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Ca+ Tropomyosin alpha-1 chain Tropomyosin beta chain Beta-1 adrenergic receptor 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 Pindolol Ca+ Ca+ Ca+ Na+ Na+ Ca+ Ca+ Ca+ Pindolol Pindolol 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 pindolol Without pindolol Pindolol, by antagonizing beta-1 adrenergic receptors, decreases intracellular Ca2+. Phase 4 spontaneous depolarization is Ca2+ dependent, therefore pindolol 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 Pindolol 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 Pindolol is administered as an oral tablet
Mitochondria Calcium TPM1 TPM2 ADRB1 CACNA1C CACNA2D2 CACNB1 RYR2 PRKAR1A SLC8A1 CACNA1H CACNA1G ATP2A2 PRKACA Pindolol Calcium Calcium Calcium Sodium Sodium Calcium Calcium Calcium Pindolol Pindolol Adenosine triphosphate Water Calcium Adenosine diphosphate Phosphate Calcium Calcium Troponin Troponin G-Protein Signaling Cascade Muscle Contraction
Ca+ TPM1 TPM2 ADRB1 CACNA1C CACNA2D2 CACNB1 RYR2 PRKAR1A SLC8A1 CACNA1H CACNA1G ATP2A2 PRKACA Pindol Ca+ Ca+ Ca+ Na+ Na+ Ca+ Ca+ Ca+ Pindol Pindol ATP H2O Ca+ ADP Pi Ca+ Ca+ Troponi Troponi PW000728 Mus Con 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 pindolol Without pindolol Pindolol, by antagonizing beta-1 adrenergic receptors, decreases intracellular Ca2+. Phase 4 spontaneous depolarization is Ca2+ dependent, therefore pindolol 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 Pindolol 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 Pindolol is administered as an oral tablet
Mitochondria Ca2+ TPM1 TPM2 ADRB1 CACNA1C CACNA2D2 CACNB1 RYR2 PRKAR1A SLC8A1 CACNA1H CACNA1G ATP2A2 PRKACA Pindol Ca2+ Ca2+ Ca2+ Na+ Na+ Ca2+ Ca2+ Ca2+ Pindol Pindol ATP H2O Ca2+ ADP Pi Ca2+ Ca2+ Troponi Troponi PW000728 Mus Con