•Fig. 16.6 Effects of Isoproterenol on the Ca++ Currents. ThecurrentswereconductedbyT-type(upper panel) andL-type(lower panel) calciumchannelsinatrialmyocytes.Upper panel, Themembranepotentialwaschangedfrom−80to−20mV.Lower panel, Themembranepotentialwaschangedfrom−30to+30mV.(RedrawnfromBeanBP.J Gen Physiol. 1985;86:1.) •Fig. 16.7 Effectsofdiltiazem,acalciumchannelantagonist,ontheactionpotentials(inmillivolts[mV])andisometriccontractileforces(inmillinewtons[mN])recordedfromapapillarymuscleinvitro.Thetrac-ingswererecordedundercontrolconditions(C)andinthepresenceofdiltiazeminconcentrationsof3,10,and30µmol/L.(RedrawnfromHirthC,etal.J Mol Cell Cardiol. 1983;15:799.)20 50 msec Action potential Force 0 mV 10 30 C and 3 C 3 10 30 mN 0.5 50 msec
However, as Vm approaches and then attains positive values near the peak of the action potential upstroke, gK suddenly decreases (
Fig. 16.8 ). The diminished K+ current associated with the reduction in gK prevents excessive loss of K+ from the cell during the plateau.
ToenhancegCa,catecholaminesfirstbindtoβ-adrenergicreceptorsinthecardiaccellmembrane.Thisinteractionstimulatesthemembrane-boundenzymeadenylatecyclase,whichraisestheintracellularconcentrationofcyclicadenosinemonophosphate(cAMP;seealso ).TheriseincAMPactivatescAMP-dependentproteinkinase,whichinturnpromotesphosphorylationofL-typecalciumchannelsinthecellmembraneandthusaugmentstheinfluxofCa++ intothecells(see
Fig.16.6 ).Conversely,acetylcholineinteractswithmuscarinicreceptorsinthecellmembranetoinhibitadenylatecyclase.Inthisway,acetylcholineantagonizestheactivationofcalciumchannelsandtherebydiminishesgCa.
Calciumchannelantagonistsaresubstancesthatblockcalciumchannels.Examplesincludethedrugsverapamil,amlodipine,anddiltiazem.ThesedrugsdecreasegCaandtherebyimpedetheinfluxofCa++ intomyocardialcells.Calciumchannelantagonistsdecreasethedurationoftheactionpotentialplateauanddiminishthestrengthofthecardiaccontraction(see
Fig.16.7 ).Calciumchannelantagonistsalsodepressthecontractionofvascularsmoothmuscleandtherebyinducegeneralizedvasodilation.Thisdiminishedvascularresistancereducesthecounterforce(afterload)thatopposesthepropulsionofbloodfromtheventriclesintothearterialsystem,asexplainedin .Hence,vasodilatordrugssuchasthecalciumchannelantagonistsareoftenreferredtoasafterload-reducing drugs.
The reduction in gK at both positive and low negative values of Vm is called inward rectification. Inward rectification is a characteristic of several K+ currents, including iK1 (
Fig. 16.9 ). For these channels, large K+ currents flow at negative values of Vm (i.e., gK is large). However, when Vm is near 0 mV or positive, as occurs during the plateau (phase 2), little or no K+ current flows (i.e., gK is small). Thus the substantial gK that prevails during phase 4 of the cardiac action potential (see
Fig. 16.8 ) is large because of the iK1 channels, but current through these channels is greatly diminished during the plateau (see
Fig. 16.9