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In the human body, the level of extracellular sodium (Na+) affects the amount of sodium entering the cells and exchanging with calcium (Ca++). This, in turn, impacts the concentration of intracellular calcium and subsequently influences the force of contraction. An increase in intracellular sodium or the administration of cardiac glycosides inhibiting Na+,K+-ATPase can raise intracellular sodium levels, leading to a reversal in the 3Na+-Ca++ antiporter and a decrease in calcium removal from the cell. This increase in intracellular calcium concentration ultimately results in an enhanced contractile force. Conversely, a reduction in extracellular calcium, an increase in the sodium gradient across the sarcolemma, or the use of a calcium channel antagonist can decrease intracellular calcium levels, subsequently diminishing contractile force.

During systole, the influx of calcium ceases, and the sarcoplasmic reticulum, stimulated to release calcium, actively takes up calcium through Ca++-ATPase. The sarcoplasmic reticulum's Ca++-ATPase is similar yet distinct from the Ca++-ATPase found in the sarcolemma. Additionally, cytosolic calcium levels decrease during diastole through the action of the 3Na+-Ca++ antiporter in the sarcolemma and a sarcolemmal Ca++-ATPase.

Catecholamines play a role in accelerating both cardiac contraction and relaxation. When catecholamines bind to β1-adrenoceptors, adenylate cyclase is activated, leading to increased intracellular levels of cAMP. This increase in cAMP activates cAMP-dependent protein kinase A, which phosphorylates multiple proteins within the cell. One such protein is phospholamban, which normally inhibits the Ca++-ATPase of the sarcoplasmic reticulum. However, phosphorylation of phospholamban reduces its inhibitory action, enhancing calcium uptake into the sarcoplasmic reticulum and promoting relaxation. Protein kinase A also phosphorylates troponin I, inhibiting the binding of calcium by troponin C. This action causes tropomyosin to return to its position, blocking the myosin-binding sites on the actin filaments and inducing relaxation.

The contraction of cardiac muscle is influenced by both preload and afterload. Preload refers to the force that stretches the relaxed muscle fibers by increasing their resting length. In the left ventricle, for example, preload is represented by the filling of blood and the subsequent stretching of the ventricular wall during diastole. Afterload, on the other hand, is the force exerted on the muscle that it must overcome during contraction. In the left ventricle, afterload refers to the pressure in the aorta that the contracting ventricular muscle must surpass to open the aortic valve and eject blood. Increasing the filling of the left ventricle during diastole, thereby increasing end-diastolic volume, can raise preload. Starting from lower initial end-diastolic volumes, higher filling pressures during diastole result in a greater systolic pressure during the subsequent contraction.

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Fig. 13.2 ). For example, reducing extracellular [Na+] causes less Na+ to enter the cell in exchange for Ca++ , which results in an increase in intracellular [Ca++] and thus contractile force. Raising intracellular [Na+] has a similar effect. In fact, this is the mechanism by which cardiac glycosides increase contractile force. Cardiac glycosides inhibit Na+,K+-ATPase and thereby raise intracellular [Na+] in the cells. The elevated cytosolic [Na+] reverses the direction of the 3Na+-Ca++ antiporter, and therefore less Ca++ is removed from the cell. The increase in intracellular [Ca++] results in an increase in contractile force. Finally, contractile force is diminished when intracellular [Ca++] is decreased by a reduction in extracellular [Ca++], by an increase in the Na+ gradient across the sarcolemma, or by the administration of a calcium channel antagonist that prevents Ca++ from entering the myocardial cell.
At the end of systole, the influx of Ca++ stops, and the sarcoplasmic reticulum is no longer stimulated to release Ca++ . In fact, the sarcoplasmic reticulum avidly takes up Ca++ by means of Ca++-ATPase. The Ca++-ATPase in the sarcoplasmic reticulum is similar to but distinct from the Ca++-ATPase found in the sarcolemma. Cytosolic [Ca++] is also reduced during diastole through the action of the 3Na+-Ca++ antiporter in the sarcolemma, as well as by a sarcolemmal Ca++-ATPase (see
Fig. 13.2
Both cardiac contraction and relaxation are accelerated by catecholamines (see
Fig. 13.3 ). When catecholamines bind to their receptor (β1-adrenoceptor), adenylate cyclase is activated, thereby increasing intracellular cAMP levels, which then leads to activation of cAMP-dependent protein kinase A. Protein kinase A has multiple effects in the cell. As already described, it phosphorylates the calcium channel in the sarcolemma and causes increased entry of Ca++ into the cell, thus increasing the force of contraction. In addition, protein kinase A phosphorylates other proteins that facilitate relaxation. One such protein is phospholamban. Phospholamban normally inhibits the Ca++-ATPase of the sarcoplasmic reticulum. However, when phospholamban is phosphorylated, its inhibitory action is reduced, and uptake of Ca++ into the sarcoplasmic reticulum is enhanced. The increased activity of the Ca++-ATPase in the sarcoplasmic reticulum decreases intracellular [Ca++], thereby causing relaxation. Protein kinase A also phosphorylates troponin I, which in turn inhibits binding of Ca++ by troponin C. As a result, tropomyosin returns to its position of blocking the myosin-binding sites on the actin filaments, and relaxation results.
Contraction of cardiac muscle is influenced by both preload and afterload (
Fig. 16.37 ). Preload is the force that stretches the relaxed muscle fibers, thereby increasing their resting length (see
Fig. 16.37B ). In the left ventricle, for example, the blood filling and thus the stretching of the wall during diastole represents the preload. Afterload is the force added to the muscle (see
Fig. 16.37C ) against which the contracting muscle must act (see
Fig. 16.37D ). Again from the perspective of the left ventricle, afterload is the pressure in the aorta that must be overcome by the contracting left ventricular muscle to open the aortic valve and eject the blood.
Preload can be increased by greater filling of the left ventricle during diastole (i.e., increasing end-diastolic volume). From lower initial end-diastolic volumes, increments in filling pressure during diastole increase resting fiber length and elicit a greater systolic pressure during the subsequent contraction (see