BMD 317 ch 25 pharmacology of cardiac contractility (exam 2)

primary determinants of cardiac output

- preload
- afterload
- heart rate

cardiac contraction cycle

- ATP hydolysis (muscle is relaxed and energized) -> formation of active complex (now active complex) -> product dissociation (now rigor complex) -> dissociation of actin and myosin (ATP is added and muscle is relaxed)
- increased cytosolic Ca2+ is key between excitation and contraction
- influx of extracellular Ca2+ (via L-type channels) "triggers" release of SR Ca2+ via RyR receptor
- Ca2+ binds to the troponin C -> releases inhibitory TN-I -> exposes binding site on actin -> cross-bridge formation

what is critical for both contraction and relaxation of muscles

ATP

cardiac myocyte Ca2+ flux steps for myofibril contraction

- "Trigger" Ca2+ enters the cell via L-type Ca2+ channels
- next there is a release of Ca2+ from the SR
- now the myofibril contracts

cardiac myocyte Ca2+ flux steps for relaxation

- for relaxation to occur Ca2+ has to be removed from the cytoplasm
- first NCX extrudes Ca2+ from the cell
- next the Na+/K+ ATPase maintains Na+ gradient in cytoplasm
- SERCA then pumps Ca2+ into SR
- the sarcolemmal Ca2+ ATPase also pumps Ca2+ out of the cell

Beta adrenergic receptor effects on contractility

- activates G-alpha-s -> adenylyl cyclase -> PKA -> sarcolemmal Ca2+ channels open
- PKA also phosphorylates phospholamban -> SERCA can now pump Ca2+ into SR -> enhances relaxation
- PKA also leads to increased activity of sarcolemmal Na+ pump
- PDE converts cAMP to AMP and terminates B1-AR- mediated actions -> PDE= drug target

Cardiac effects of B1-AR activation

- increases Ca2+ entry in Myocytes (positive inotropic effect) -> increases stroke volume
- increase heart rate at pacemakers (positive chronotropic effect)

Peripheral effects of B1-AR activation

- peripheral B2 receptors dilate vascular smooth muscle (decreases systemic vascular resistance and afterload)
- alpha 1 receptor activation constricts vascular smooth muscle (increases SVR and afterload)

Cardiac glycosides

- drug name is Digoxin
- increases intracellular Ca2+ concentration
- does this via inhibition of sarcolemmal Na+/K+ ATPase
- selective inhibitor of

low dose of B-agonist

- peripheral vasodilation
- reduced afterload

intermediate dose of B-agonist

- B1-AR -> increases contractility and HR
- B2-AR -> vasodilation

High dose of B-agonist

- peripheral vasoconstriction
- increased afterload
- alpha 1 AR activation in periphery dominates -> vasoconstriction

millrinone

- PDE inhibitor