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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 Laβlol Ca+ Ca+ Ca+ Na+ Na+ Ca+ Ca+ Ca+ Laβlol Laβlol ATP H2O Ca+ ADP Pi Ca+ Ca+ Troponin Troponin G-Protein Signaling Cascade Muscle Relaxation Cardiac Myocyte Sarcoplasmic Reticulum Normally, calcium binding to troponin displaces tropomyosin from the myosin binding sites on the actin filaments. Low concentrations of calcium disallow this from occurring. Myosin and actin filaments slide further away from each other leading to muscle relaxation. Actin Filament Myosin Filament The beta-1 adrenergic receptor is coupled to and antagonizing this receptor results in the G protein signalling cascade not being activated. The G-protein signalling cascade activates protein kinase which activates calcium channels on the membrane, resulting in calcium influx. Low calcium cannot 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 labetalol Without labetalol Labetalol, 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 Labetalol 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 Labetalol is administered as an oral tablet or via intravenous injection
Mitochondria Calcium TPM1 TPM2 ADRB1 CACNA1C CACNA2D2 CACNB1 RYR2 PRKAR1A SLC8A1 CACNA1H CACNA1G ATP2A2 PRKACA Laβlol Calcium Calcium Calcium Sodium Sodium Calcium Calcium Calcium Laβlol Laβlol Adenosine triphosphate Water Calcium Adenosine diphosphate Phosphate Calcium Calcium Troponin Troponin G-Protein Signaling Cascade Muscle Relaxation