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