Dr. Declan McKernan
Email: declan.mckernan@universityofgalway.ie
Course Code: PM309
Myocyte Contraction: Understand the contraction cycle and key proteins involved.
Dysfunction and Disease: Recognize how dysfunction arises in contraction.
Drug Mechanisms: Compare the mechanisms of action of drugs for cardiac contractility dysfunction.
The heart receives deoxygenated blood, pumps it to the lungs, and distributes oxygenated blood.
Contractility depends on:
Tension generated during systole.
Left ventricle filling during diastole.
Key determinants of cardiac output include preload (blood volume in ventricles) and afterload (resistance to ejection).
Contraction begins with action potentials that depolarize the myocyte membrane.
Excitation-contraction coupling:
Voltage-gated Ca2+ channels (VGCCs) open, increasing intracellular [Ca2+].
Activates contractile proteins and shortens contractile elements via actin-myosin interactions.
Structure of myocytes includes:
Sarcolemma, T-tubules, sarcoplasmic reticulum (SR), myofibrils.
Myofibrils have organized contractile proteins that interact in a coordinated manner.
Sarcolemma: Ca2+ flux is mediated by Na+ pump and Na+-Ca2+ exchanger (NCX).
Sarcoplasmic Reticulum: Ca2+ channels and pumps regulate Ca2+ release and reuptake.
Adrenergic System: Modulates Ca2+ through channels and transporters.
Involves:
Ca2+ influx through L-type calcium channels.
Ryanodine receptors (RyRs) enable Ca2+-induced Ca2+ release from SR.
Binding of Ca2+ to troponin C allows myosin to bind to actin.
Contraction involves:
Formation of cross-bridges and sliding of filaments.
Myocyte relaxation requires sufficient ATP supply.
Structure and Function:
Myosin ratchets along actin, shortening sarcomere.
Actin structure includes polymers, troponin proteins (TN-I, TN-C, TN-T), and tropomyosin.
Key Steps in Contraction Cycle:
ATP hydrolysis to ADP initiates contraction.
Active complex formation from Ca2+ binding to TN-C.
Myosin head bends and detaches from actin.
New ATP binding allows for complex dissociation and cycle restarts.
Causes of Myocyte Dysfunction:
Replacement of myocardium with fibrous tissue due to myocyte death.
Major cause is coronary artery disease (CAD), leading to myocardial infarction (MI).
Other causes include systemic hypertension and valvular heart disease.
Leads to systolic heart failure (HF) and more dysfunction at cellular level:
Dysregulated Ca2+.
Changes in contractile protein expression.
Altered β-adrenoreceptor signaling.
Elevated diastolic Ca2+ due to phospholamban inhibition of SERCA.
Increased NCX expression leads to Ca2+ extrusion over storage.
Decreased phosphorylation of TN-I reduces actin-myosin interaction efficiency.
Increased expression of fetal isoform TN-T.
β-arrestin inhibition of β-adrenergic receptors.
Elevated Gαi expression decreases cyclic AMP signaling.
Example: Digoxin
Mechanism:
Inhibits Na+/K+-ATPase leading to increased intracellular [Ca2+].
Clinical uses: Increases contractility, manages heart failure.
Side Effects: Narrow therapeutic index and drug interactions.
Example: Dobutamine, Dopamine, Adrenaline.
Mechanism of action involves stimulation of cAMP pathways and enhancement of contractility.
Clinical use: Short-term support for failing circulation.
Increase cardiac contractility by elevating cAMP levels.
Examples: Amrinone, Milrinone.
Side effects: Thrombocytopenia and increased mortality upon long-term use.
Example: Levosimendan.
Mechanism: Enhances troponin C sensitivity to Ca2+.
Clinical use: Severe chronic heart failure with potential side effects like hypotension.
Interaction of Ca2+ with cardiac structural proteins enables contraction.
Major proteins involved in calcium regulation: Na+/K+-ATPase, Na+/Ca2+ exchanger, and Ca2+-ATPase.
Cardiac dysfunction arises from disrupted calcium homeostasis, contractile protein alterations, and adrenergic signaling changes.