BME 501 Advanced Topics in Biomedical Systems Spring 2014 Dr. KayBME 501 Lecture Notes – Apr 2 Cardiac Cycle (Overview) • Structure of Heart • Contraction Cycle in Heart Cardiac Action Potentials (APs) • Resting Membrane Potential • Five Phases of Cardiac APs • Two Types of Cardiac APs • Propagation of Cardiac APsSA Node AV Node Contraction Cycle in Heart Ventricular diastole: • Ventricles at rest, fill with blood Atrial systole: • Atria push additional blood into ventricles during ventricular diastole Ventricular systole: • Blood ejected from ventricles • Atria in diastole, refill with bloodResting Membrane Potential • Membrane potential – Electrical potential between interior and exterior of a cell – Can be measured using a microelectrode • Intracellular potential of resting cardiac myocyte: –80 mV to –90 mV (i.e., 80 to 90 mV lower than extracellular fluid) • The result of differences in ion concentrations across cell membrane (due to ion-conducting channels in membrane) • Behavior/type of ion channels characterized by patch clampingResting Membrane Potential • Three classes of cation-conducting channels in cardiac myocytes, – K+ (potassium) – Na+ (sodium) – Ca2+ (calcium) • Each class of channels is selective for one cation, but multiple subtypes exist in each class • Channel selectivity not absolute (e.g., one type of potassium channel has a K+/Na+ permeability ratio of ~100/1) • Most channels can flip repeatedly between open and closed • Probability that open or closed state predominates depends on membrane potential and other factorsResting Membrane Potential • Na+ and Ca2+ channels mostly closed at negative potentials • Potassium ions generate resting membrane potential – High intracellular K+ concentration (140 mM) relative to extracellular K+ concentration (4 mM) – Specific K+-permeable channels, inward rectifier channel (Kir), partly open in resting cell membrane • Intracellular [K+] ~35 times greater than extracellular [K+] • K+ tends to diffuse out of cell through Kir channels = resting outward current of K+ (iKir or iK1)Resting Membrane Ion Gradients and CurrentsResting Membrane Potential • Nernst Equation predicts K+ equilibrium potential • If negative intracellular potential big enough, electrical attraction to K+ can offset concentration gradient • Balance occurs at potassium equilibrium potential, EK • Changes in extracellular [K+] affect resting membrane potential EX=61.5zæèçöø÷×log10CeCiæèçöø÷EX: electrical equilibrium potential for ionic species X z : ion valencyCe: extracellular concentration of ion Ci: intracellular concentration of ionEK=61.5+1æèçöø÷×log104140æèçöø÷= -95mVResting Membrane Potential • Na+ background current creates non-equilibrium conditions • Chemical and electrical gradient draw Na+ into cell (ENa = +70 mV) • Small resting inward current of cations, mostly Na+ = inward background current (ib) • Membrane potential, Vm, depends on ratio of ionic permeabilities iKir= gKVm- EK( )ib= gNaVm- ENa( )Vm=EK+ ENa×gNa/ gK1+ gNa/ gK=-95 + 70×1/101+1/10= -80mVCell at restResting Membrane Ion Gradients and CurrentsResting Membrane Potential • Na+-K+ pump preserves intracellular ion levels • Uses energy from ATP to pump Na+ out of cell and K+ in a ratio of 3 Na+ to 2 K+ • Pump generates a net outflow of positive charge; called ‘electrogenic’ • Pump rate increases with increase in intracellular [Na+] or extracellular [K+] • Several ion-exchangers depend on Na+ gradient set up by Na+-K+ pump – Na+-Ca2+ exchanger important for cardiac AP – Na+-H+ exchanger regulates intracellular pHResting Membrane Potential • Calcium transporters regulate diastolic Ca2+ and Ca2+ store • Na+-Ca2+ exchanger on surface membrane acts as main Ca2+ transporter out of cell • ATP-powered Ca2+ pumps more abundant on sarcoplasmic reticulum (SR; holds intracellular store of Ca2+)Relative Intracellular and Extracellular Concentrations of Several Important Ions Concentration Voltage Ion Intracellular (mM) Extracellular (mM) EX (mV) Na+ Low (15) High (145) +60 K+ High (150) Low (4) –94 Ca2+ Low (0.07) High (2) +129 Resting Membrane PotentialFive Phases of Cardiac APs • Action potential: an abrupt reversal of membrane potential to a positive value • Triggered by an AP in an adjacent myocyte • Neighboring AP creates current that reduces negative resting potential • When membrane potential reaches threshold level of –60 mV to –70 mV, conductance of sarcolemma increases suddenly due to opening of Na+ channelsFive Phases of Cardiac APs • Phase 0: rapid depolarization – Caused by sudden, inward current of Na+ – Characterized by overshoot: potential reaches +20 mV to +30 mV • Phase 1: early, partial repolarization • Phase 2: plateau – Occurs at 0 to –20 mV – Lasts 200 to 400 ms – Myocardial AP lasts ~100 times longer than APs of nerve and skeletal muscle cellsFive Phases of Cardiac APs • Phase 3: repolarization – Occurs at 1/1000th the rate of depolarization • Phase 4: resting potential • Particular shape of AP differs depending on location in the heart/particular cell typeFive Phases of Cardiac APs • Phase 0: rapid depolarization – Fast Na+ channels open when Vm greater than –60 mV to –70 mV (voltage-gated) – Allow inward Na+ current, causing rapid depolarization – Open for short period, then inactivate (time-dependent) • Phase 1: early, partial repolarization – Transient outward current (ito) is carried mostly by voltage-gated K+ channels – Channels open transiently in response to depolarization, then quickly inactivateFive Phases of Cardiac APs • Phase 2: plateau – Early plateau generated by small, long-lasting inward current of Ca2+ ions (iCa) – Carried by long-opening (L-type) Ca2+ channels – Outward K+ current (iKir) reduced because membrane K+ conductance falls upon depolarization (inward rectification)Five Phases of Cardiac APs • Phase 2: plateau (cont.) – Late plateau maintained by Na+-Ca2+ exchangers – Carries a net inward current (3 Na+ in for 1 Ca2+ out) • Phase 3: repolarization – Delayed rectifier/slow K+ channels (KV or KS) activated by depolarization open slowly – Finally produce sufficient outward K+ current (iKv) to overcome inward, late-plateau currentsChemicals Affecting Cardiac AP • Tetrodotoxin (TTX) –