The contribution of Ca++ extrusion mechanisms varies between species, with rat and mouse myocytes relying primarily on Ca++ reuptake by the SR. In these species, the SR accounts for 92% of Ca++ transport.

The heart cannot increase the force of contraction by recruiting more muscle cells because it is an electrical syncytium where all cardiac muscle cells contract during a single beat. Additionally, tetany of the heart would be lethal as it would hinder the critical pumping action of the heart. However, the heart has developed alternative strategies to increase the force of contraction. The long refractory period caused by the long duration of the action potential in cardiac muscle prevents tetany. Modulation of Ca++ influx through L-type calcium channels during an action potential allows the heart to alter cytosolic [Ca++] and thus the force of contraction.

In vitro, the force of contraction of cardiac muscle cells can be modulated by varying extracellular [Ca++]. Decreasing extracellular [Ca++] from a normal range of 1 to 2 mmol/L to 0.5 mmol/L, for example, reduces the force of contraction without changing the duration of the contraction. This reduction in force of contraction is due to unmodified kinetic characteristics of Ca++ sequestration by the SR and Ca++ extrusion. However, this approach is not commonly used to modulate the force of cardiac contraction in vivo.

In vivo, an increase in the size of the intracellular Ca++ transient and consequently the force of contraction occurs in response to sympathetic stimulation. Sympathetic stimulation, often occurring during periods of excitement or fright, involves activation of β-adrenergic receptors on the heart by norepinephrine or epinephrine. Isoproterenol, a β-adrenergic agonist, dramatically increases the size of the intracellular Ca++ transient, resulting in a more forceful contraction. This increase in force of contraction is called positive inotropy. β-adrenergic stimulation also increases the rate of relaxation, leading to a shorter contraction, termed positive lusitropy. It also increases the frequency of contractions, known as positive chronotropy. Thus, β-adrenergic stimulation produces stronger, briefer, and more frequent contractions.

The sympathetic nervous system is stimulated in situations that prepare the individual for "fight or flight." Increased levels of epinephrine from the adrenal medulla or norepinephrine from sympathetic nerve terminals activate β-adrenergic receptors on cardiac muscle cells. This activation triggers adenylate cyclase, resulting in increased cyclic adenosine monophosphate (cAMP) levels and subsequent cAMP-dependent phosphorylation of numerous proteins in cardiac muscle cells.
Fig. 13.2 ). The relative contribution of the Ca++ extrusion mechanisms, however, varies between species. For example, rat and mouse myocytes rely primarily on Ca++ reuptake by the SR (i.e., the SR accounts for 92% of Ca++ transport).
Regulation of the Force of Contraction
Because the heart represents an electrical syncytium, in which all the cardiac muscle cells contract during a single beat, it is not possible to increase the force of contraction by recruiting more muscle cells. Moreover, tetany of the heart would be lethal because it would defeat the critical pumping action of the heart. The heart has therefore developed alternative strategies to increase the force of contraction. The long duration of the action potential found in cardiac muscle, which is due to activation of the voltage-gated L-type calcium channel, results in a long refractory period, which in turn prevents tetany. Modulation of Ca++ influx through L-type calcium channels during an action potential, however, provides the heart with a mechanism to alter cytosolic [Ca++] and hence the force of contraction.
A simple means of modulating the force of contraction of cardiac muscle cells in vitro is to vary extracellular [Ca++]. As noted previously, contraction of the heart requires extracellular Ca++ . Decreasing extracellular [Ca++] from a normal range of 1 to 2 mmol/L to 0.5 mmol/L, for example, reduces the force of the contraction. This reduction in force of contraction is not associated with a change in the duration of the contraction because the kinetic characteristics of Ca++ sequestration by the SR and Ca++ extrusion have not been modified. Although this approach of varying extracellular [Ca++] to alter the force of contraction is demonstrable in vitro, it is not a common means of modulating the force of cardiac contraction in vivo.
In vivo, an increase in the size of the intracellular Ca++ transient and hence the force of contraction occurs in response to sympathetic stimulation (see the section
Chapter 18). Sympathetic stimulation often occurs during periods of excitement or fright and involves activation of β-adrenergic receptors on the heart by norepinephrine (released from nerve terminals in the heart) or epinephrine (released from the adrenal medulla into the bloodstream). As shown in
Fig. 13.3 , the β-adrenergic agonist isoproterenol results in a dramatic increase in the size of the intracellular Ca++ transient and, consequently, a more forceful contraction. An increase in the force of contraction is termed positive inotropy. Typically, the rate of relaxation accompanying this β-adrenergic stimulation also increases, which results in a shorter contraction. The increase in the rate of muscle relaxation is termed positive lusitropy. The frequency of contractions of the heart also increases with β-adrenergic stimulation and is termed positive chronotropy. Thus β-adrenergic stimulation of the heart produces stronger, briefer, and more frequent contractions.
The sympathetic nervous system is stimulated when a human or an animal becomes excited, and it is said to prepare the individual for “fight or flight.” In the case of the heart, increased levels of the adrenal medullary hormone epinephrine or the sympathetic neurotransmitter norepinephrine activate β-adrenergic receptors on the cardiac muscle cells, which in turn activates adenylate cyclase, increases cyclic adenosine monophosphate (cAMP), and thus promotes cAMP-dependent phosphorylation of numerous proteins in cardiac muscle cells (
Fig. 13.4