Cardiac Inotropy

Inotropy! Aside from being a nice word that I'm not 100% sure how to pronounce, inotropy is also the term used to refer to the amount of contraction for the same amount of load.

Summarise the excitation contraction coupling of cardiac cells

When an action potential comes along, it stimulates the opening of L-type Ca²⁺ channels. These let Ca²⁺ enter the cell. Ca²⁺ activates ryanodine receptors (RyR) on the sarcoplasmic reticulum (SR), resulting in release of Ca²⁺ from the SR. (This phenomenon is known as "calcium-induced calcium release.") When Ca²⁺ is in the cytosol, it can bind to troponin. The troponin-Ca²⁺ complex can move tropomyosin, which normally blocks myosin binding sites on actin, allowing myosin to bind to actin and contraction to take place.

Eventually, Ca²⁺ is pumped back into the SR by SERCA, which is short for "Sarcoplasmic Endoplasmic Reticulum Calcium ATPase." Some calcium is also removed from the cell altogether via a Na⁺/Ca²⁺ antiport (a.k.a. NCX) on the cell membrane.

Describe the intracellular signalling pathway through which β-adrenergic receptors produce inotropy

β-adrenergic receptors are G-protein coupled receptors with G_s subunits. These activate adenylate cyclase, which produces cyclic AMP (cAMP) from ATP. cAMP goes on to activate protein kinase A, which indirectly results in the phosphorylation of L-type Ca²⁺ channels, increasing their opening probability, and SERCA, increasing the pump rate. This results in increased inotropy due to the increased Ca²⁺ influx, but also shortens the duration of contraction: increasing the activity of SERCA increases the rate at which Ca²⁺ gets "mopped up" by the sarcoplasmic reticulum. Both of these things combined also increases the amount of Ca²⁺ that gets stored by the sarcoplasmic reticulum so that even more can be released during the next contraction.

Fun fact- cAMP is usually degraded to AMP by phosphodiesterase. Phosphodiesterase can be inhibited by caffeine, leaving more cAMP to bounce around and produce inotropy.

Another fun fact- muscarinic receptors do the opposite. They are also G-protein coupled, but they have G_i subunits, which deactivate adenylate cyclase.

Explain how Digitalis and inhibition of Na⁺/K⁺ATPase produces inotropy

Digitalis, derived from the foxglove plant, is a drug that inhibits the Na⁺/K⁺ ATPase. This decreases the concentration gradient for Na⁺. The Na⁺/Ca²⁺ antiport (NCX), which brings in three Na⁺ ions for every Ca²⁺ ion removed from the cell, is very sensitive to changes in the sodium gradient. Hence, the effects of digitalis on the Na⁺/K⁺ ATPase also affects the Na⁺/Ca²⁺ antiport, resulting in less removal of Ca²⁺ from the cell. SERCA can also load more Ca²⁺ into the sarcoplasmic reticulum for later use. As increased Ca²⁺ results in increased inotropy, digitalis produces inotropy.