potentiated in Hypertensive Rats D MAP (mmhg) A 80 60 40 20 Free WKY Occlusion SHR B 0 20 C 150 100 0 10 20 30 Time (s) WKY 0 10 20 30 Time (s) SHR D WKY SHR D RSNA (%) D MAP (mmhg) 80 60 40 Free Occlusion 20 0 Free Occlusion 200 150 Free Occlusion 50 D RSNA (%) 100 Mizuno et al. J Physiol 589: 6191-6204, 2011 0 50
Question By what mechanism does the exercise pressor reflex drive the abnormal blood pressure response to exercise in hypertension?
What Component of the Exercise Pressor Reflex Arc is Functionally Abnormal in Hypertension? Central Processing Receptors Group III (A- fibers) Contracting Muscle Afferents Mechanically Sensitive Afferents Group IV (C fibers) Metabolically Sensitive Afferents Vagal and Sympathetic Efferents End Organ Efferents Blood Pressure Heart Rate
Exercise Pressor Reflex Mediated Changes in SNA are Enhanced in Hypertension Mizuno et al. Am J Physiol 300: H968-H977, 2011
Question What causes the enhanced sympathetic response to activation of the exercise pressor reflex?
What Component of the Exercise Pressor Reflex Arc is Functionally Abnormal in Hypertension? Central Processing Receptors Group III (A- fibers) Contracting Muscle Afferents Mechanically Sensitive Afferents Group IV (C fibers) Metabolically Sensitive Afferents Vagal and Sympathetic Efferents End Organ Efferents Blood Pressure Heart Rate
Muscle Mechanoreceptors Mediate EPR Dysfunction in Hypertension Mizuno et al. Am J Physiol 300: H968-H977, 2011
Mizuno et al. J Physiol 589: 6191-6204, 2011 The TRPv1 Receptor Mediates Exercise Pressor Reflex Dysfunction In Hypertension
What Component of the Exercise Pressor Reflex Arc is Functionally Abnormal in Hypertension? Central Processing Receptors Group III (A- fibers) Contracting Muscle Afferents Mechanically Sensitive Afferents Group IV (C fibers) Metabolically Sensitive Afferents Vagal and Sympathetic Efferents End Organ Efferents Blood Pressure Heart Rate
NO buffers the EPR IML Spinal Cord Sympathetic Efferents Cardiac Muscle Vascular Smooth Muscle
Blocking the Endogenous Production of NO within the NTS Recapitulates The Exercise Pressor Reflex Overactivity Manifest in Hypertension DMAP / D Tension (mm Hg kg -1 ) 75 50 25 Muscle Stretch Contraction * * ** WKY SHR ** 0 30 acsf con L-NAME (5 mm) acsf rec ension n -1 kg -1 ) 20 Leal et al. Exp Physiol, 97: 1292-3014, 2012 * *
Increasing NO within the NTS Partially Corrects the Exaggerated CV Response to Exercise Pressor Reflex Activation in Hypertension DMAP / D Tension (mm Hg kg -1 ) Muscle Stretch 75 Stretch WKY 50 25 * * * SHR * 0 acsf con L-Arginine (1 M) D-Arginine (1 M) 75 Capsaicin (0.3 g / 100 l) Leal et al. Exp Physiol 98: 1337-1348, 2013
Question What mediates a decrease in NO production and/or availability within the NTS in hypertension?
What are the mechanisms of decreased NO production/availability within the NTS in hypertension? Angiotensin II O 2 (+) NAD(P)H Oxidase. O2 - (-) L-arginine (+) NOS NO ONOO L-citrulline
Expression of Brainstem Proteins that Modify EPR Function Are Decreased in Hypertension Murphy et al. Am J Physiol, 304: H1547-H1557, 2013
Derived Targets for Treatment from Rat Model 1. The EPR Sympathetic Overactivity Mechanoreceptors Metaboreceptors Nitric Oxide / NOS within the Brain Stem
Application in Multiple Rat Models of Hypertension
Application
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Question What about central command and the arterial baroreflex?
Neural Control of the Cardiovascular System During Exercise
MLR Stimulation Elicits Exaggerated Increases in BP & SNA in Hypertension * Liang et al. Am J Physiol, 310: H123-H131, 2016
Neural Control of the Cardiovascular System During Exercise
Effects of Baro-Denervation on the CV Response to Exercise in Hypertension DMAP / D Tension (mm Hg kg -1 ) 90 60 30 Muscle Contraction * * * 0 30 * D HR / D Tension (beats min -1 kg -1 ) 20 10 * 0 WKY (Intact) WKY (SAD) SHR (Intact) SHR (SAD) Smith et al. J Physiol 577: 1009-1020, 2006