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Ca+ Tropomyosin alpha-1 chain Tropomyosin beta chain Beta-1 adrenergic receptor Voltage Gated Potassium Channel Voltage- depenent L-type calcium channel Voltage- depenent L-type calcium channel Voltage- depenent L-type calcium channel Ryanodine receptor 2 cAMP-dependent protein kinase type I-alpha regulatory subunit Sodium/calcium exchanger 1 Voltage-gated T-type calcium channel (ICaT) Voltage-gated T-type calcium channel (ICaT) Sarcoplasmic/endoplasmic reticulum calcium ATPase 2 cAMP-dependent protein kinase catalytic subunit alpha Sotalol Ca+ Ca+ Ca+ Na+ Na+ Ca+ Ca+ Ca+ Sotalol Sotalol K+ K+ ATP H2O Ca+ ADP Pi Ca+ Ca+ Troponin Troponin G-Protein Signaling Cascade Muscle Contraction Cardiac Myocyte Sarcoplasmic Reticulum Low calcium is unable to bind to troponin to displace tropomyosin from the myosin binding sites on the actin filaments Myosin and actin are unbound allowing the filaments to slide further apart, resulting in muscle relaxation Actin Filament Myosin Filament The beta-1 adrenergic receptor is coupled to and activates the G-protein signalling cascade. Antagonizing the beta-1 receptor blocks this from occurring. The G-protein signalling cascade activates protein kinase which activates calcium channels on the membrane, resulting in calcium influx. Low calcium is unable to activate the ryanodine receptor on the sarcoplasmic reticulum. Time Membrane potential (mV) -40mV (threshold) Pacemaker Action Potential Phase 0- depolarization Phase 3- repolarization Phase 4-spontaneous depolarization With sotalol Without sotalol Sotalol, by antagonizing beta-1 adrenergic receptors, decreases intracellular Ca2+. Phase 4 spontaneous depolarization is Ca2+ dependent, therefore sotalol decreases the slope of phase 4, increasing the time it takes for threshold to be reached and thus slows heart rate Cytosol Since calcium is linked to activation of muscle contraction. Reducing cytosolic calcium levels reduces muscle contraction Sotalol enters the bloodstream and once it reaches the heart, it antagonizes the beta-1 adrenergic receptor on the cell membrane of myocytes such that epinephrine stimulation of the heart is reduced. T-tubule Sotalol is administered as an oral tablet Sotalol inhibits potassium channels to slow repolarization
Mitochondria Calcium TPM1 TPM2 ADRB1 KCND2 CACNA1C CACNA2D2 CACNB1 RYR2 PRKAR1A SLC8A1 CACNA1H CACNA1G ATP2A2 PRKACA Sotalol Calcium Calcium Calcium Sodium Sodium Calcium Calcium Calcium Sotalol Sotalol Potassium Potassium Adenosine triphosphate Water Calcium Adenosine diphosphate Phosphate Calcium Calcium Troponin Troponin G-Protein Signaling Cascade Muscle Contraction