PROBLEM #1 INTRODUCTION Cardiac muscle contractile strength can be changed by al

Question

PROBLEM #1 INTRODUCTION

Cardiac muscle contractile strength can be changed by altering its inotropic state (IS). An increase in IS increases contractile activity without requiring a change in muscle fiber length. This mechanism is absent in skeletal muscle.

PROBLEM #1: Digitalis (ouabain) is a drug used to counteract the effects of cardiac failure. In heart failure, one or both ventricles are incapable of developing a normal contractile force or producing a normal stroke volume without an increase in end diastolic filling. In such situations, digitalis increases the inotropic state (contractility) of heart muscle. Digitalis acts by inhibiting the Na+/K+ pump. (By the way, the Na+/K+ pump located in cardiac myocytes has a digitalis-binding site not found on Na+/K+ pumps outside of the heart. This is how digitalis can affect the Na+/K+ in the heart but not elsewhere in the body.)

http://ajpheart.physiology.org/content/289/5/H1781.long

http://www.cvpharmacology.com/cardiostimulatory/digitalis.htm

1. What effect will treatment with digitalis have on the distribution of ions across the membrane of cardiac muscle cells?

2. The cardiac muscle membrane contains a secondary active transporter, a Na+Ca2+ exchanger. This countertransporter is one of the mechanisms that maintains a low cytosolic Ca2+ concentration during diastole. It uses the energy content in the trans-sarcolemmal Na+ electrochemical gradient to transport 3 Na+ into the cell for each Ca2+ it extrudes from the cell. Explain how the action of digitalis interacts with the action of the transporter to increase the force of contraction of the myocardium.

Explanation / Answer

Cardiac action potential consists of four distinct phases. In phase 0, upstroke occurs due to rapid transient influx of Na+. Later, Na+ channels are inactivated, combined with a transient efflux of K+. In phase 2, also known as the plateau phase, the efflux of K+ and the influx of Ca2+ are counterbalanced. At the end of the plateau, sustained repolarization occurs due to K+ efflux via the delayed rectifier K+ channels exceeding Ca2+ influx; this constitutes phase 3 of the action potential. Finally, as part of phase 4, resting potential in myocytes is maintained.

Digitalis has a profound effect on myocyte intracellullar concentrations of Na+, K+, and Ca2+. These effects are caused by digitalis inhibiting the cardiac glycosides bind to and block the action of the Na+/K+ ATPase. This leads to increased intracellular Sodium. The diminished sodium gradient results in less CA2+ being extruded from the cell via the Na+/Ca2+ exchanger.

Heart failure results when cardiac output is inadequate for the needs of the body. A defect in cardiac contractility is complicated by the multiple compensatory processes that further weaken the failing heart. The drugs used in HF fall into 3 major groups with varying targets and actions.Positive inotropic drugsare cardiac glycosides (digoxin), beta agonists (dobutamine) PDE inhibitors (amrinone, milrinone)

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