3. Cardiac Contractility Drugs

Cardiac Contractility Drugs

Introduction

  • Dr. Declan McKernan

  • Email: declan.mckernan@universityofgalway.ie

  • Course Code: PM309

Learning Outcomes

  • 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.

Cardiac Contractility Cycle

  • 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).

Myocyte Contraction

  • 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.

Regulation of Cardiac Contraction

Calcium Cycling Mechanisms

  1. Sarcolemma: Ca2+ flux is mediated by Na+ pump and Na+-Ca2+ exchanger (NCX).

  2. Sarcoplasmic Reticulum: Ca2+ channels and pumps regulate Ca2+ release and reuptake.

  3. Adrenergic System: Modulates Ca2+ through channels and transporters.

Mechanism of Ventricular Action Potential

  • 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.

Contractile Proteins

  • 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:

    1. ATP hydrolysis to ADP initiates contraction.

    2. Active complex formation from Ca2+ binding to TN-C.

    3. Myosin head bends and detaches from actin.

    4. New ATP binding allows for complex dissociation and cycle restarts.

Dysfunctions and Diseases

  • 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:

      1. Dysregulated Ca2+.

      2. Changes in contractile protein expression.

      3. Altered β-adrenoreceptor signaling.

Altered Calcium Homeostasis

  • Elevated diastolic Ca2+ due to phospholamban inhibition of SERCA.

  • Increased NCX expression leads to Ca2+ extrusion over storage.

Contractile Protein Changes

  • Decreased phosphorylation of TN-I reduces actin-myosin interaction efficiency.

  • Increased expression of fetal isoform TN-T.

Altered Adrenoreceptor Signaling

  • β-arrestin inhibition of β-adrenergic receptors.

  • Elevated Gαi expression decreases cyclic AMP signaling.

Therapeutic Agents for Cardiac Dysfunction

Cardiac Glycosides

  • 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.

Beta Adrenergic Agonists

  • Example: Dobutamine, Dopamine, Adrenaline.

  • Mechanism of action involves stimulation of cAMP pathways and enhancement of contractility.

  • Clinical use: Short-term support for failing circulation.

Phosphodiesterase Inhibitors

  • Increase cardiac contractility by elevating cAMP levels.

  • Examples: Amrinone, Milrinone.

  • Side effects: Thrombocytopenia and increased mortality upon long-term use.

Calcium Sensitizing Agents

  • Example: Levosimendan.

  • Mechanism: Enhances troponin C sensitivity to Ca2+.

  • Clinical use: Severe chronic heart failure with potential side effects like hypotension.

Summary

  • 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.

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