27: Contractility

Purpose of increasing contractility

Increase cardiac output

Excitation-contraction coupling pathway in a cardiac myocyte

AP travels along T tubule → L-type Ca⁺⁺ channel opens → small amount of Ca⁺⁺ comes in → opens Ca⁺⁺ gated Ryanodine receptor on the sarcoplasmic reticulum → massive efflux of Ca⁺⁺ from SR → activates cross bridge cycle

Protein that facilitates cardiac myocyte relaxation

SERCA pump → sequesters Ca⁺⁺ back into the SR

Cardiac glycoside drug example

Digoxin

Digoxin mechanism of action

Inhibits Na⁺/K⁺ ATPase

How does digoxin increase contractility

Blocking the Na⁺/K⁺ ATPase in a depolarized cell provides more Na⁺ to be swapped for Ca⁺⁺ via a Na⁺/Ca⁺⁺ exchanger → more Ca⁺⁺ to be sequestered in SR → greater Ca⁺⁺ release during systole

Extent of cardiac glycoside effects

Mild inotropic agent

How does digoxin act as a negative chronotropic agent

Increases PS-ANS tone; decreases rate of node firing and increases refractory period via Na⁺/K⁺ ATPase inhibition

Electrical indications for digoxin treatment

Supraventricular tachyarrhythmias

Contraindications for treatment with digoxin

HCM and severe V fib

Toxicity associated with digoxin

• Calcium overload due to high ICF [Ca⁺⁺]

• Arrhythmias

• Ectopic beats

• GIT and CNS signs

Conditions that predispose an animal to cardiac glycoside toxicity

• Hypokalemia (more binding sites open for the drug)

• Renal failure (excreted in the urine)

• Hypercalcemia and hypernatremia

ECG signs that are indicative of toxicity in a patient getting digoxin

Prolonged P-R interval

β adrenergic agonist mechanism of action

Activates adenylyl cyclase → cAMP → activates PKA  → positive inotropic and chronotropic action

How does PKA activation result in positive inotropy and chronotropy

• PKA is a subunit of L-type and Ryanodine receptors → more Ca⁺⁺ released

• PKA is a subunit of SERCA → Ca⁺⁺ reuptaken faster

Structure of a β adrenergic receptor

GPCR

β adrenergic agonist drugs

Dopamine and dobutamine

Which β adrenergic agonist is better and why

Dobutamine; β-1 specific, dopamine causes NE release, which stimulates α and β

Side effects associated with β adrenergic agonists

• Down regulation of β-1 → decreased efficacy

• Tachycardia and hypertension

Type of heart failure that benefits from βAR agonists

Systolic dysfunction (HFrEF/DCM)

Phosphodiesterase inhibitor mechanism of action

…inhibits PDE

How does inhibiting PDE result in postivity inotropy and chronotropy

PDE normally breaks down cAMP. Inactive enzyme → prolonged cAMP → prolonged PDA activation → same effects as βAR agonists

Additional effect of some PDE inhibition

PDE also breaks down cGMP. Inhibition → vasodilation (NO cycle secondary messenger!)

PDE inhibitor drug examples

Pimobendan and sildenafil

Which PDE inhibitor is an inodilator

Pimobendan

Sildenafil action

Only inhibits the PDE that breaks down cGMP → only a vasodilator

Clinical indication for sildenafil

Pulmonary hypertension

How do β blockers fit into CHF treatment

Purpose is to decrease S-ANS stimulation even if it means negative inotropy and decreased cardiac output

β blocker drug examples

Propranolol and atenolol

Type of heart failure that benefits from β blockers

Diastolic dysfunction (HFpEF/HCM)

How do β blockers cause negative inochronotropy

Blocks NE action → no cAMP production → decreased activation of PKA → less calcium mobilization

Ca⁺⁺ channel blocker drug examples

Diltiazem and verapamil

Ca⁺⁺ channel blocker mechanism of action

Blocks Ca⁺⁺ channels → less Ca⁺⁺ movement → decreased inochronotropy and afterload

Indications for Ca⁺⁺ channel blockers

HCM and any supraventricular tachyarrhythmia