Fundamentals of Physiology
Fundamentals of Physiology BMS 360
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2 March Lecture ObjectivesStudy Guide Understand that blood pressure is tightly regulated by multiple mechanisms Know what blood pressure range is healthy for an adult Understand the differences between central vs local control of blood pressure Understand the differences between long and short term regulation of blood pressure Be able to explain and diagram the baroreflex response and understand the structures used by this reflex for sensing comparing and altering blood pressure Regulation of Blood Pressure Blood pressure is perhaps the most tightly controlled physiological variable Normal Values human Infant 9565 mmHg Child 10065 Adult 11065 14090 Control is achieved by multiple overlapping mechanisms Too high stroke hemorrhagic damage kidney structures Too low hypotensive Central vs Local Control Mechanism Central control Cardiovascular reflex Neuronal responses Mediated by the medullary CV center Exa m ple ba roreceptor reflex Local intrinsic control Mediated by local release of neuroendocrine factors Examples Renin released by renal afferent arterioles Atrial naturitic peptide released by the heart Long vs Short Term Regulation Short term within a few heart beats Cardiovascular reflexes Long term hours to days Blood volume regulation Regulation of Blood Pressure Remember MAP C0 x R Blood pressure is controlled by regulating CO and R CO SV x HR SV stroke volume Contractility and venous return VR HR heart rate Autonomic nervous system R vascular resistance also called TPR total peripheral resistance Primarily regulated by arterial tone luminal radius Arterial Ba roreflex The baroreflex or baroreceptor reflex is a homeostatic mechanism for maintaining blood pressure at a particular set point Negative feedback loop Elevated blood pressure reflexiver causes CO and vascular resistance to decrease causing blood pressure to fall Decreased blood pressure cause CO and vascular resistance to increase causing blood pressure to rise Changes in CO and vascular resistance are mediated by the autonomic nervous system Sensors Arterial baroreceptors Located in the adventia of the carotid sinus and aortic arch Respond to distension of the receptors Mechano or stretch receptor neurons AP firing rate increases in response to elevations in Mean arterial pressure Increased pulse pressure SBP DBP Increased rate of rise in pressure Carotid sinus afferents travel in the carotid sinus nerve which joins the glossopharyngeal IX nerve Aortic baroreceptors send afferent information via the aortic nerve of the vagus X Controller The cardiovascular control center resides in the medulla of the brainstem in the nucleus of the tractussolitarious NTS l arterial pressure 9 arterial baroreceptors l firing 9 reflex via medullary cardiovascular center I parasympathetic outflow to heart J sympathetic outflow to heart arterioles veins Baroreflex acts very rapidly within 2 5 heartbeats Baroreflex regulation of blood pressure is short term If blood pressure is maintained at a chronically elevated level the baroreflex re sets to acutely regulate the pressure around a new higher setpoint 28 February Autoregulation Active hyperemia Exercise 9 increased release of metabolites decreased Oz levels lglucose O2 I lactic acid ATP W ions H ions C02 Increase in blood flow as a result through arteriolar dilation Prominent in skeletal muscle and brain Veins Most of the blood in the body is present in veins Major function regulation of cardiac output throughvenus return Veins are low resistance high compliance Compliance of veins is much greater than that of arteries Factors Influencing Venous Return Sympathetic nervous system Increased in SNS output 9 decreased compliance Skeletal muscle pump think legs Flow valves only allow flow towards heart Muscles contract vein is squeezed Driving force towards heart Respiratory pump During respiratory inspiration VR increases because of a decrease in right atrial pressure Breath in 9 diaphragm drops 9 pressure in thoracic cavity drops Capillaries Enable the exchange of water 02 C02 nutrients and waste substances between blood and surrounding tissues Lecture ObjectivesStudy Guide I39 39 Ithat 39 39 quot 39 39 f 39 is 39 Iwith quot 39 disease Know the physiological functions of the endothelium Identify the three main classes of endotheliumdependent vasodilators how each is produced and how each is thought to elicit smooth muscle cell relaxation Endothelial Cells Single cell layer lining the lumen of all blood vessels collectively called the endothelium Exposed to circulating factors Have receptors for a wide range of hormones autocrine and paracrine factors Meta bolically very active Produce a wide range of vasoactive factors growth factors and adhesion molecules What does the endothelium do Antithrombotic Prevents the formation of blood clots thrombi in blood vessels Arterial relaxation Endothelial cells produce substances that relax underlying smooth muscle cells This causes arterial dilation and lowers vascular resistance Regulates the movement of substances from blood into the interstitial space and vice versa capillary diffusion Endothelial Dysfunction Prothrombic clot formation Reduced vasodilation increased vascular resistance Proinflammatory state altered permeability Associated with most forms of cardiovascular disease Hypertension Atherosclerosis Stroke Diabetes Chronic renal failure Endothelial Cells Are Sensors of the Properties of Blood Sense shear stress Frictional force of blood against vessel wall Bloodborne substances Internal elastic lamina separates endothelial cells from smooth muscle cells Shear Stress Stress applied parallel or tangential to a face of a material Directly proportional to fluid velocity and viscosity Shear stress is greater when flow is laminar Flow in a parallel fashion fast velocity Shear stress is decreased when flow is turbulent Partial blockage bumpsridges Molecules change direction interact Blood flow is most turbulent at arterial bifurcations splits Low shear stress Promotes formation of atherosclerotic plaques Shear stress stimulates production of endothelium derived factors Increased intracellular Ca2 Increased production of anticlotting factors Increased production of relaxing factors BloodBorne Substances Endothelial cells express many different types of cell surface receptors Muscarinic receptors acetylcholine ACh Purinergic receptors nucleotides ATP ADP UTP Receptors for Bradykinin BK Endothelinl ET1 Arginine vasopressin AVP Many others Bind to receptors 9 I Call 9 4 production ofanticlotting and relaxing factors Antithrombotic Mechanisms Healthy endothelial cell secretes nitric oxide NO and prostacyclin PGIZ These substances help to prevent the formation of blood clots in blood vessels Arterial Relaxation Endothelial cells are very close to vascular smooth muscle cells Factors produced by the endothelium can readily diffuse to underlying vascular smooth muscle cells and cause relaxation and arterial dilation EndotheliumDerived Vasodilators Nitric oxide NO Prostacyclin PGIZ r 39 39 quot 39 39 iyvcl 39 39 39 EDHl Nitric Oxide NO First identified as quotendotheliumderived relaxing factor or EDRF by Furchgot and Zawadzki Nobel Prize in Medicine 1998 Measuring effects of ACh on smooth muscle cells of veins Wiped off endothelium 9 ACh caused contraction One day that step was forgotten 9 ACh caused relaxation instead Subsequent work demonstrated that EDRF was NO Produced from LArg by NOS nitric oxide synthase Calicalmodulin necessary for action of endothelial and neuronal NOS Endogenous NO production contributes to regulation of blood pressure Blood pressure I heart rate J reflex How Does NO Relax Smooth Muscle cGMP activates protein kinase G PKG NO activates GTP 9 cGMP through sGC Vasodilation PKG also J Ca2 Effects on ion channels Ca2 transporters Ca2 sensitivity cGMP is metabolized by phosphodiesterase PDE enzymes ViagraCialis block phosphodiesterase activity Prostacyclin PGIZ First endotheliumderived vasodilatory factor to be discovered late 1970 s Produced by cyclooxygenase COX enzymes from arachidonic acid Endothelial cell Ca2 influx activates the enzyme phospholipase A2 PLAZ which liberates AA from the plasma membrane PGIZ causes relaxation of smooth muscle via receptordependent stimulation of adenylyl cyclase AC and production of the second messenger cyclic AMP cAMP Increased cAMP stimulate the activity of protein kinase A PKA and protein kinase G PKG PKA and PKG relax smooth muscle by decreasing intracellular Ca2 5 March Lecture ObjectivesStudy Guide Understand how blood volume is regulated and how changes in blood volume and extracellular fluid distribution influence cardiac output and blood pressure Understand what the term pressure natriuresis means Understand the difference between volume sensing by stretch receptors and atrial cardiomyocytes and how these mechanisms influence blood volume and pressure Be able to explain and diagram how the reninangiotensinaldosterone system regulates blood pressure Understand the central importance of the kidney in blood pressure regulation Fluid Distribution Total body water volume 40 L 60 body weight Intracellular fluid volume 25 L 40 body weight Extracellular fluid volume 15 L 20 body weight Interstitial fluid volume 12 L 80 of ECF Plasma volume 3 L 20 of ECF Blood Volume Regulation An increase in blood volume increases central venous pressure right atrial pressure and right ventricular enddiastolic pressure and volume Blood volume is regulated by the kidneys by adjusting the excretion of water and sodium into the urine Increased blood volume increases arterial pressure renal perfusion and glomerular filtration rate This leads to an increase in renal excretion of water and Na Pressure natriuresis Reflex Regulation Stretch receptors are present in the atria ventricles and pulmonary artery Sense intravascular volume preload Two types of receptors atrial stretch receptors A and B A fibers fire during atrial systole B fibers fire during ventricular systole Afferent fibers from stretch receptors innervate the medulallary cardiovascular centers and the hypothalamus Activation of receptors causes a reflex fall in mean arterial pressure Increasing stretch of the receptors stimulates both neuronal and hormonal changes Neuronal changes Sympathetic and parasympathetic responses of the heart and blood vessels are similar to those of the baroreflex Reduction of renal sympathetic nerve activity Reduces renin release resulting in diminished activity of the reninangiotensin aldosterone system Hormonal Regulation Vasopressin aka antidiuretic hormone ADH Results in vasoconstriction and renal fluid reabsorption 9 increased blood volume both of which lead to increased arterial pressure Activation of stretch receptors causes a decrease in the release of vasopressin Decreased vasopressin secretion results in an increase of urine excreted serving to lower fluid volume and blood pressure Atrial Natiuretic Peptide ANP Stretching of atrial myocytes increases secretion of ANP Promote Nai loss and diuresis Decrease renin and aldosterone release Release of ANP is independent of stretch receptor activation and is inherent to atrial cardiomyocytes ReninAngiotensinAldosterone System Blood pressure falls 9 renin converts angiotensinogen to angiotensin I 9 converted by angiotensinconverting enzyme to g39 39 9 39 39 of 39 39 9 salt retention 9 blood pressure rises Juxtaglomerular apparatus JGA of the kidney senses changes in blood pressure and blood flow Renin is secreted by the kidney from granular cells of the JGA in response to A decrease in arterial blood pressure as detected by baroreceptors leading to stimulation of renal sympathetic nerve activity most important A decrease in Nai levels in the ultrafiltrate of the nephron This flow is measured by the macula densa of the juxtaglomerular apparatus A decrease in renal perfusion Angiotensin II Renin catalyze the conversion of angiotensinogen to angiotensin I Angiotensin is converted to angiotensin II by angiotensin converting enzyme ACE Angiotensin II is the active form Physiological effects of angiotensin II ang II I sympathetic activity I tubular Nai Cl reabsorption and K excretion H20 retention 4 aldosterone secretion via adrenal gland cortex 4 arteriolarvasoconstriction blood pressure I ADH secretion via pituitary gland 9 4 H20 absorption in collecting duct Water and salt retention Effective circulating volume increases Perfusion of the juxtaglomerular apparatus increases J renin production by kidney Aldosterone Aldosterone is a steroid hormone produced by the adrenal cortex The overall effect of aldosterone is to increase reabsorption of ions and water in the kidney Acts on the distal tubules and collecting ducts of the kidney to cause the conservation of Na secretion of K and increased water retention Possible direct effects on cardiac myocytes and vascular smooth muscle Promotes increases in blood pressure by increasing blood volume ACE inhibitors and angiotensin II receptor blocker ARB drugs are used to treat hypertension Standing Pooling of blood in veins 9 pressure drop 9 baroreceptor reflex 9 l sympathetic outflow 9 4 HR contractility CO constriction of arterioles 9 l TPR constriction of veins 9 J unstressed volume 9 pressure toward normal 22 February The Heart Heart is a muscular organ that pumps blood Enclosed in a fluid filled membranous structure Outer layer pericardium fibrous Inner layer epicardium or visceral pericardium The walls of the heart are called the myocardium composed of cardiac muscle cells or ca rdiomyocytes The inner surface of the chambers of the heart is lined with endothelial cells Sometimes called the endocardium Heart Valves AV valves Left bicuspid mitral Right tricuspid Pulmonary and aortic semilunar valves Systole Contraction AV valves closed Semilunar valves open Diastole Semilunar valves closed AV valves open Lecture ObjectivesStudy Guide Understand the differences between electrically stable and electrically unstable cells and why this is important Understand how action potentials are generated in the pacemaker cells of the sinoatrial SA node and why this is important for cardiac function Understand electrical conduction in the heart and why the atrioventricular AV node is important for cardiac function Understand how action potentials are generated in cardiac muscle cells how they differ from SA node action potentials and why they are important Understand how the structure of cardiac muscle cells contributes to their function Understand what the term quotexcitationcontraction couplingquot means and how heart muscle cells contract Electrical Properties of the Heart Why does the heart beat Spontaneous electrical activity electrically unstable Sinoatrial SA node No resting membrane potential In right atria Generation of Action Potentials in Pacemaker Cells SA node pacemaker cells K channels T type Ca2 channels transient L type Ca2 channels longacting Nonselective cation channels Na and Ca2 F type Na currents The F stands for quotfunnyquot 1 F type channels open at hyperpolarized membrane potentials This channel is called HCN 2 Cation influx depolarizes the membrane which activates T type Ca2 channels 3 Ca2 influx via T type channels further depolarizes the membrane and activates L type Ca2 channel 4 L type Ca2 channels slowly inactivate and voltagedependent K channels are slowly activated Atrioventricular AV node The AV node slows the impulse conduction to about 005 msec Allows atrial systole prior to ventricular systole AV block Impairment of electrical continuity between the atria and ventricles Atrial depolarization fails to reach the ventricles or is conducted with a delay Results from injury or a genetically inherited disorder onic Basis of the Action Potential in Cardiomyocytes Electrically stable Resting membrane potential 90 mV Set by K efflux from the cell 1 Pacemaker AP excite the membrane 2 Voltagegated Na channels open K channels close Further depolarizes the membrane 3 Nai channels close rapidly 4 Plateau phase is maintained because membrane depolarization activates L type Ca2channels Ca2 influx depolarizes the membrane W channels remain closed 5 L type Ca2 channels inactivate and voltagegated K channels called delayed rectifier channels open Repolarization Electrical Properties of the Heart Atrial excitation Ventricular excitation Ventricular relaxation The Electrocardiogram The ECG or EKG noninvasive monitoring of the electrical activity of the heart P wave atrial depolarization PR interval Beginning of the P wave onset of atrial depolarization to the beginning of the QRS complex onset of ventricular depolarization QRS complex Ventricular depolarization QT interval Begins at the onset of the QRS complex and to the end of the T wave Time of ventricular depolarization until ventricular repolarization T wave is due to ventricular repolarization Cellular Structure of Cardiac Muscle Electrical and mechanical syncytium Coupled acts as a single unit ntercalated disk Gap junctions present in intercalated disks Thick and thin filaments Ttubules Thin filaments Actin Tropomyosin Three types of troponin I C T Contraction of Cardiac Muscle ExcitationContraction Coupling Excitationcontraction EC coupling The process of converting an electrical stimulus to mechanical response Electrical stimulus action potential causes muscular contraction Depends on voltage dependent Ca2 channels and Ca2 dependent contractile apparatus The mechanisms that cause Ca2 release and contraction of cardiac muscle are different from those of skeletal muscle Removal of Ca2 from Cytoplasm During Diastole Sarcoendoplasmic reticulum Ca2 ATPase SERCA 70 NaiCazi Exchanger NCX 28 3 Na1 Ca2 Plasma membrane Ca2 ATPase PMCA 1 Mitochondrial uptake 1 6 March Lecture ObjectivesStudy Guide Understand that cardiovascular disease is the leading cause of death in the US Understand diseases that can cause heart failure Understand what hypertension is and what the pathophysiological consequences of the disease are Be able to describe what atherosclerosis is and understand the pathophysiological consequences of the disease Be able to identify common risk factors for cardiovascular disease Cardiovascular Disease Blood diseases Diseases leading to heart failure Cardiomyopathies Arrhythmias Conduction disorders Channelopathies Vascular diseases Hypertension Arthrosclerosis Coronary artery disease and ischemic cardiomyopathy Peripheral artery disease Aneurism Stroke Diseases of the cardiovascular system account for over 40 of all deaths in the US Deaths due to total cardiovascular lung and blood disease 434 Heart Failure Inability of the heart to adequately deliver blood to the body Congestive heart failure CHF Most commonly occurs in the left heart SV and C0 are diminished Blood backs up in the venous system and pulmonary circulation Massive edema Pulmonary edema causes death Affects nearly 5 million Americans 2 of the population More men than women 550000 new cases diagnosed annually 300000 deaths per year Health care dollars 2008 372 billion Chronic condition often taking years to develop Diseases Resulting in Heart Failure Electrical arrhythmias conduction problems channelopathies Valve disease Congenital malformations Cardiomyopathies Primary or intrinsic Secondary related to atherosclerosis hypertension etc very common Intrinsic Cardiomyopathies Literally defined as lldiseased heart muscle Dilated cardiomyopathy DCM most common Hypertrophic cardiomyopathy HCM Dilated Cardiomyopathy DCM Ventricular dilation Ejection fractions often lt 40 Direct causes of DCM Genetic 20 40 Alcohol Peripartium Myocarditis Chronic anemia Adriamycin Hypertrophic Cardiomyopathy HCM Involves thickening of the ventricular usually left and septal walls Systolic function is normal but diastolic relaxation impaired Cannot hold as much blood Most intrinsic cases are genetic in origin Hypertrophic cardiomyopathy is the leading cause of sudden cardiac death in young people Vascular Diseases Hypertension atherosclerosis Usually involve endothelial cell dysfunction Loss of endothelial derived factors or impairment of their signaling pathways Associated with many diseases including hypertension and atherosclerosis Risk factors genetics smoking diabetes Hypertension Systemic hypertension Primary or essential hypertension unknown cause Secondary hypertension Pulmonary hypertension Hypoxiainduced Primary Classification of blood pressure for adults age 18 years and older Category I Systolic mm Hg I Diastolic mm Hg Normal I Less than 120 and less than 80 Prehypertension I 120 139 or 80 89 Hypertension I Stage 1 140 159 or 90 99 Stage 2 I 160 or higher or 100 or higher WHO world health organization systolic pressure greater than 160 Blood pressure less than 9060 is considered hypotensive 65000000 Americans are hypertensive Greater than 1 billion worldwide 1999 2000 study 39 normotensive 31 prehypertensive 29 hypertensive 2003 primary or contributing cause of 113 of all deaths What Causes Essential Hypertension Problems with the mechanisms regulating MAP The kidney Blood volume regulation Reninangiotensinaldosterone system Extrinsic vascular control Neuronal ANS and circulating factors Local control mechanisms that reside at the level of vascular wall smooth muscle cells and endothelial cells Mosaic theory multiple causes of hypertension Pathophysiological Consequences of Hypertension Elevated pressure damages small arterioles Eye loss of vision Kidney renal failure Brain hemorrhagic stroke Elevated afterload in the heart causes hypertrophic cardiomyopathy Increased mean arterial pressure and afterload causes ventricular hypertrophy Most cardiovascular diseases are related to atherosclerosis Atherosclerosisrelated diseases 70 of all CVD 2006 Atherosclerosis an inflammatory disease of the artery wall Results from damage to the endothelium and subsequent responses to this damage Complex chronic inflammatory response in the walls of arteries Deposition of lipoproteins plasma proteins that carry cholesterol and triglycerides causes much of the damage Causes of Endothelial Injury Oxidized lowdensity lipoprotein LDL cholesterol Infectious agents Toxins including the byproducts of cigarette smoking Hyperglycemia Cholesterol Cholesterol is an essential membrane component as well as a steroid hormone precursor If your diet is cholesterol free the liver will make what you need Cholesterol was recognized as the lipid present in atheromatous plaques in the 19 h century Two Types of Cholesterol quotBadquot cholesterol is carried by lowdensity lipoproteins LDL quotGoodquot cholesterol is carried by highdensity lipoproteins HDL Total cholesterol levels greater than 200 mgdL indicated a risk for heart disease Greater than 240 mgdL indicates high risk LDL levels less than 100 mgdL are optimal LDL levels greater than 130 159 mgdL indicate risk for heart disease Why is LDL bad Transports cholesterol to periphery Keeps cell membranes etc healthy HDL moves to liver 9 breakdown LDL builds up in peripheral arteries Consequences of Atherosclerosis Coronary artery disease CAD Peripheral artery disease PAD Aneurysms Stroke Coronary Artery Disease CAD Atherosclerosis of the coronary arteries Leads to ischemic cardiomyopathy and myocardial infarction MI 1 of every 5 deaths in the US 2005 Blood flow to the heart is interrupted and becomes ischemic The heart enlarges because of muscle damage The heart becomes stiff and noncontractile Aneurysms Artery wall becomes thin weak Stroke Two types of stroke Hemorrhagic stroke 20 Bleeding into brain lschemic stroke 80 Plaque buildup Bloodflow blocked 700000 people suffer a stroke every year in the US Stroke killed more than 150000 people in the US in 2004 Third largest cause of death behind diseases of the heart and cancer Women amount for 6 in 10 stroke deaths Leading cause of serious longterm disability in the US 57 million stroke survivors are alive today Risk Factors Things we can t change Personal or family history of heart disease Age Male gender Diabetes Things we can change High blood pressure High cholesterol Highfat diet Obesity Smoking Male gender age and high body mass index BMI are risk factors for hypertension Normal BMI 20 25 English BMI formula BMI weight in pounds height in inches x height in inches x 703 Metric BMI formula BMI weight in kilograms height in meters x height in meters Is there anything we can do Do not smoke Antioxidants help by reducing LDL oxidation Fish oilOmega 3 supplements Drink alcohol in moderation Ethanol increases HDL levels and inhibits platelet aggregation Other substances in red wine may also be cardioprotective 1 2 drinksday is considered protective 21 February Further Sources of Information Textbooks Boron ampBoupaep 2nd edition Section IV p 427 609 Guyton amp Hall 10 h edition Chapters 9 24 p 96 262 Berne amp Levy 6 h edition Section IV p 287 415 Costanzo 4 h edition Chapter 4 p 111 181 Smith ampKampine 3rd edition Cardiovascular Physiology Concepts httpwwwcvphysiologycom Cardiovascular Pharmacology Concepts httpwwwcvpharmacologycom Lecture ObjectivesStudy Guide Understand the basic organization of the cardiovascular system Know what the terms hemodynamics mean arterial pressure cardiac output venous return central venous pressure and vascular resistance mean Understand what physical factors regulate these parameters Understand how cardiac output venous return and vascular resistance influence mean arterial pressure Learn the basic anatomy of the heart and heart valves Why Study the Cardiovascular System Cardiovascular disease is very common Cardiovascular disease is the leading cause of death in US males and females The Cardiovascular System Three principle components Blood Heart Blood vessels Arteries Capillaries Veins William Harvey reported in 1628 that the cardiovascular system is a closed loop There are in reality two closed loops The systemic circulation The pulmonary circulation Chambers of the Heart Atria top chambers Ventricles bottom chambers Septum separates heart halves Systole Ventricles are contracted pumping Diastole Ventricles are relaxed filling Left heart supplies systemic circulation Right heart supplies pulmonary circulation The Great Vessels of the Heart Aorta leaves left ventricles 9 body artery Vena cava main vein body 9 right atria Pulmonary artery right ventricle 9 lungs Pulmonary vein lungs 9 left atria The Systemic Circulation Transports blood through all organs except the lungs High pressure 100 mm Hg high vascular resistance compared to the pulmonary circulation The Pulmonary Circulation The pulmonary circulation is a low pressure 10 20 mmHg low vascular resistance system Hemodynamics Hemodynamics blood flowblood pressure relationships The blood flowpressure relationship is influenced by Heart Blood vessels Physical properties of blood Classic Hemodynamic Laws Blood flowblood pressure relationships can be modeled using a corollary of Ohm s Law of Electricity V Ix R Where V voltage I current R electrical resistance Ohm s Law of Hydrodynamics PFxR Where P pressure difference between two points F flow R resistance to flow Mean Arterial Pressure P systemic circulation P aorta P vena cava Mean Arterial Pressure MAP Since P Fx R MAP Fx R Note that blood pressure is pulsatile not constant MAP N Pdiaslolic l39 13 Psyslemic Pdiastolic Pulse Pressure PsvslemiC Pdiaswnc Example BP is 12070 mmHg 120 systolic 70 diastolic MAP 70 13 50 85 mmHg Pulse pressure 120 70 50 mmHg Cardiac Output and Venous Return Cardiac output CO Total flow of blood from the heart to the body Venous return VR Total flow of blood back to the heart VR C0 when averaged over time cardiovascular system is a closed loop CO and VR are interdependent but each can be independently regulated Cardiac Output MAP F x R Flow F Cardiac output CO MAPCOXR CO Heart rate HR x stroke volume SV MAP HRxSVx R C0 of the right and left hearts are equal CO in a healthy adult at rest is 55 Lmin Normal CO in all resting mammals is a linear function of their weight 01 Lminkg Venous Return Rearrange P F x R to F PR or VR PV PRARV Where PV venous pressure PM right atrial pressure gradient RV venous resistance Central Venous Pressure CVP Central venous pressure CVP describes the pressure in the thoracic vena cava near the right atrium CVP is a measure of VR Normally very low 2 6 mmHg Vascular Resistance The diameter of small arteries has a large effect on R and blood flow Resistance lr4 r radius MAP C0 x R Resistance to flow can be described by Poiseuille s equation Where r1 viscosity of fluid in the tube blood I length of the tube assumed to be constant for our purposes Blood r radius of the tube Notice R is directly proportional to r1 R is inversely proportional to r to the fourth power TPR total peripheral resistance The vascular resistance of the entire systemic circulation Sometimes called systemic vascular resistance SVR PVR Pulmonary vascular resistance Resistance can be calculated for a single organ ie renal vascular resistance Blood is a mixture of formed elements cells and cell fragments suspended in a fluid called plasma Plasma Proteins nutrients metabolic wastes and other molecules being transported between organ systems Formed elements Erythrocytes red blood cells Leukocytes white blood cells Platelets cell fragments The average blood volume ofa 70 kg 154 lb person is 55 L The fraction of blood volume that is composed of erythrocytes is called the hematocrit Normal values for hematocrit Men 45 Women 42 Hypoxia blood 02 levels lower than normal and certain drugs can increase hematocrit This process is called polycythemia Blood Viscosity MAPCOXR sn39z R nr4 R and MAP are directly proportional to r1 Increases in blood viscosity result in increased vascular resistance and increased MAP Increased hematocrit increased viscosity 24 February Lecture ObjectivesStudy Guide Learn the phases of the cardiac cycle Understand how pressurevolume loops are generated how they describe cardiac function and why this is important Understand how cardiac output is regulated The Cardiac Cycle Coordinated activity of the chambers and valves of the heart Atrial systole 9 isovolumetric contraction ventricular systole 9 ventricular diastole Phases of the Cardiac Cycle Inflow sovolumetric contraction Outflow sovolumetric relaxation Stroke volume enddiastolic volume endsystolic volume Ejection fraction SVEDV Same things happen on left and right side of heart but right side is lower pressure Contractility of the heart cardiac performance How to evaluate in the clinic The endsystolic pressurevolume relationship ESPVR is used most frequently to describe cardiac contractility Afterload pressure against which heart has to pump aorta Cardiac PressureVolume PV Loops LV volume mL vs LVP mmHg on graph Makes a loop Left side isovolumteric relaxation bottom ventricular filling right side isovolumetric contraction top ejection 1 P and V at the end of ventricular filling As the ventricle begins to contract but before the aortic valve opens LVP increases by LV volume remains the same sovolumetric contraction 2 When LVP exceeds aortic diastolic pressure the aortic valve opens and ejection of blood occurs 3 The aortic valve closes ejection ceases sovolumetric relaxation 4 When the LVP falls below left atrial pressure the mitral valve opens and the ventricle begins to fill Once the ventricle is fully relaxed the LVP gradually increases as the LV volume increases Key Points The width of the loop represents the difference between EDV and ESV SV Systolediastole Ejection fraction Regulation of Cardiac Function Preload SV and CO increase in response to increases in ventricular blood volume prior to systole Frank Sterling mechanism Afterload SV and C0 are decreased if the opposing pressure is increased notropy Modifiers of contractility that are independent of preload and afterload Preload Technically preload describes the initial stretch on a single myocyte prior to contraction Practically preload is a function of ventricular pressure after passive filling atrial contraction and is closely related to enddiastolic volume Preload is affected by the rate of venous return Preload increases with exercise increasing blood volume and excitement FrankStarling Relationship Lengthtension relationship Increased enddiastolic volume increases the stretch on the individual muscle fibers Causes the force of muscular contraction to increase Stretching of the muscle fibers increase the affinity of troponin C for Ca2 Greater number of crossbridges Afterload Afterload is the pressure that the heart must eject blood against Usually only important for the left heart afterload aortic pressure Increased afterload results from increased vascular resistance and is associated with hypertension notropy Modifiers of contractility that are independent of preload and afterload Results from altered Ca2 handling in cardiomyocytes Inotropic Agents Autonomic Nervous System ANS Cardiac Glycosides The heart is innervated by the ANS Vagus nerves Parasympathetic Acetylcholine Muscarinic receptors Thoracic spinal nerves Sympathetic Norepinephrine Badrenergic receptors Epinephrine from bloodstream adrenal medulla Sympathetic Increases heart rate SA node Increased conduction velocity AV node Increased contractility atrial ca rdiomyocytes Increased contractility ventricular cardiomyocytes Parasympathetic Decreased heart rate SA node Decreased conduction velocity AV node Decreased contractility atrial ca rdiomyocytes No significant effect ventricular cardiomyocytes Cardiac Glycosides Positive inotropic agent Comes from foxglove plant Block activity of NalKi pump Intracellular Na increases Activity of NalCab pump decreases normally Ca2 out 3 Nai in 2 Intracellular Ca Increases 29 February EndotheliumDependent Hyperpolarization EDH Defined as endotheliumdependent smooth muscle hyperpolarization and relaxation that occurs in the absence of NOS and COS activity Pharmacology knockout models EDH may be more important than NO or PGIZ in maintaining vascular tone in small arteries that are the primary site of vascular resistance EDH may be more prominent in femalesvs males Also called endotheliumderived hyperpolarizing factor EDHF but there may be no factor What is EDH Spread of electrical information from endothelial cells to smooth muscle cells via myoendothelial gap junctions Causes arterial dilation 9 lower vascular resistance 9 lower blood pressure Key Points Endothelial Cell Vasodilator Pathways Agonistsshear stress 4 Cali Activates NO production PGIZ production K channels 9 hyperpolarization EDH Lecture ObjectivesStudy Guide Becomes familiar with the general anatomy and functions of the microcirculation Understand what factors influence capillary exchange by diffusion Fick s Law Understand the Starling Forces and how they influence capillary exchange via bulk flow Learn the general anatomy and function of the lymphatic system General Anatomy of the Microcirculation Arteriole branches into capillaries 9 venules Exchange takes place in capillary bed Precapillary sphincters smooth muscle between arteriolecapillary Closed 9 capillary bypassed Functions of the Microcirculation Capillary exchange Gas exchange Transport of nutrients to the tissues Removal of waste products Arteries and arterioles Temperature regulation skin Autoregulation of blood flow Capillary Exchange GlucoseOz into cells CO2 into capillary Structural Classification of Capillaries Continuous found in muscle skin lung central nervous system lowest permeability Fenestrated found in exocrine glands renal glomeruli intestinal mucosa perforations result in relatively high permeability Discontinuous found in liver spleen bone marrow large intercellular gaps and gaps in basement membrane result in extremely high permeability Capillary Exchange Molecules can cross the capillary endothelium by a number of mechanisms Diffusion gases Bulk flow fluids are electrolytes Mechanisms that are not specific to endothelial cells Vesicular transport pinocytosis macromolecules Active transport ions glucose amino acids Diffusion Important for gases Oz and C02 and lipidsoluble substances eg anesthetics Fluid and electrolytes are also exchanged in part by diffusion forces Fick s first law of diffusion dndt DA ACAX dndt is flux or movement in molessec D is diffusion constant A is surface area delta C is concentration difference delta X is thickness of barrier to diffusion Fick s Law tells us that movement or flux of a molecule is directly related to Diffusion constant across the barrier D Surface area available for diffusion A Concentration gradient across the barrier AC Example To increase Oz diffusion into a tissue Increase p02 in the plasma AC Andor increasing the surface area for exchange ie the number of open capillaries A Bulk Flow Bulk flow of fluid or electrolytes occurs through quotporesquot and intercellular clefts Particularly important in the kidney however it occurs in nearly all tissues Bulk flow follows Poiseuille s equation for hydrodynamic flow Changes in pressure driving forces and in the size of pores or clefts will alter exchange Controls extracellular fluid 14 L total 11 L interstitial fluid 3 L plasma Filtrates to interstitial fluid Absorbed into the plasma Physical Factors Regulating Bulk Flow Capillary Exchange Starling forces The rate of exchange by bulk flow is determined by Driving forces Hydrostatic pressure Oncotic pressure Permeability of the capillary wall Surface area available for transport Two opposing hydrostatic driving forces Capillary hydrostatic pressure PC Tissue hydrostatic pressure PT PC is normally much greater than PT Net hydrostatic pressure gradient across the capillary is positive Oncotic pressure is a form of osmotic pressure exerted by proteins in blood plasma or tissue There are two opposing oncotic driving pressures Capillary plasma oncotic pressure TIC Tissue interstitial oncotic pressure TIT TIC is much greater than TIT therefore the oncotic pressure gradient across the capillary if unopposed by hydrostatic forces would reabsorb fluid from the interstitium into the capillary The net driving force for exchange NDF can be calculated as NDF PC PT 0 TIC TlTl o reflection coefficient a correction factor that accounts for the relative impermeability of large proteins f NDF is positive filtration occurs and if negative reabsorption occurs Hydrostatic and oncotic forces are normally expressed in units of mm Hg Other Factors Regulating Bulk Flow Capillary Exchange The permeability of the capillary wall can be altered by certain blood borne substances histamine K filtration constant a measure of capillary permeability K has a value between 0 and 1 0 impermeant 1 no barrier to bulk flow The surface area A available for exchange can increase under certain circumstances This process is called recruitment Starling Equation Considers all of the factors discussed Jv Kr A Pc PT 0 TIC TlTll JV fluid flux per unit time K filtration constant A surface area Typical Values of Starling Forces PC PT nC nT NDF I Arteriolar End I 35 mmHg I 2 mmHg I 25 mmHg I 01 mmHg I 12 mmHg I I Venular End I 15 mmHg I 2 mmHg I 25 mmHg I 3 mmHg I 5 mmHg I The hydrostatic forces gradually decrease over the length of the capillary while the oncotic pressure remains constant Vasodilation transient localized increased arterial pressure Edema excess interstitial fluid Hemorrhagic shock decreased arterial pressure quotAutotransfusionquot fluid enters bloodstream to help stabilize vascular pressure Congestive heart failure increased venous pressure Protein loss due to malnutrition burns decreased plasma oncotic pressure Lymphatic System Network of conduits that carry a clear fluid called lymph The functions of the lymphatic system are the maintenance of fluid balance and immunity Lymph is produced when plasma is filtered into the interstitial spaces from blood flowing through the capillaries A small amount of interstitial fluid is not reabsorbed into the capillaries If left behind increased interstitial fluid would cause massive edema Lymphatic vessels act as quotdrainsquot to collect the excess fluid and return it to the venous blood just before it reaches the heart Lymphatic vessels have an inherent pumping mechanism and a series of oneway flow valves The disease elephantiasis results from destruction of lymphatic vessels 120 million people infected worldwide 27 February Lecture ObjectivesStudy Guide Learn the general anatomy and function of the major segments of the vascular system arteries veins and capillaries Understand the terms resistance and compliance as they relate to the vasculature how they are regulated and why they are important Understand how the contractile state of smooth muscle cells influences the diameter of arteries and vascular resistance and how this influences vascular function Understand how smooth muscle contractility is regulated Understand how veins influence cardiac output The Vascular System The vascular system consists of all of the blood vessels in the body Large arteries conduit vessels ie aorta Small arteries and arterioles resistance vessels Capillaries site of exchange Venules small veins Larger veins compliance vessels Blood Vessel Structure Arteries and veins Outermost adventitia structural framework Media smooth muscle cells thickest portion Basement membrane internal elastic lamina EL ntima endothelium single cell layer thick Capillaries Outermost pericyte unknown function Basement membrane Endothelial cells Lumen Artery Connective tissue smooth muscle endothelium Muscular and elastic thick walled Arteriole Muscular little connective tissue Capillary Endothelial layer no muscle Venule Thin walls with some smooth muscle Vein Thin walled with smooth muscle flaccid First order arteriolevenule r 30 um Fourth order arteriolevenule r 5 pm Capillary r 3 pm Arterial Compliance Compliance C change in volumechange in pressure More compliant more stretchy The walls of large conduit arteries contain more elastin than smaller muscular arteries Act as llpressure reservoirsquot expand and contract as blood is ejected by the heart Allows blood flow in smaller arteries to be continuous Cardiovascular diseases such as 39 39 39 and a 39 39 39 causes quot to decrease Less compliance with age part of why cardiovascular disease increases with age Vascular Resistance Small arteries and arterioles Vascular resistance is the term used to define the resistance to flow that must be overcome to push blood through the circulatory system Inverser proportional to luminal diameter Small change in r radius large change in R resistance How Does Vascular Smooth Muscle Work Different from skeletal and cardiac muscle Vascular smooth muscle is a type of tonic smooth muscle Graded changes in muscle tension and membrane potential Em Do not generate action potentials under physiological conditions Apply constrictor stimulus depolarizes Apply dilator stimulus hyperpolarizes Depolarization 9 L type Ca2 channels open Biochemistry of Smooth Muscle Contraction Smooth muscle cell contraction requires interaction of actin thin filaments and myosin thick filament Calidependent activation of myosin MLCK myosin light chain kinase Calmodulin binds Cali 9 complex w MLCK 9 activated 9 phosphorylated light chains activating myosin Activated myosin can form crossbridges with actin to cause muscle contraction Crossbridge Cycling Contraction when phosphorylated Dephosphorylated by myosin light chain phosphatase M LCP Relaxation when dephosphorylated Rho activates Rho kinase phosphorylates MLCP Less MLCP activity More contraction Calcium sensitization What Stimuli Regulate the Contractility of Vascular Smooth Muscle Cells Epinephrinenorepinephrine act on ot adrenergic receptors Membrane depolarization activates Ltype Ca2 channels Increases Ca2 sensitivity Greater contraction Circulating hormones angiotensin II vasopressin oxytocin etc Hormones bind to and activate special cell surface receptors on the smooth muscle cell plasma membrane Receptor binding activates signaling pathways leading to Membrane depolarization Ca2 influx via Ltype Ca2 channels Increased Ca2 sensitivity All of these events increase smooth muscle contractility leading to vasoconstriction Autoregulation Tendency of an organ or tissue to maintain constant blood flow despite changes in arterial pressure Vascular myogenic responses Brain global Kidney The adjustment of blood flow through an organ in accordance with its metabolic needs Active hyperemia Skeletal muscle exercise Brain local neurovascular coupling Vascular myogenic response Small arteries constrict in response to increasing perfusion pressure and dilate in response to decreased pressure
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