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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) Multidrug resistance- associated protein 4 Cytochrome P450 2D6 Sarcoplasmic/endoplasmic reticulum calcium ATPase 2 cAMP-dependent protein kinase catalytic subunit alpha Pindolol Ca+ Ca+ Ca+ Na+ Na+ Ca+ Ca+ Ca+ Pindolol Pindolol Bopindolol Bopindolol Bopindolol ATP H2O Ca+ ADP Pi Ca+ Heme Ca+ Troponin Troponin Muscle Contraction G-Protein Signaling Cascade 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 apart and muscle relaxation to occur. Actin Filament Myosin Filament The beta-1 adrenergic receptor is coupled to and activates the G-protein signalling cascade.Antagonizing this receptor blocks the G-protein signalling cascade 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 propranolol 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 Endoplasmic Reticulum Bopindolol is a prodrug for pindolol. Hepatocyte Bopindolol is administered as an oral tablet.
Mitochondria Endoplasmic Reticulum Calcium TPM1 TPM2 ADRB1 CACNA1C CACNA2D2 CACNB1 RYR2 PRKAR1A SLC8A1 CACNA1H CACNA1G ABCC4 CYP2D6 ATP2A2 PRKACA Pindolol Calcium Calcium Calcium Sodium Sodium Calcium Calcium Calcium Pindolol Pindolol Bopindolol Bopindolol Bopindolol Adenosine triphosphate Water Calcium Adenosine diphosphate Phosphate Calcium Calcium Troponin Troponin Muscle Contraction G-Protein Signaling Cascade
Ca+ TPM1 TPM2 ADRB1 CACNA1C CACNA2D2 CACNB1 RYR2 PRKAR1A SLC8A1 CACNA1H CACNA1G ABCC4 CYP2D6 ATP2A2 PRKACA Pindol Ca+ Ca+ Ca+ Na+ Na+ Ca+ Ca+ Ca+ Pindol Pindol Bop Bop Bop ATP H2O Ca+ ADP Pi Ca+ Heme Ca+ Troponi Troponi Mus Con PW000728 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 apart and muscle relaxation to occur. Actin Filament Myosin Filament The beta-1 adrenergic receptor is coupled to and activates the G-protein signalling cascade.Antagonizing this receptor blocks the G-protein signalling cascade 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 propranolol 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 Endoplasmic Reticulum Bopindolol is a prodrug for pindolol. Hepatocyte Bopindolol is administered as an oral tablet.
Mitochondria Endoplasmic Reticulum Ca2+ TPM1 TPM2 ADRB1 CACNA1C CACNA2D2 CACNB1 RYR2 PRKAR1A SLC8A1 CACNA1H CACNA1G ABCC4 CYP2D6 ATP2A2 PRKACA Pindol Ca2+ Ca2+ Ca2+ Na+ Na+ Ca2+ Ca2+ Ca2+ Pindol Pindol Bop Bop Bop ATP H2O Ca2+ ADP Pi Ca2+ Ca2+ Troponi Troponi Mus Con PW000728