The following is a paraphrased version of the excerpt:

The effects of Isoproterenol on calcium currents in atrial myocytes were observed in Fig. 16.6. The upper panel shows the conducted currents by T-type calcium channels, while the lower panel shows the currents conducted by L-type calcium channels. The membrane potential was altered from -80 to -20mV in the upper panel, and from -30 to +30mV in the lower panel. The redrawn figures were taken from a study conducted by Bean BP and published in the Journal of General Physiology in 1985.

In Fig. 16.7, the effects of diltiazem, a calcium channel antagonist, on action potentials and isometric contractile forces in papillary muscles were recorded. The tracings were recorded under control conditions (C) and in the presence of diltiazem at concentrations of 3, 10, and 30µmol/L. The redrawn figures were taken from a study conducted by Hirth C et al. and published in the Journal of Molecular and Cellular Cardiology in 1983.

When the membrane potential approaches and reaches positive values near the peak of the action potential upstroke, the potassium current suddenly decreases, as shown in Fig. 16.8. This reduction in potassium current, associated with a decrease in gK, prevents excessive loss of potassium from the cell during the plateau phase.

To increase the influx of calcium, catecholamines first bind to β-adrenergic receptors in the cardiac cell membrane. This interaction stimulates the membrane-bound enzyme adenylate cyclase, which increases the intracellular concentration of cyclic adenosine monophosphate (cAMP). The rise in cAMP activates cAMP-dependent protein kinase, which promotes phosphorylation of L-type calcium channels in the cell membrane. This enhances the influx of calcium into the cells, as depicted in Fig. 16.6. Conversely, acetylcholine interacts with muscarinic receptors in the cell membrane to inhibit adenylate cyclase. Acetylcholine antagonizes the activation of calcium channels and diminishes gCa.

Calcium channel antagonists, such as verapamil, amlodipine, and diltiazem, block calcium channels. These drugs decrease gCa and impede the influx of calcium into myocardial cells. They also decrease the duration of the action potential plateau and diminish the strength of cardiac contraction, as shown in Fig. 16.7. Calcium channel antagonists also depress the contraction of vascular smooth muscle, leading to generalized vasodilation. This reduction in vascular resistance reduces the counterforce (afterload) opposing the propulsion of blood from the ventricles into the arterial system, as explained elsewhere. Therefore, vasodilator drugs like calcium channel antagonists are often referred to as afterload-reducing drugs.

Inward rectification refers to the reduction in gK at both positive and low negative values of membrane potential (Vm). It is a characteristic observed in several K+ currents, including iK1, as depicted in Fig. 16.9. These channels allow large K+ currents to flow at negative Vm values (i.e., gK is large). However, when Vm is near 0 mV or positive during the plateau phase (phase 2), little to no K+ current flows (i.e., gK is small). Therefore, the significant gK observed during phase 4 of the cardiac action potential is primarily due to the iK1 channels, but the current through these channels is greatly diminished during the plateau phase, as shown in Fig. 16.9.
•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