ANS and Hemodynamics Lecture 2004

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Information about ANS and Hemodynamics Lecture 2004

Published on October 30, 2008

Author: aSGuest2193


Slide 1: Autonomic Nervous System and Hemodynamics Myles Akabas Dept. of Physiology & Biophysics and Neuroscience Slide 2: 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 ? Slide 3: Principles of Neural Science, 3rd Ed. Kandel et al., p. 762 Synaptic Connectivity – Voluntary vs Autonomic Nerves skeletal muscle somatic motor neuron Slide 4: Synaptic Transmission in Autonomic Ganglia Preganglionic neurons release acetylcholine LGIC/cys-loop.html 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 Slide 5: Subdivisions of the Autonomic Nervous System Primary Neurotransmitter Slide 6: Cell body in spinal cord autonomic ganglion Focus on this synapse Slide 7: 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) Slide 8: Rockman et al., (2002) Nature 415:206-212 G-Protein Coupled Receptors Slide 9: Principles of Neural Science, 3rd Ed. Kandel et al., p. 768 Time Course of Post-Synaptic Potentials nicotinic AChR muscarinic GPCR peptidergic GPCR Slide 10: A Brief Digression on Parts of the Brain Berne and Levy, Physiology 3rd Ed. p. 94-95 Slide 11: Berne and Levy, Physiology 3rd Ed. p. 96 A Brief Digression on Parts of the Brain – Part 2 Slide 12: Principles of Neural Science, 3rd Ed. Kandel et al., p. 763 Sympathetic Parasympathetic thoracic lumbar sacral brainstem cranial nerves Slide 13: Principles of Neural Science, 3rd Ed. Kandel et al., p. 772 Opposing Effects of Sympathetic and Parasympathetic Stimulation on Heart Rate Slide 14: Goodman and Gilman’s The Pharmacological Basis of Therapeutics 9th Ed. p. 110-111 Summary of Effector Organ Responses to Autonomic Stimulation Part I Be sure to memorize all entries in this table Slide 15: Goodman and Gilman’s The Pharmacological Basis of Therapeutics 9th Ed. p. 110-111 Summary of Effector Organ Responses to Autonomic Stimulation Part II This part of the table you do not need to memorize Slide 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? Slide 17: Laminar vs Turbulent Flow Berne and Levy, Physiology 3rd Ed. p. 447 Slide 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 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 2 100 ml/sec 100 ml/s Velocity = Flow/Cross sectional area Note: This assumes constant flow r = 1 r = 2 r = 4 velocity Flow Slide 19: 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 Slide 20: Relationship Between Pressure, Flow and Resistance Similar to Ohm’s Law I = for electricity V R or V = IR P = QR Change in Pressure = Flow x Resistance Slide 21: 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 Pressure distance P = QR Slide 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 Slide 23: } r l length viscosity radius Q Determinants of Resistance in Laminar Flow – Poiseuille’s Law R = 8  l  r4  = 3.14159 as always l = tube length = fluid viscosity r = tube radius Slide 24: Some Implications of Poiseuille’s Law If P is constant, flow is very sensitive to tube radius 8  l  r4 (P) = Q = P R = 8  l (P) r4 ( ) Slide 25: Path of Blood Flow in the Circulatory System Heart (left ventricle) aorta arteries arterioles capillaries venules veins vena cava Heart (right atrium) Slide 26: West, Physiological Basis of Medical Practice 11th Ed. p. 120 Blood Vessel Diameter and Blood Velocity Slide 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 Berne and Levy, Physiology 3rd Ed. p. 457 pressure (mm Hg) Arterial Blood Pressure Slide 28: 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. Converting Intermittent Pumping to Continuous Flow 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 Slide 29: What Can the Body Regulate to Alter Blood Flow and Specific Tissue Perfusion? 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 Slide 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 Slide 31: Katzung, Basic and Clinical Pharmacology, 2001, p. 123 -Adrenergic Receptor Signal Transduction Pathways Slide 32: West, Physiological Basis of Medical Practice 11th Ed. p. 121 Autonomic Nervous System Regulates Distribution of Blood Volumes in Different Parts of the Vascular System Slide 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. Slide 34: 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 Slide 35: hypoxia Other Local Factors in the Control of Arteriolar Resistance arteriolar vasodilation increased tissue perfusion Slide 36: Determinants of Arterial Blood Pressure and Flow 1) Heart – Cardiac Output 2) Vascular Resistance 3) Vascular Volume (Capacitance) 4) Blood Volume Slide 37: Factor #1: Heart – Cardiac Output Blood Pressure = (Blood Flow)*(Total Peripheral Resistance) BP = Q * TPR venous return and venous blood pressure (preload) duration of diastole (heart rate) ventricular wall relaxation during diastole arterial blood pressure (afterload) Determinants of Blood Flow (Cardiac Output) cardiac output = (heart rate) x (stroke volume) Determinants of Stroke Volume Slide 38: West, Physiological Basis of Medical Practice 11th Ed. p. 120 Arterial blood pressure – systole vs diastole Perfusion pressure largely determined by arterial blood pressure Major site of pressure drop is in arterioles Factor #2: Determinants of Vascular Resistance Slide 39: Fractional Drop in Pressure Total Peripheral Resistance = Rartery + Rarteriole + Rcapillary + Rvenule + Rvein P = mean arterial pressure – mean venous pressure Drop in Pressure in the arterioles = P*(Rarterioles/TPR) Slide 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 Slide 43: 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. Mechanism of Smooth Muscle Contraction Slide 44: Bárány, K. and Bárány, M. (1996). Myosin light chains. In Biochemistry of Smooth Muscle Contraction (M. Bárány , Ed.), pp. 21-35, Academic Press. CaM = Calmodulin MLCK = myosin light chain kinase IP3 = inositol trisphosphate A Simplified View of Smooth Muscle Contraction Slide 45: Smooth Muscle Contraction: A More Complicated View

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