Animal Models for the Study of Autonomic Cardiovascular Control. Scott Alan Smith, PhD

Transcription

1 Animal Models for the Study of Autonomic Cardiovascular Control Scott Alan Smith, PhD

2 *

3 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

4 AUTONOMIC CONTROL OF CARDIOVASCULAR FUNCTION

5 Camilla Martin Christian Eriksen Eskild Ebbesen Thomas Bjorn

6 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

7 example

8 mm Hg The Pressor Response to Static Exercise is Exaggerated in Hypertensive Patients Isometric Handgrip (30% MVC) * NT (119/79) HT (162/112) * 20 0 D SBP D DBP Kazatani et al. Am J Ther 2: , 1995

9 Risks Associated with Abnormal Blood Pressure Control During Exercise in Hypertension Stroke Arrhythmia Acute Myocardial Infarction Cardiac Arrest

10 Question What could be causing these abnormally exaggerated blood pressure responses to exercise in hypertension?

11 Neural Control of the Cardiovascular System During Exercise

12 Question Is the exercise pressor reflex responsible for the abnormal blood pressure response to exercise in hypertension?

13 Tension (Kg) MAP (mmhg) HR (beats min -1 ) ABP (mmhg) 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: , 2001

14 The Exercise Pressor Reflex is Overactive in Hypertension D MAP (mm Hg) WKY SHR * D MAP (mmhg) WKY (r=0.65) SHR (r=0.70) 0 10 D HR (beats min -1 ) D Tension (kg) * D MAP (mmhg) Percent Maximal Tension (%) 50 WKY SHR * * 0.0 Smith et al. J Physiol 577: , Percent Maximal Tension (%)

15 Question Which component of the exercise pressor reflex mediates its overactivity in hypertension?

16 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

17 D HR (beats min -1 ) D MAP (mmhg) The Cardiovascular Response to Activation of Mechanically Sensitive Muscle Afferent Fibers is Enhanced in Hypertensive Rats WKY SHR * * Percent Maximal Tension (%) * * 5 Leal et al. Am J Physiol 295: H1429-H1438, Percent Maximal Tension (%)

18 The Pressor Response to Ischemic Muscle Contraction is Potentiated in Hypertensive Rats D MAP (mmhg) A Free WKY Occlusion SHR B 0 20 C Time (s) WKY Time (s) SHR D WKY SHR D RSNA (%) D MAP (mmhg) Free Occlusion 20 0 Free Occlusion Free Occlusion 50 D RSNA (%) 100 Mizuno et al. J Physiol 589: ,

19 Question By what mechanism does the exercise pressor reflex drive the abnormal blood pressure response to exercise in hypertension?

20 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

21 Exercise Pressor Reflex Mediated Changes in SNA are Enhanced in Hypertension Mizuno et al. Am J Physiol 300: H968-H977, 2011

22 Question What causes the enhanced sympathetic response to activation of the exercise pressor reflex?

23 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

24 Muscle Mechanoreceptors Mediate EPR Dysfunction in Hypertension Mizuno et al. Am J Physiol 300: H968-H977, 2011

25 Mizuno et al. J Physiol 589: , 2011 The TRPv1 Receptor Mediates Exercise Pressor Reflex Dysfunction In Hypertension

26 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

27 NO buffers the EPR IML Spinal Cord Sympathetic Efferents Cardiac Muscle Vascular Smooth Muscle

28 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 ) 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: , 2012 * *

29 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 * * * 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: , 2013

30 Question What mediates a decrease in NO production and/or availability within the NTS in hypertension?

31 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

32 Expression of Brainstem Proteins that Modify EPR Function Are Decreased in Hypertension Murphy et al. Am J Physiol, 304: H1547-H1557, 2013

33 Derived Targets for Treatment from Rat Model 1. The EPR Sympathetic Overactivity Mechanoreceptors Metaboreceptors Nitric Oxide / NOS within the Brain Stem

34 Application in Multiple Rat Models of Hypertension

35

36 Application

37 Thank you!!!

38

39 Question What about central command and the arterial baroreflex?

40 Neural Control of the Cardiovascular System During Exercise

41 MLR Stimulation Elicits Exaggerated Increases in BP & SNA in Hypertension * Liang et al. Am J Physiol, 310: H123-H131, 2016

42 Neural Control of the Cardiovascular System During Exercise

43 Effects of Baro-Denervation on the CV Response to Exercise in Hypertension DMAP / D Tension (mm Hg kg -1 ) Muscle Contraction * * * 0 30 * D HR / D Tension (beats min -1 kg -1 ) * 0 WKY (Intact) WKY (SAD) SHR (Intact) SHR (SAD) Smith et al. J Physiol 577: , 2006