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Autonomic Nervous System and Hemodynamics

Autonomic Nervous System and Hemodynamics. dr shabeel pn. Enteric. Voluntary. Autonomic. Two or “Three” Subdivisions of the Nervous System. ?. Innervates. skeletal muscle. smooth muscle cardiac muscle secretory glands. intestine controls intestinal motility secretion

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Autonomic Nervous System and Hemodynamics

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  1. Autonomic Nervous System and Hemodynamics dr shabeel pn

  2. Enteric Voluntary Autonomic Two or “Three” Subdivisions of the Nervous System ? Innervates skeletal muscle smooth muscle cardiac muscle secretory glands intestine controls intestinal motility secretion absorption Neurotransmitter ACh norepinephrine ACh neuropeptides norepinephrine ACh serotonin neuropeptides Receptors nicotinic muscle AChR adrenergic GPCRs muscarinic ACh GPCRs nicotinic neuronal AChR GPCRs

  3. visceral effectors Somatic motor system Autonomic motor system smooth muscle central nervous system central nervous system autonomic ganglion gland cells preganglionic fiber postganglionic fiber cardiac muscle dorsal ventral Synaptic Connectivity – Voluntary vs Autonomic Nerves somatic motor neuron skeletal muscle Principles of Neural Science, 3rd Ed. Kandel et al., p. 762

  4. Synaptic Transmission in Autonomic Ganglia Preganglionic neurons release acetylcholine Postganglionic Cell Receptors 1) Neuronal nicotinic acetylcholine receptors different pharmacology from muscle nAChR different subunit composition 2 : 3  cation-selective channel 2) Muscarinic (GPCR) receptors http://www.pasteur.fr/recherche/banques/ LGIC/cys-loop.html

  5. Sympathetic Parasympathetic Subdivisions of the Autonomic Nervous System Primary Neurotransmitter

  6. Focus on this synapse autonomic ganglion Cell body in spinal cord

  7. Sympathetic Parasympathetic Subdivisions of the Autonomic Nervous System Primary Neurotransmitter norepinephrine epinephrine (~20%) acetylcholine Receptors & Second Messenger Systems Adrenergic GPCRs 1 – IP3/DAG, [Ca2+]i PKC 2 - cAMP/PKA 1 - cAMP/PKA 2 - cAMP/PKA 3 - cAMP/PKA Muscarinic GPCRs M1 – IP3/DAG, [Ca2+]i PKC M2 – cAMP/PKA, PI(3)K M3 – cAMP/PKA, IP3/DAG, [Ca2+]i PKC M4 – M5 – IP3/DAG, [Ca2+]i PKC Adrenal Medulla (epi:norepi::80:20)

  8. G-Protein Coupled Receptors Rockman et al., (2002) Nature 415:206-212

  9. Nicotinic Muscarinic Fast EPSP ACh 20 msec Slow EPSP 10 sec Peptidergic EPSP 1 min Peptidergic Time Course of Post-Synaptic Potentials nicotinic AChR muscarinic GPCR peptidergic GPCR Principles of Neural Science, 3rd Ed. Kandel et al., p. 768

  10. 4 parts of the brain • Forebrain • Midbrain • Hindbrain • Spinal cord cervical thoracic spinal cord lumbar sacral A Brief Digression on Parts of the Brain Berne and Levy, Physiology 3rd Ed. p. 94-95

  11. A Brief Digression on Parts of the Brain – Part 2 Berne and Levy, Physiology 3rd Ed. p. 96

  12. Sympathetic Parasympathetic brainstem cranial nerves thoracic lumbar sacral Principles of Neural Science, 3rd Ed. Kandel et al., p. 763

  13. Opposing Effects of Sympathetic and Parasympathetic Stimulation on Heart Rate Principles of Neural Science, 3rd Ed. Kandel et al., p. 772

  14. Summary of Effector Organ Responses to Autonomic Stimulation Part I Be sure to memorize all entries in this table Goodman and Gilman’s The Pharmacological Basis of Therapeutics 9th Ed. p. 110-111

  15. Summary of Effector Organ Responses to Autonomic Stimulation Part II This part of the table you do not need to memorize Goodman and Gilman’s The Pharmacological Basis of Therapeutics 9th Ed. p. 110-111

  16. Hemodynamics or Why Blood Flows and What Determines How Much Laminar vs Turbulent Flow Relation of Pressure, Flow and Resistance Determinants of Resistance Regulation of Blood Flow Role of Large Vessel Elasticity in Maintaining Continuous Flow Determinants of Blood Pressure Why do atherosclerotic blockages reduce blood flow? How does blood pressure change as it moves through a resistance vessel?

  17. Laminar vs Turbulent Flow Berne and Levy, Physiology 3rd Ed. p. 447

  18. Difference Between Flow and Velocity Flow is a measure of volume per unit time Velocity is a measure of distance per second along the axis of movement r = 4 Velocity = Flow/Cross sectional area r = 2 r = 1 Flow velocity 100 ml/sec 100 ml/s radius (cm) 1 2 4 area (cm2) (r2) 3.14 12.56 50.24 flow (cm3/sec) 100 100 100 fluid velocity (cm/sec) 32 8 2 Note: This assumes constant flow

  19. r = 4 r = 2 r = 1 velocity Flow 100 ml/sec 100 ml/s Pressure P(r = 4) > P(r = 2) > P(r = 1) ASSUMES CONSTANT FLOW Relationship Between Velocity and Pressure Pressure is a form of potential energy. Differences in pressure are the driving force for fluid movement. Kinetic energy is proportional to (velocity)2 If we ignore turbulence and friction, total energy (Potential + Kinetic) of the fluid is conserved and so as velocity increases, pressure decreases

  20. Change in Pressure Flow = Resistance P Q = R Relationship Between Pressure, Flow and Resistance P = QR Change in Pressure = Flow x Resistance V or V = IR Similar to Ohm’s Law I = for electricity R

  21. P1 P2 resistance Fluid flow Resistance to Fluid Flow The preceding discussion ignored resistance to flow in order to focus on some basic concepts. Resistance is important in the Circulatory System. As fluid passes through a resistance pressure drops. A resistance dissipates energy, so as the fluid works its way through the resistance it must give up energy. It gives up potential energy in the form of a drop in pressure. P1 > P2 P = QR Pressure distance

  22. Origin of Resistance in Laminar Flow resistance arises due to 1) interactions between the moving fluid and the stationary tube wall 2) interactions between molecules in the fluid (viscosity) West, Physiological Basis of Medical Practice 11rd Ed. p. 133

  23. P  r4 (P) = Q = 8  l R Determinants of Resistance in Laminar Flow – Poiseuille’s Law } 8  l r R = Q  r4 l length viscosity radius •  = 3.14159 as always • l = tube length • = fluid viscosity r = tube radius

  24. % decrease in flow % decrease in radius r (10 - r/10)*100 Q/X [1 - (Q/Qr=10)]*100 10 0% 10,000 0% 9 10% 6,561 35% 5 50% 625 94% 1 90% 1 99.99% (P) X = 8  l Some Implications of Poiseuille’s Law ( ) (P) P  r4 r4 (P) = = Q = 8  l 8  l R If P is constant, flow is very sensitive to tube radius

  25. Path of Blood Flow in the Circulatory System Heart (left ventricle) aorta arteries arterioles capillaries venules veins vena cava Heart (right atrium)

  26. Blood Vessel Diameter and Blood Velocity West, Physiological Basis of Medical Practice 11th Ed. p. 120

  27. A Brief Digression on the Cardiac Pump Cycle Each pump cycle is subdivided into two times 1) Diastole – filling, no forward pumping (~2/3) 2) Systole – forward pumping (~1/3) Blood Pressure (mm Hg) = systolic / diastolic normal BP ??? 120/80 mmHg Hypertension > 140/90 mm Hg Arterial Blood Pressure pressure (mm Hg) Berne and Levy, Physiology 3rd Ed. p. 457

  28. Converting Intermittent Pumping to Continuous Flow The heart is the pump that keeps the fluid circulating. The heart is a pulsatile, intermittent pump. During each pump cycle blood flows out of the heart for only 1/3 of the time. THE PROBLEM: To maintain continuous flow during diastole. THE SOLUTION: Large elastic arteries distend during systole to absorb ejected volume pulse relax during diastole maintaining arterial pressure and flow to the periphery volume ejected large elastic arteries distend aortic valve closes blood flows into periphery under pressure created by elastic recoil of arteries while the heart fills during diastole Berne and Levy, Physiology 3rd Ed. p. 457

  29. What Can the Body Regulate to Alter Blood Flow and Specific Tissue Perfusion? 8  l R = r4 P  r4 (P) = Q = 8  l R P = Mean Arterial Pressure – Mean Venous Pressure P, not subject to significant short term regulation R = Resistance 8, , l,  are not subject to significant regulation by body r4 can be regulated especially in arterioles, resistance vessels

  30. Arterioles are Heavily Innervated Radius Controlled by Autonomic Nervous System and Local Factors In most arterial beds sympathetic stimulation > norepinephrine release > vasoconstriction of arterioles “fight or flight” reflex Blood flow redirected from internal organs to large skeletal muscle groups. Vasoconstriction stimulation of  adrenergic receptors >  [Ca2+]i in vascular smooth muscle cells In some arterial beds parasympathetic stimulation > acetylcholine release muscarinic receptors causes vasodilation of arterioles

  31. -Adrenergic Receptor Signal Transduction Pathways Katzung, Basic and Clinical Pharmacology, 2001, p. 123

  32. Autonomic Nervous System Regulates Distribution of Blood Volumes in Different Parts of the Vascular System West, Physiological Basis of Medical Practice 11th Ed. p. 121

  33. Vaso-Vagal Episodes – Neural Control Lying down > stand up quickly > briefly feel lightheaded Failure of the venoconstrictor system to respond in a timely fashion. To prevent blood pooling in large veins must constrict veins on standing or the rise in hydrostatic pressure will cause veno-dilation and thus blood pooling in the large veins of the legs and abdomen. This pooling reduces venous return to the heart. This in turn reduces forward cardiac output and reduces arterial blood pressure and perfusion of the brain. Thus, the feeling of lightheadedness.

  34. Intracellular Ca++ Stores Ca++ Membrane Bound Guanylate Cyclase C.M. Ca++ NO GTP Ca++ Soluble Guanylate Cyclase NO NO Synthetase + Citrulline GTP PDE GMP cGMP Arginine Ion Channels cGMP-Dependent PK PDEase Activity Local Factors in the Control of Arteriolar Resistance endothelial derived relaxing factor (EDRF) – nitric oxide (NO) endothelin bradykinin angiotensin II vasopressin, ADH atrial naturetic peptide adenosine

  35. Other Local Factors in the Control of Arteriolar Resistance hypoxia arteriolar vasodilation increased tissue perfusion

  36. Determinants of Arterial Blood Pressure and Flow 1) Heart – Cardiac Output 2) Vascular Resistance 3) Vascular Volume (Capacitance) 4) Blood Volume

  37. Factor #1: Heart – Cardiac Output Blood Pressure = (Blood Flow)*(Total Peripheral Resistance) BP = Q * TPR Determinants of Blood Flow (Cardiac Output) cardiac output = (heart rate) x (stroke volume) Determinants of Stroke Volume venous return and venous blood pressure (preload) duration of diastole (heart rate) ventricular wall relaxation during diastole arterial blood pressure (afterload)

  38. Factor #2: Determinants of Vascular Resistance Arterial blood pressure – systole vs diastole Perfusion pressure largely determined by arterial blood pressure Major site of pressure drop is in arterioles West, Physiological Basis of Medical Practice 11th Ed. p. 120

  39. Fractional Drop in Pressure Total Peripheral Resistance = Rartery + Rarteriole + Rcapillary + Rvenule + Rvein Drop in Pressure in the arterioles = P*(Rarterioles/TPR) P = mean arterial pressure – mean venous pressure

  40. Factor #3: Vascular Volume - Capacitance CNS control arterial volume by regulating vessel diameter venous volume by regulating vessel diameter ratio of arterial to venous volume Examples vaso-vagal episodes shock – peripheral vasodilation drops pressure Factor #4: Determinants of Blood Volume Kidney Function in Lectures Coming on Wed. Nov. 3

  41. Mechanism of Smooth Muscle Contraction • The Contractile Event of Smooth Muscle • A scheme for smooth muscle contraction is shown on next slide. Contraction is initiated • by the increase of Ca2+ in the myoplasm; this happens in the following ways: • Ca2+ may enter from the extracellular fluid through channels in the plasmalemma. • These channels open, when the muscle is electrically stimulated depolarizing the • plasmalemma. • 2. Due to agonist induced receptor activation, Ca2+ may be released from the • sarcoplasmic reticulum (SR). In this pathway, the activated receptor interacts with • a G-protein (G) which in turn activates phospholipase C (PLC). The activated PLC • hydrolyzes phosphatidyl inositol bisphosphate; one product of the hydrolysis is • inositol 1,4,5-trisphosphate (IP3). IP3 binds to its receptor on the surface of SR, • this opens Ca2+ channels and Ca2+ from SR is entering the myoplasm. • 3. Ca2+ combines with calmodulin (CaM) and the Ca2+ -CaM complex activates • myosin light chain kinase (MLCK), which in turn phosphorylates myosin LC. The • phosphorylated myosin filament combines with the actin filament and the • muscle contracts. http://www.uic.edu/classes/phyb/phyb516/smoothmuscleu3.htm#contractile http://www.uic.edu/classes/phyb/phyb516/

  42. A Simplified View of Smooth Muscle Contraction GPCR heterotrimeric G-protein phospholipase C SR myosin myosin light chain actin CaM = Calmodulin MLCK = myosin light chain kinase IP3 = inositol trisphosphate Bárány, K. and Bárány, M. (1996). Myosin light chains. InBiochemistry of Smooth Muscle Contraction (M. Bárány , Ed.), pp. 21-35, Academic Press.

  43. Smooth Muscle Contraction: A More Complicated View http://www.neuro.wustl.edu/neuromuscular/pathol/diagrams/smmusccont.htm

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