The NO bond distance in nitric oxide is 115 pm, which is intermediate between a triple bond (106 pm) and a double bond (120 pm). (a) Draw two resonance structures for NO and comment on their relative importance. (b) Is it possible to draw a resonance structure having a triple bond between the atoms?
CHAPTER 12 NOTES Material NOT REQUIRED from chapter 12: Figures 2, 6, 1820, 29, 32, 34.b, 42; Tables 4, 6 and 9; p394395 sections on “Flow autoregulation, reactive hyperemia, and response to injury”; p399 section on “Velocity of capillary blood flow”; Sections 12.7, 12.12, 12.17 and 12.18; Section F Key Terms in Intro Circulatory system aka cardiovascular system: responsible for transportation of molecules/substances over long distances; contains the following Heart: the pump Blood vessels/vascular system: interconnected tubes Blood: fluid connective tissue, contains water, solutes, cells 12.1 – Components of the Circulatory System Blood o Formed elements: includes erythrocytes (RBC), leukocytes (WBC, fight infection and cancer), platelets (cell fragments, blood clotting) o 99% RBC carrying oxygen to tissues/carbon dioxide from tissues o Plasma: liquid that formed elements are dissolved in o Hematocrit: % RBC in blood; normally 4245% depending on gender (the rest is plasma) Plasma o Plasma proteins: most of plasma solutes by weight; exert osmotic pressure that favors absorption of extracellular fluid into capillaries Albumins (most abundant, synthesized in liver), globulins, fibrinogen (functions in clotting) o Serum: plasma with fibrinogen/other proteins in clotting removed o Also contains nutrients, wastes, hormones, mineral electrolytes (Na , K , etc.) Blood cells are all descended from multipotent hematopoietic stem cells Erythrocytes (RBC) o Major function: gas transport (oxygen/carbon dioxide); contain large amounts of hemoglobin that reversibly bind to gases (1415.5 g/100 mL blood depending on gender) o Biconcave disk and small size allow for large surface area to volume ratio for oxygen/carbon dioxide to rapidly diffuse to/from cell o Produced in bone marrow; do not contain nuclei and organelles after differentiation into RBC (only some ribosomes present in young RBC or reticulocytes; mature/lose ribosomes in a day) o Average life span: 120 days (1% or 250 billion cells are replaced each day) breaks down in spleen and liver (produces bilirubin as result) o Erythropoiesis: RBC production; needs iron, folic acid, vitamin B 12 Iron: needed for oxygen binding to hemoglobin in RBC o Must be replaced by ingestion of ironcontaining foods as it is lost through sweat, feces, urine, menstrual blood o Iron deficiency: leads to inadequate hemoglobin production o Hemochromatosis: excess iron in body; leads to abnormal iron deposits, organ damage o Homeostatic control is in intestinal epithelium (which absorbs iron from food) o Ferritin: protein in body that stores iron (in liver) to buffer against deficiency o Transferrin: irontransport plasma protein that collects iron released from old RBC and takes it to bone marrow for recycling into new RBC Folic acid and vitamin B 12 o Folic acid: found in leafy plants, yeast, liver; required for synthesis of thymine ( formation of DNA and cell division) o Folic acid deficiency fewer RBC produced o Vitamin B : 12quired for action of folic acid; found only in animal products; contains cobalt o Intrinsic factor needed in GI tract to absorb vitamin B ; lack of protein causes 12 pernicious anemia (vitamin B d12iciency RBC deficiency) Hormones o Erythropoietin: controls erythropoiesis; secreted into blood by connective tissue cells in kidneys Acts on bone marrow to stimulate proliferation and differentiation Secreted at a rate to produce RBC equal to loss of RBC (receives negative feedback from oxygen decreased oxygen to kidneys leads to increase erythropoietin production) Testosterone can stimulate release ( why hematocrit is higher in men) Anemia: decreased ability of blood to carry oxygen; due to one of following: o Decrease in total number of RBC with normal quantity of hemoglobin o Low concentration of hemoglobin per RBC o Combination of both Sicklecell disease: caused by single base mutation that leads to abnormal hemoglobin molecules that interact with each other to form fibrous polymers, causing sickle shape o Blocks capillaries, leads to tissue damage/pain, destruction of RBC, anemia o Heterozygotes only show symptoms when oxygen levels are unusually low and have resistance to malaria (blood infection spread by mosquitos) Polycythemia: more RBC than normal (increased hematocrit) causes increased viscosity (more friction) and difficulty in moving blood through vessels, puts strain on heart o Basis for “blood doping” Leukocytes o Major function: immune defenses o Neutrophils: phagocytes in blood; most abundant; released during infections/inflammation; contains antibacterial protein defensing o Eosinophils: blood/mucosal linings of GI/respiratory/urinary tracts; release toxic chemicals to kill parasites o Monocytes: phagocytes in blood; develop into microphages in tissues/organs o Macrophages: located to encounter invaders at skin/lining of respiratory and digestive tracts; can engulf viruses/bacteria o Basophils: secretory cells that produce anticlotting factor and histamine o Lymphocytes: T and B types; protect against specific viruses, bacteria, toxins, cancer cells by either directly killing or creating antibodies Platelets o Produced when megakaryocytes (large bone marrow cells) pinch off and enter circulation o Functions in blood clotting Regulation of blood cell production o Only bones of chest/base of skull/spinal vertebrae/pelvis/limb bones produce blood cells after childhood o Hematopoietic growth factors (HGFs) help proliferation and differentiation and inhibit apoptosis of new cells (ex: erythropoietin) Many types produced by a variety of cells Can be used to supplement deficiencies due to disease/damage Circulation o Bulk flow: rapid flow of blood through body produced by pressures created by pumping heart; all components of blood move together o Branching allows all cells to be within 2 layers from blood vessels (specifically capillaries) for nutrient/metabolic waste product exchange (diffusion and mediated transport) o Pulmonary circulation (right ventricle via the pulmonary trunk lungs (pulmonary arteries from trunk go to each lung) left atrium via pulmonary veins) o Systemic circulation (left ventricle via the aorta body right atrium via the inferior vena cava and the superior vena cava) Allows systemic tissues to receive oxygenated blood and independent variation in blood flow through different tissues as needed (Figure 12.6) Portal system: unique system used by liver and anterior pituitary glands for blood circulation o Arteries arterioles capillaries: blood moving away from heart o Capillaries venules veins: blood moving towards heart o Microcirculation: arterioles, capillaries, venules o Left side of the heart has high oxygen content, right side has low oxygen content 12.2 – Pressure, Flow, and Resistance Hemodynamics: collective term for all 3 factors o Blood flow (F): always from regions of high to low pressure o Hydrostatic pressure = pressure (P): force exerted by blood, generated by heart contractions (L/min; ΔP in mmHg) o Resistance (R): how difficult it is for blood to flow between two points at any given pressure difference; can only be measured by F and ΔP Greater viscosity, greater length of tube, or smaller radius = greater resistance R=1/r 4 o F=∆ P/R Applies to flow through blood vessels and through heart chambers (resistance comes from valves in this case) Ultimate function of circulatory system: ensure adequate blood flow through capillaries of various organs 12.3 – Anatomy General structures o Pericardium: protective fibrous sac surrounding heart o Epicardium: fibrous layer in between pericardium and heart o Myocardium: wall of the heart, cardiac muscle cells, lined on inside with endothelial cells (endothelium) o Interventricular septum: separates right and left ventricles o Atrioventricular valves (AV valves): separates atrium and ventricle; one way blood flow atrium ventricle; open/close passively due to pressure differences (opens when atrial pressure is higher; closed with high ventricular pressure) Tricuspid valve: right side Bicuspid valve: left side (aka mitral valve) Chordae tendineae: fibrous strands connected valves to papillary muscles to prevent valves from inverting (prolapse; can occur with injury and disease) o Semilunar valves: pulmonary and aortic valves; open/close passively due to pressure differences to ensure blood moves in one direction through heart o There are no valves at entrances of superior and inferior venae cavae or pulmonary veins Atrial contraction is enough to constrict backflow Cardiac muscle o Cardiac muscle cells in myocardium must be very resilient to come together and exert pressure on blood enclosed during a contraction Only 1% of heart cells are replaced per year o Entire heart (all cells) contract with each beat 3 billion contractions without rest in a lifetime o Innervation by sympathetic (entire heart; release norepinephrine for beta adrenergic receptors) and parasympathetic (special cells in atria; release ACh for muscarinic receptors) nerve fibers Blood supply o No exchange of nutrients/metabolic waste occurs until blood passes through capillaries Coronary arteries: arteries supplying myocardium (coronary blood flow) so cells can exchange nutrients/waste products 12.4 – Heartbeat Coordination Efficient pumping of blood requires that the atria contract first, followed almost immediately by the ventricles o Contraction is triggered by depolarization starting at the sinoatrial (SA) node in right atrium near entrance of superior vena cava; gap junctions allow this to happen quickly/excite entire heart o SA node acts as pacemaker for heart, determines heart rate Sequence of excitation: o Action potential in SA node depolarization spreads through atria atrioventricular (AV) node at base of right atrium (connected to SA node via internodal pathways) through ventricles via bundle of His divides into left and right bundle branches that reach bottom of heart/walls of ventricles Propagation of action potentials through AV node is slow; atria will contract first and ventricles will contract when atria relax Fiber bundles are composed of Pukinje fibers: large diameter, rapid conduction, low resistance gap junctions Myocardial cell action potentials + + o Resting membrane is more permeable to K than Na = negative resting membrane potential; depolarizing is due to influx of Na + + + o Na depolarization transient K repolarization depolarized plateau 2+ound 0 mV as K permeability declines and Ca enters cell (Ltype Ca channels: long lasting) Ca channels inactivate, K exits and causes repolarization o Ventricular cells have a longer plateau than atrial cells Nodal cell action potentials o Pacemaker potential: gradual depolarization of the SA node (does not have a steady resting potential) that causes an action potential when threshold is eventually reached; contributed to by: + Progressive reduction in K permeability Unique set of channels that open at negative membrane potential values (F (funny)type channels for Na influx) 2+ T(transient)type Ca channels: opens briefly and gives important final depolarizing boost o SA node is brought to threshold faster than AV node due to pacemaker currents Automaticity: ability of SA node for spontaneous, rhythmic self excitation (inherent rate is about 100 depolarizations per minute) determines how quickly threshold is reached/action potential is generated o Pacemaker mechanism creates action potential depolarizing due to Ca (not 2+ Na ) slow transmission of cardiac excitation to AV node repolarization o Ectopic pacemakers: when slower inherent pacemaker rates of other cells in conducting system create own rhythm (still driven to threshold by SA node) AV conduction disorder: reduction/elimination of action potential transmission from SA node to AV node due to disease/druginduced malfunction of AV node; cause ectopic pacemakers to start Very slow (2540 beats/min); causes ventricles to contract out of synch with atria Fix AV conduction disorders with artificial pacemaker Electrocardiogram (ECG or EKG): tool for evaluating electrical events in the heart o Recording electrodes detect currents running through fluids surrounding heart after action potentials in multiple cells (NOT direct record of changes in membrane potential across individual cells) o Shows P wave (atrial depolarization), QRS complex (ventricular depolarization), T wave (ventricular repolarization) Atrial repolarization takes place during QRS complex; cannot be seen o ECG leads record at different locations on limbs and chest for comparison o Use to diagnose myocardial defects Excitationcontra2+ion coupling o When Ca influxes into cell through Ltype channels and creates plateau, ryanodine receptors in sarcoplasmic reticulum are stimulated to release even more Ca Ca activates thin filaments muscle contraction Ca returns to 2+ + 2+ sarcoplasmic reticulum via Ca ATPase pumps and Na /Ca countertransporters o More Ca released = stronger contraction (i.e. during exercise) Refractory period o Summation of contractions is impossible due to long absolute refractory period Unlike skeletal muscle; absolute refractory period lasts almost as long as contraction (250 msec) 12.5 – Mechanical Events of the Cardiac Cycle Cardiac cycle: recurring cycle of atrial and ventricular contractions and relaxations o Two major phases: systole (ventricular contraction and blood ejection) and diastole (ventricular relaxation and blood filling) Systole can be broken down into isovolumetric ventricular contraction (contraction of ventricles while valves are closed, increases ventricular BP and develops tension, but muscle does not shorten) and ventricular ejection (pressure in ventricles exceeds pressure in aorta/pulmonary trunk, valves open, muscles shorten to push blood out) Stroke volume (SV): volume of blood ejected from each ventricle during systole Diastole can be broken down into isovolumetric ventricular relaxation (ventricles begin to relax while valves are closed), ventricular filling (AV valves open to allow blood flow), and atrial contraction o ***see page 381 in textbook for a really indepth explanation of cardiac cycle (timing of pressure/electrical/mechanical changes) o At rest, 80% of ventricular filling occurs before atrial contraction (early diastole) Ensures that filling is not seriously impaired during periods when the heart is beating rapidly and that diastole duration is reduced Heart rates greater than 200 beats/min don’t leave enough time for filling and blood volume leaving heart decreases (bad) Explains why conduction defects that affect atrial pumping abilities do not seriously impair ventricular filling (ex: during atrial fibrillation when atria fails to work as effective pumps) Pulmonary circulation pressures o Pressure changes in right ventricle and pulmonary arteries are same as left ventricle and aorta (pg. 381) Typical pulmonary arterial systolic and diastolic pressures are 25 mmHg and 10 mmHg (lowpressure system, thinner walls) Systemic arterial pressures are 120 mmHg and 80 mmHg Both have same stroke volume Heart sounds: result from cardiac contraction normally head through a stethoscope o “lub” = closure of AV valves; onset of systole o “dup” = closer of pulmonary and aortic alves; onset of diastole o Heart murmurs: other sounds heard from heart, usually indicative of disease or defects Laminar flow: smooth blood flow (normal) may become turbulent with defect (detected with heart murmurs) Stenosis: abnormally narrowed valve, causes turbulent blood flow Insufficiency: blood flowing backward through a damaged, leaky valve Septal defect: blood flowing between two atria or two ventricles through a small hole 12.6 – The Cardiac Output Cardiac output (CO): the volume of blood each ventricle pumps as a function of time, usually expressed in L/min o At steady state, CO flowing through the systemic and pulmonary circuits is the same o CO=HR×SV HR = heart rate (beats/min) SV = stroke volume (L/beat) o CO of 5.0 L/min average for a resting, averagesized adult (nearly all of 5.5 L total blood volume is pumped around the circuit once each minute) o CO will increase with strenuous exercise o HR and SV do not always change in the same direction (ex: SV can decrease with blood loss, but HR will increase) Control of heart rate o In the absence of nervous/hormonal influences, the heart beats around 100 beats/min (inherent autonomous discharge rate of the SA node) At rest, influence of parasympathetic neurons results in resting HR of 70 75 beats/min o Parasympathetic and sympathetic postganglionic neurons end on the SA node Parasympathetic = HR decreases (reduces inward current, hyperpolarizes SA node cells by increasing permeability to K = slower depolarization) Sympathetic = HR increases (increases Ftype channel permeability = faster depolarization) Also innervate other parts of conducting system (sympathetic = increases conduction velocity through entire cardiac system; parasympathetic = decreases rae of spread of excitation through atria and AV node) o Epinephrine (adrenal medulla) speeds heart up by acting on same beta adrenergic receptors as norepinephrine released by neurons o Body temperature, plasma electrolyte concentrations, hormones, adenosine (myocardial cell metabolite) also affect cardiac nerves (Figure 12.26) Control of stroke volume (volume of blood ejected during each contraction) o A change in force during contraction can produce a change in stroke volume (will never fully empty ventricles) Changes in enddiastolic volume (preload: volume in ventricles before contraction) Changes in magnitude of sympathetic NS input to ventricles Changes in afterload (ex: changes in arterial pressures that ventricles pump against) o FrankStarling mechanism: all other factors being equal, the SV increases as the enddiastolic volume increases, seen in a ventricularfunction curve Lengthtension relationship: enddiastolic volume is a major determinant of how stretched the ventricular sarcomeres are just before contraction must contract harder with greater stretch (more voume) Complex mechanism: stretching cardiac muscle cells towards optimum length decreased space between thick and thin filaments more cross bridges can bind during a twitch increased sensitivity to troponin for binding Ca and increased Ca release from sarcoplasmic reticulum At any given HR, an increase in venous return = increase CO (increase enddiastolic volume, increase SV) so blood does not accumulate in pulmonary circulation Sympathetic regulation o Distributed to entire myocardium o Norepinephrine acts on betaadrenergic receptors to increase ventricular contractility (strength of contraction at any enddiastolic volume) along with increase HR Any increased force of contraction and stroke volume resulting from sympathetic regulation is independent from any change in enddiastolic ventricular volume Not related2+o FrankSterling mechanism (Figure 12.28a) Overall Ca concentrations increases more quickly in cytosol, reaches greater excitation value, and returns to preexcited state more quickly faster, stronger contraction o Ejection fraction: helps quantify contractility (directly related) EF=SV/EDV EDV = enddiastolic volume 50%75% under resting conditions in healthy heart o Neglect parasympathetic effects on ventricular contractility Afterload o The greater the load, the less contracting muscle fibers can shorten at a given contractility (Figure 9.17 for review) An increased arterial pressure tends to reduce SV SKIP 12.7 12.8 – Arteries Thick walls containing large quantities of elastic tissue; “elastic tubes” Large radii allow lowresistance conduction of blood to various organs as well as act as a “pressure reservoir” for maintaining blood flow through tissues during diastole Arterial blood pressure o Compliance: ΔV/ΔP; how easily a structure will stretch (greater compliance = greater ability to stretch) o A volume of blood equal to about 1/3 of SV leaves arteries during systole; rest of SV remains in arteries which increases pressure allows blood to continue to be driven into arterioles during diastole (Figure 12.33) Ventricular contraction always occurs before arterial pressure can reach zero (equal pressure of blood entering heart as leaving heart) o Systolic pressure (SP): maximum arterial pressure reached during peak ventricular ejection o Diastolic pressure (DP): minimum arterial pressure occurring just before ventricular ejection o Usually measured as systolic/diastolic (ex: 120/80 mmHg) o Pulse pressure: difference between systolic and diastolic pressure (ex: 40 mmHg) Can be felt as pulse/throb in arteries in neck/wrist/etc. Magnitude dependent on SV (direct relationship), speed of ejection of SV (direct), and arterial compliance (indirect; higher pressure with lower compliancy) o Arteriosclerosis: stiffening of arterial walls, progress with age and leads to higher pulse pressure o Mean arterial pressure (MAP): average pressure driving blood into tissues averaged over the entire cardiac cycle 1 MAP=DP+ (SP−DP) 3 Compliance has NO major influence on MAP (effects on systolic and diastolic pressure change but in opposite directions) Measurement of systemic arterial pressure o Sphygmomanometer: blood pressure cuff used to measure systolic and diastolic pressures (used in conjunction with a stethoscope) Inflate until no sound is heard, release air slowly and record first number when sound is first heard again (systolic) and second number when sound disappears again (diastolic) Korotkoff’s sounds: highvelocity turbulent blood flow that produces audible vibrations (with stethoscope) *** NOT the same as the lubdup sounds heard when valves close 12.9 – Arterioles 2 major functions: in organs, responsible for determining the relative blood flows to given organs at any given mean arterial pressure and as a whole, determine mean arterial pressure o F=∆ P/R=MAP/Resistance organ Venous pressure is ignored (close to zero); MAP is constant throughout body o Differences in flow are determined by differences in the resistance to flow offered by each tube Wide tubes = les resistance = greater flows If radius of each tube is independently altered, blood flow through each is independently altered (smaller radius = less flow) Large main arteries serve as pressure reservoir Contain smooth muscle that can relax (vasodilation, increased radius) or contract (vasoconstriction, decreased radius) o Pattern of bloodflow distribution depends upon degree of arteriolar smooth muscle contraction within each organ/tissue Intrinsic tone: spontaneous contractile activity of arteriolar smooth muscle; sets baseline level of contraction that can be increased/decreased by external signals o Increase in contractile force above IT causes vasoconstriction o Decrease in contractile force causes vasodilation o Controlled by local controls and extrinsic (reflex) controls Local controls: mechanisms independent of nerves/hormones that organs/tissues use to alter their own arteriolar resistances (selfregulate blood flow) o Active hyperemia: manifestation of increased blood flow during increased metabolic activity; direct result of arteriolar dilation Metabolic activity decreased oxygen (used in ATP production), increased CO ,2H ions (lactic acid), adenosine (ATP byproduct), K ions (action potential repolarization), eicosanoids (phospholipid byproduct), bradykinin (peptide generated from protein kininogen generated from enzyme kallikrein secreted from gland cells) and nitric oxide arteriolar dilation Most highly developed in skeletal/cardiac muscle and glands Extrinsic controls: reflex mechanisms serves wholebody needs (ex: regulating arterial blood pressure; redistributing blood flow for specific function such as heat loss) o Sympathetic neurons innervate most arterioles Release norepinephrine to bind to alphaadrenergic receptors vasoconstriction (vasodilation via reducing presence of hormone) *** betaadrenergic receptors in heart, alphaadrenergic in arterioles allows for antagonists to block actions of norepinephrine in certain places Reflex serves wholebody needs (ex: regulating arterial blood pressure; redistribute o Parasympathetic neurons do not have important innervations in arterioles o Noncholinergic, nonadrenergic, autonomic neurons Release neither ACh or norepinephrine Release vasodilator substances particularly nitric oxide; contributes to control of GI system blood vessels Innervate arterioles in penis/clitoris to mediate erection (sildenafil (Viagra) and tadalafil (Cialis) work by enhancing nitric oxide pathway to facilitate vasodilation) o Hormones Epinephrine and norepinephrine can bind to alphaadrenergic receptors on arteriolar smooth muscle and cause vasoconstriction Can also bind to beta 2adrenergic receptors and relax muscle (less common than alpha in most vascular beds no effect; arterioles in skeletal muscle are important exception) Angiotensin II: constricts most arterioles Vasopressin: released by posterior pituitary in response to decreased blood pressure + Atrial natriuretic peptide: vasodilator by regulating Na balance and blood volume; overall physiological importance unknown Endothelial cells and vascular smooth muscle o Can be acted on by substances/mechanical stimuli to secrete several paracrine agents that diffuse to the adjacent vascular smooth muscle to induce relaxation/constriction o Nitric oxide: important paracrine vasodilator (aka EDRF) Released continuously in significant amounts by endothelial cells in arterioles (maintains basal level vasodilation) Responds quickly to large number of chemical mediators involved in reflex/local control o Prostacyclin (prostaglandin I [PG2 ]): 2icosanoid, vasodilator; is not secreted until needed o Endothelin1 (ET1): vasoconstrictor released by endothelial cells in response to mechanical/chemical stimuli Can function as a hormone if high enough concentrations in blood are reached for widespread arteriolar vasoconstriction Arteriolar control in specific organs o Figure 12.39 – factors that determine arteriolar radius o Table 12.7 – importance of local and reflex controls in specific organs 12.10 – Capillaries Approximately 5% of blood is moving through capillaries at any time, allowing exchange of nutrients, metabolic end products, and cell secretions o Some exchange also occurs in venules Permeate every tissue in body except cornea; cells are no more than a few cells away from the nearest capillary o Allows for highly efficient diffusion/exchange Has essential role in tissue function leads to questions about angiogenesis (capillary growth and development) and what stimulates it in injury/healing/cancer o Known that vascular endothelial cells initiate new capillary networks through stimulation by angiogenic factors (cancer cells also secrete these) Angiostatin: naturallyoccurring peptide involved in inhibition of blood vessel growth can be used to reduce size of tumors in mice Anatomy of capillary network o Thinwalled tube of endothelial cells only one layer thick o No surrounding smooth muscle or elastic tissue o In some organs, they have a second set of cells that surround basement membrane to affect diffusion ability of substances (i.e. in brain) o Intercellular clefts: waterfilled spaces in between flat cells of endothelial wall o Fusedvesicle channels: form when endocytotic and exocytotic vesicles fuse o Vasodilation/vasoconstriction of other vessels (arterioles) affects blood flow through capillaries Blood sometimes enters through metarterioles that connect arterioles to venules moves though precapillary sphincter into capillary (can close off capillary completely if needed; open when tissue is active) Diffusion across the capillary wall: exchanges of nutrients and metabolic end products o Blood flow is slow to maximize exchange time o Substance movement between interstitial fluid and plasma relies on diffusion, vesicle transport, and bulk flow (sometimes mediated transport too) In all capillaries (except brain), diffusion is only important means of net nutrient/oxygen/waste movement o Lipidsoluble substances (oxygen and CO ) easi2y diffuse while ions/polar molecules need to pass through waterfilled channels in endothelium Waterfilled channels allows rate of ion/polar molecule movement to be high (not as high as lipid rates) intercellular clefts and fused vesicles Only small amounts of protein can diffuse (usually need vesicular transport) o “Leakiness” of capillaries differs between organs due to waterfilled channels One extreme: tight capillaries (brain) with no intercellular clefts, only tight junctions need carriermediated transport through bloodbrain barrier Other extreme: large intercellular clefts (liver) that allow even proteins to move easily o Transcapillary diffusion gradients occur as a result of cellular utilization of substance (established by local metabolic rate: increased metabolism leads to increased need for glucose/oxygen and increased production of CO ) 2 Glucose: continuously transported from interstitial to cells by carrier mediated transport mechanisms Oxygen: moves in same direction as glucose (into cells) by diffusion Carbon dioxide: continuously produced by cells and diffuses from cells to interstitial fluid (ultimately diffusing into capillary) Active hyperemia and increased cellular utilization of materials both lead to increasing diffusion gradients increasing rate of diffusion Bulk flow across the capillary wall: distribution of extracellular fluid o Bulk flow of proteinfree plasma to distribute the extracellular fluid volume (plasma and interstitial fluid) o Capillary walls are highly permeable to water and all plasma solutes except proteins Proteinfree plasma moves by bulk flow when hydrostatic pressure difference exists (capillary blood pressure vs. interstitial fluid hydrostatic pressure) filtration Capillary blood pressure is usually higher hydrostatic pressure difference exists to filter proteinfree plasma out of capillaries into interstitial fluid (protein stays in capillaries) o Osmotic flow of water brings solutes with it to penetrate membranes (to balance nonpenetrating solute concentrations); high to low concentration o Effects of solutes Crystalloids: lowMW solutes present in large quantities in plasma; can easily penetrate capillary pores ( concentrations in plasma/interstitial fluid are the same); includes Na , Cl, and K + Colloids: plasma proteins that cannot move though capillary pores and have low concentrations in interstitial fluid water concentration is slightly lower in plasma than interstitium, creating osmotic gradient from interstitium to capillary o Starling forces: four factors that determine net filtration pressure NFP=P +π cP −IF IF c Capillary hydrostatic pressure, osmotic force due to interstitial fluid protein concentration, interstitial hydrostatic pressure, osmotic force due to plasma protein concentration (respectively) + = favors movement out of capillary; – = favors movement into capillary *** usually can ignore P IFvirtually 0 mmHg) If net outward pressure exceeds inward pressure, bulk filtration of fluid will occur (leaving proteins behind in capillaries as fluid leaves) Can be applied to pulmonary circulation (Starling forces favor filtration slightly more in lungs than other tissues) o Regional differences in capillary pressure Capillary hydrostatic pressures vary in different regions of the body and are strongly influenced by laying down/standing/sitting Capillary hydrostatic pressures are also subject to physiological regulation mostly by changes in resistance of arterioles in that region Dilating arterioles = increased capillary hydrostatic pressure (less pressure is lost in overcoming resistance between arteries and capillaries) favors movement of fluid out of capillary/increased filtration Edema: abnormal accumulation of fluid in interstitial spaces (due to imbalance in Starling’s forces) o Can be caused by heart failure (increased venous pressure reduces blood flow out of capillaries excess filtration and accumulation of interstitial fluid) o Can occur in systemic or pulmonary tissues o Injury ( release of histamines/etc.) can cause dilated arterioles increase in capillary pressure and filtration increased size of intercellular clefts/ability of plasma proteins to escape from bloodstream Increase in protein osmotic force in interstitial fluid can increase filtration/edema o Can be caused by abnormal decrease in protein plasma concentration (water does not need to remain in capillaries to balance concentration leaves capillary) Caused by liver disease (decreased protein production) or kidney disease (protein loss in urine) or kwashiorkor (protein malnutrition) 12.11 – Veins Capillaries venules veins Last set of tubes that blood flows through on way back to heart o Pressure difference between peripheral veins (1015 mmHg) and right atrium (close to 0 mmHg) drives venous return in systemic circulation Adequate pressure due to low resistance to flow from veins (large diameters) Major functions: act as lowresistance conduits for blood flow from tissues to heart and reflexively alter diameters in response to changes in blood volume to maintain venous return pressure o Peripheral veins in arms/legs contain oneway valves that ensure blood moves towards heart o Rate of venous return = major determinant of enddiastolic ventricular volume ( SV) Determinants of venous pressure o Volume of fluid in tube o Compliance of walls o Veins can accommodate large volumes of blood with relatively small increase in internal pressure 60% of total blood volume is in systemic veins, but pressure is only 10 mmHg (compared to 15% of blood in systemic arteries at 100 mmHg) o Walls contain smooth muscle innervated with sympathetic neurons (norepinephrine release muscle contraction, increase pressure) Drives more blood into right side of heart Can also respond to hormonal/paracrine vasodilators and vasoconstrictors o Skeletal muscle pump: increases local venous pressure of veins running through muscles during contraction; forces more blood to heart o Respiratory pump: diaphragm descends during inhalation increase in abdominal pressure increase in intraabdominal vein pressure; also results in decrease in pressure in intrathoracic veins/right atrium; bigger pressure difference forces more blood to heart Any changes in venous return almost immediately causes equivalent changes in cardiac output through FrankStarling mechanisms ( they are the same except for transient differences) SKIP 12.12 12.13 – Baroreceptor Reflexes Arterial baroreceptors o Respond to changes in pressure o Found where left and right common carotid arteries divide into two smaller arteries that supply the head with blood (carotid sinus) and in the arch of the aorta (aortic arch baroreceptor) Afferent neurons travel from these points to the brainstem and provide input to the neurons of cardiovascular control centers o At a particular steady pressure (ex: 100 mmHg), there is a certain rate of action potential discharge from neurons, which increases/decreases with increased/decreased pressure Medullary cardiovascular center o Located in the medulla oblongata o Receive input from the various baroreceptors throughout the body uses it to determine the action potential frequency sent back to the vagus (parasympathetic) neurons in the heart/sympathetic neurons in the heart/arterioles/veins Increased rate of discharge = decreased sympathetic activity and increased parasympathetic activity Angiotensin II and vasopressin are also altered (decreased pressure = increased secretion = arteriole constriction) Arterial baroreceptor reflex operation o Ex) decreased arterial pressure (due to hemorrhage) = decreased rate of firing Leads to increased heart rate (due to increased sympathetic activity and decreased parasympathetic activity) Increased ventricular contractility Arteriolar constriction Increased venous constriction Net result: increased cardiac output, increased total peripheral resistance, and BP returns to normal o Functions primarily as a shortterm regulator of arterial BP Will adapt to prolonged change in BP (new set point) Other baroreceptors contribute to a feedforward component of arterial pressure control 12.14 – Blood Volume and LongTerm Regulation of Arterial Pressure Baroreceptors cannot set longterm arterial pressure as they will adapt to any prolonged change blood volume controls longterm regulation Blood volume influences venous pressure/return, enddiastolic/stroke volumes, and cardiac output o All related, thus increased blood volume increases arterial pressure (and increased arterial pressure decreases blood volume) negative feedback loops Blood volume can only stabilize longterm arterial pressure if blood volume itself is stabilized o Urinary and circulatory systems both interact to help maintain this 12.15 – Other Cardiovascular Reflexes and Responses Causes of increased blood pressure: o Decreased arterial oxygen concentration o Increased arterial carbon dioxide concentration o Decreased blood flow to brain o Pain originating in the skin (from viscera/joints decrease in BP) Other physiological states (eating, sexual activity, sleeping) affect BP Mood influences BP (lower when happy) Changes triggered by higher brain centers to medullary cardiovascular center Cushing’s phenomenon: increased intracranial pressure causes a dramatic increase in mean arterial pressure o Cranium cannot expand to accumulate pressure pressure is directed inwards on brain, which decreases blood flow to all parts of brain accumulation of waste/not enough oxygen o Fluid must be removed to fix 12.16 – Hemorrhage and Other Causes of Hypertension Hypotension: low blood pressure, regardless of cause o Consequences: reduced blood flow to brain/muscles Hemorrhage: type of hypotension caused by significant deceased blood volume o Immediate response: arterial baroreceptor reflex Cannot restore all the way back to normal: directly affected factors (stroke volume, cardiac output, arterial pressure) remain below normal; values not directly affected (affected only by reflex; heart rate, total peripheral resistance) are higher than normal Increased peripheral resistance vasoconstriction (less blood flow) why skin can become pale/cold o Interstitial fluid will move into capillaries due to decreased hydrostatic pressure autotransfusion; can restore blood volume to normal in 1224 hours after moderate hemorrhage o Both responses can restore up to 30% blood volume lost Blood volume must actually be restored by increased fluid ingestion/minimized water loss (initiated by increased thirst/reduction in water and salt lost in urine) mediated by hormones RBC must be recreated to replenish blood Severe sweating, burns, diarrhea, and vomiting can also cause hypotension o Depletes body of water and essential ions Cardiac contractility can cause hypotension (ex: during a heart attack) Strong emotion can cause hypotension (and sometimes fainting) vasovagal syncope o Higher brain centers inhibit sympathetic activity to circulatory system/enhance parasympathetic activity ( decreased blood flow to brain & arterial pressure) Shock: any situation in which a decrease in blood flow to the organs and tissues damages them o Hypovolemic shock: caused by decrease in blood volume secondary to hemorrhage or loss of fluid other than blood o Lowresistance shock: due to a decrease in total peripheral resistance secondary to excessive release of vasodilators (allergy/infection) o Cardiogenic shock: due to extreme decrease in cardiac output from any variety of factors (ex: during heart attack) o Deterioration of the heart leads to decreased cardiac output more shock; which can become irreversible SKIP 12.1712.18 12.19 – Hypertension Hypertension: chronically increased systemic arterial pressure (above 140/90 mmHg) o 26% of adults worldwide affected; 34% U.S. citizens affected o Left ventricle is chronically pumping against an increased arterial pressure develops muscle mass: left ventricular hypertrophy Initially helps maintain heart function; leads to diminished contractile function and heart failure over time o Can lead to atherosclerosis, heart attacks, kidney damage, stroke (blockage/rupture of a cerebral blood vessel, causing brain damage) Risk of heart disease/stroke doubles with every 20 mmHg increase in systolic pressure and every 10 mmHg increase in diastolic pressure Primary hypertension: hypertension of uncertain cause; more common o Suspected genetic/environmental factors Changes in lifestyle can reduce factors (weight loss, reduced salt intake, cessation of smoking/heavy drinking, clean eating, exercise) o Genes associated with angiotensinaldosterone system and regulation of endothelial cell function/arteriolar smooth muscle contraction suspected o Most significant factor: increase in total peripheral resistance caused by reduced arteriolar radius Secondary hypertension: identified causes o Renal hypertension: due to kidney damage increased renin release leads to excessive concentrations of angiotensin II (vasoconstrictor) and low urine production Treat with lowsodium diet and diuretics o Endocrine disorders (syndromes involving hypersecretion of cortisol, aldosterone, thyroid hormone) can cause it o Medications (oral contraceptives, nonsteroidal antiinflammatory drugs) can cause it o Sleep apnea linked to it Table 12.11 – drugs used to treat hypertension by decreasing cardiac output and/or total peripheral resistance 12.20 – Heart Failure Collection of signs and symptoms that occur when the heart does not pump an adequate cardiac output o May be pumping against a chronically increased arterial pressure (hypertension) Or structural damage to the myocardium due to decreased coronary blood flow and etc. Can group patients into two categories o Diastolic dysfunction: reduced compliance of the ventricle (abnormal stiffness) Results in reduced ability to fill adequately at normal diastolic filling pressures leads to reduced enddiastolic volume = reduced SV Contractility is still normal Causes: systemic hypertension hypertrophy o Systolic dysfunction: results from myocardial damage (ex: from heart attack); decrease in cardiac contractility (lower SV at any given enddiastolic volume) Presents as decrease blood ejection; enddiastolic volume increases Triggers arterial baroreceptor reflexes, which are elicited more than usual because afferent baroreceptors become less sensitive o Less discharge = brain thinks pressure decrease has occurred tries to compensate (increased HR, total peripheral resistance, concentrations of hormonal vasoconstrictors) Eventually leads to increased fluid retention and massive expansion of extracellular fluid o When fluid retention increases, problems arise Ventricles with systolic dysfunction will become very distended with blood worsens situation Edema will eventually occur, swelling of the legs and feet Failure of left ventricle with fluid will lead to pulmonary edema (fluid in lungs), which impairs normal gas exchange o Left ventricle fails to pump blood to the same extent as the right ventricle increased blood volume in pulmonary vessels faster rate of filtration than lymphatics can deal with o Worse at night due to laying down while sleeping Treatment of heart failure: o Correct precipitating cause (ex: hypertension) with drugs o Cardiac transplant 12.21 – Hypertrophic Cardiomyopathy Condition that frequently leads to heart failure One of the most common inherited cardiac diseases (1 in 500 people) Characterized by increased thickness of heart muscle, especially interventricular septum and wall of left ventricle o Interferes with cardiac output to meet metabolic requirements o Angina pectoris: chest pain experienced by reduction of blood flow to heart Disruption of orderly array of myocytes and conducting cells in walls o Can lead to dangerous/fatal arrhythmias Usually symptomless until too late Causes unknown; possible genetic factors identified (involving myosin, troponin, and tropomyosin) Treatment: drugs to prevent arrhythmia, surgical repair of septum and valve, heart transplant 12.22 – Coronary Artery Disease and Heart Attacks Coronary artery disease: changes in one or more of the coronary arteries causes insufficient blood flow (ischemia) to the heart o Many patients with coronary artery disease experience recurrent transient episodes of inadequate coronary blood flow/angina before ultimately suffering a heart attack Myocardial infarction: death of portion of heart affected by myocardial damage o Symptoms: prolonged chest pain (often radiating from left arm), nausea, vomiting, sweating, weakness, shortness of breath o Diagnosis made by ECG and detection of specific cardiac muscle proteins in plasma o Ventricular fibrillation: abnormality in impulse conduction triggered by damaged myocardial cells; cause of sudden death during myocardial infarction Cardiopulmonary resuscitation (CPR) can sometimes save individuals (series of chest compressions and mouthtomouth) Defibrillation: electrical current passed through heart in effort to correct abnormal electrical activity Heart attacks are experienced by about 1.1 million Americans (over 40% die from it) Causes o Atherosclerosis: major cause; thickening of portion of arterial vessel wall closest to lumen with plaques made of many smooth muscle cells, macrophages, lymphocytes, deposits of cholesterol/fatty substances, and dense layers of connective tissue matrix Reduces coronary blood flow Can result in coronary thrombosis: blood clot; total occlusion, generally triggers heart attack Likely caused by initially damage/inflammation that becomes excessive, cigarette smoking, excess cholesterol, hypertension, diabetes, obesity, sedentary lifestyle, and stress Prevention o Exercise (can red