Theso-calledfunnycurrent(if)incardiacSAnodecellsisactivatedbyhyperpolarizationandgatedbycyclicnucleotides,anditschannelisdesignatedHCN.TherearefourmembersoftheHCN genefamily,andsuchchannelsarefoundincentralnervoussystemneuronsthatgenerateactionpotentialsrepetitively.Transmembranesegment4(S4)ofHCNhasmanypositivelychargedaminoacidsthatactasvoltagesensors,whicharealsopresentinvoltage-gatedsodium,potassium,andcalciumchannels.ThedominantchannelexpressedintheheartisderivedfromtheHCN4 gene.MutationsinaminoacidsinS4andintheS4-to-S5linkercausemarkedchangesinthevoltagedependenceofactivation,insuchawaythatgreaterhyperpolarizationisneededtoopenthechannel.Thiseffectislikethatofacetylcholine,andithasbeenpredictedthattheoccurrenceofsuchmutationsinthehumanheartcouldunderliesinusbradycardiaandsicksinussyndrome.
•Fig. 16.20 Membrane Action Potentials Recorded From an Sino-atrial Node Pacemaker Cell. TheconcentrationofCa++inthebathwasreducedfrom2to0.2mmol/L(“mM”).(ModifiedfromKohlhardtM,etal.Basic Res Cardiol. 1976;71:17.)–60 0 Ca++ 2 mM 500 msec Ca++ 0.2 mM mV
Fig. 16.20 ) or the addition of calcium channel antagonists diminishes the amplitude of the action potential and the slope of the slow diastolic depolarization in SA node cells. Research evidence indicates that additional ion currents—including a sustained (background) inward Na+ current (iNa), the T-type Ca++ current, and the Na+/Ca++ exchange current triggered by spontaneous release of Ca++ from the sarcoplasmic reticulum—may also be involved in pacemaking. These observations illustrate the many ways to sustain this vital function.
RegionsoftheheartotherthantheSAnodemayinitiatebeatsinspecialcircumstances.Suchsitesarecalledectopic foci orectopic pacemakers. Ectopicfocimaybecomepacemakerswhen(1)theirownrhythmicitybecomesenhanced,(2)therhythmicityofthehigherorderpacemakersbecomesdepressed,or(3)allconductionpathwaysbetweentheectopicfocusandregionswithgreaterrhythmicitybecomeblocked.Ectopicpacemakersmayactasasafetymechanismwhennormalpacemakingcentersfail.However,ifanectopiccenterfireswhilethenormalpacemakingcenterstillfunctions,theectopicactivitymayinduceeithersporadicrhythmdisturbances,suchasprematuredepolarizations,orcontinuousrhythmdisturbances,suchasparoxysmaltachycardias(seethesection“
The autonomic neurotransmitters affect automaticity by altering membrane ionic currents. The adrenergic transmitters increase all three currents involved in SA nodal automaticity. To increase the slope of diastolic depolarization, the augmentation of if and iCa by adrenergic transmitters must exceed the enhancement of iK by these same transmitters.
The hyperpolarization induced by acetylcholine released from vagus nerve endings in the heart is achieved by the activation of specific potassium channels: the aThe ionic basis for automaticity in AV node pacemaker cells resembles that in SA node cells. Similar mechanisms also account for automaticity in ventricular Purkinje fibers, except that the fast Na+ current rather than iCa is involved. Also, a voltageand time-dependent K+ current rather than the hyperpolarization-induced inward current if has been suggested to mediate the slow diastolic depolarization; however, this remains to be clarified.