Cardiotonic steroids strengthen heart muscle contraction primarily by inhibiting Na⁺-K⁺ ATPase, leading to increased intracellular sodium and calcium via the Na⁺-Ca²⁺ exchanger. This mechanism underlies their positive inotropic effect, as seen in drugs like digoxin. The correct answer is option (D).​

Option Analysis

Option (A): Inhibit K⁺-dependent dephosphorylation of Na⁺-K⁺ ATPase
Cardiotonic steroids (CTS) bind to the E2P conformation of Na⁺-K⁺ ATPase, stabilizing the phosphoenzyme and inhibiting the K⁺-induced dephosphorylation step in the enzyme cycle. This action reduces overall pump activity, contributing to elevated intracellular Na⁺, but it is an indirect description of the primary inhibition mechanism.​

Option (B): Activate Na⁺-K⁺ ATPase
CTS act as specific inhibitors of Na⁺-K⁺ ATPase, not activators, blocking ion transport and causing Na⁺ accumulation inside cells. Activation would decrease contractility by enhancing Na⁺ extrusion.​

Option (C): Increase uptake of Na⁺ by activation of Na⁺-Ca²⁺ exchanger
Na⁺-Ca²⁺ exchanger (NCX) normally extrudes Ca²⁺ using the Na⁺ gradient (forward mode). CTS-induced Na⁺-K⁺ ATPase inhibition raises intracellular Na⁺, reducing NCX forward activity and causing net Ca²⁺ gain, not Na⁺ uptake.​

Option (D): Increase uptake of Ca²⁺ by activation of Na⁺-Ca²⁺ exchanger
This is correct. Elevated intracellular Na⁺ from Na⁺-K⁺ ATPase inhibition shifts NCX toward reverse mode or reduces forward Ca²⁺ extrusion, increasing cytosolic and SR Ca²⁺ for stronger contractions.​

Cardiotonic steroids, such as digitalis and ouabain, are vital in treating heart failure by enhancing cardiac contractility through precise ion handling mechanisms. These steroids target Na⁺-K⁺ ATPase inhibition, leading to Na⁺-Ca²⁺ exchanger activation and boosted Ca²⁺ uptake in cardiomyocytes.​

Mechanism of Action

Na⁺-K⁺ ATPase maintains ion gradients by pumping 3 Na⁺ out and 2 K⁺ in per ATP hydrolyzed. CTS bind the extracellular E2P state, preventing K⁺-dependent dephosphorylation and halting the cycle, causing intracellular Na⁺ rise. This reduces the Na⁺ gradient driving NCX.​

Role in Heart Contraction

Elevated Na⁺ slows NCX forward mode (3 Na⁺ in, 1 Ca²⁺ out), favoring reverse mode (Ca²⁺ in, Na⁺ out) or net Ca²⁺ retention. Higher cytosolic Ca²⁺ binds troponin C, enhancing actin-myosin interactions for stronger contractions (positive inotropy).​

Clinical Relevance for CSIR NET

• Therapeutic Use: Digoxin manages heart failure and atrial fibrillation by this pathway.​

• Toxicity Risk: Excess Ca²⁺ causes arrhythmias via delayed afterdepolarizations.​

• Exam Tip: Focus on indirect NCX activation via Na⁺-K⁺ ATPase block, not direct enzyme effects.​