Snapshot A 64-year-old man with chronic obstructive pulmonary disease presents with palpitations and lightheadedness. In his chart, there are documented allergies to calcium channel blockers. He is tachycardic (160/min). An electrocardiogram reveals an irregular supraventricular rhythm with polymorphic P waves. A medication that increases contractility is given. (Digoxin) Introduction Generation of action potential initiated by the sinoatrial (SA) node delayed by the atrioventricular (AV) node allows for ventricular filling prior to contraction Excitability and refractory periods excitability myocytes are able to generate an action potential in response to depolarization cells must reach the threshold potential to achieve an action potential note, myocytes are electrically coupled via gap junctions that allow propagation of the action potential refractory period occurs after depolarization prevents further depolarization as the inactivation gates on the Na+ channels are closed and no current can flow through them once a cell is repolarized, the inactivation gates on the Na+ channels re-open a cell is once again excitable Excitation-Contraction Coupling The action potential causes a rush of Ca2+ into the cell via L-type voltage-gated Ca2+ channels indirectly blocked by β-blockers via ↓ cAMP directly blocked by non-dihydropyridine Ca2+ channel blockers This triggers the release of more Ca2+ from the sarcoplasmic reticulum via ryanodine receptors blocked by the ryanodine toxin Ca2+ binds to troponin C tropomyosin is moved out of the way Actin and myosin can now bind cross-bridges are formed and broken, and thin and thick filaments slide past each other creating tension Contraction occurs Contractility Contractility, or level of tension generated, is determined by intracellular Ca2+ positive inotropic agents increase intracellular Ca2+ digoxin inhibits extracellular K+ binding site of the Na+-K+ ATPase on myocyte cell membrane when the ATPase is inhibited, ↑ Na+ intracellular concentration Ca2+-Na+ exchanger decreases the amount of Ca2+ it pumps out of the cell ↑ Ca2+ intracellular concentration Relaxation Relaxation and repolarization of the cell membrane occurs when ↓ intracellular Ca2+ concentration back to resting levels Ca2+ ATPase on sarcoplasmic reticulum membrane Ca2+ returns to sarcoplasmic reticulum Ca2+ ATPase on cell membrane Ca2+ extruded out of the cell Ca2+-Na+ exchange on cell membrane exchanges 1 Ca2+ out of the cell for 3 Na+ into the cell