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.