CONTROL OF CARDIAC FUNCTION

Neural Regulation of Cardiac Function

The two limbs of the autonomic nervous system provide opposing input to regulate cardiac function.^[40] The neurotransmitter of the sympathetic nervous system is norepinephrine, which provides positive chronotropic (heart rate), inotropic (contractility), and lusitropic (relaxation) effects. The parasympathetic nervous system has a more direct inhibitory effect in the atria and has a negative modulatory effect in the ventricles. The neurotransmitter of the parasympathetic nervous system is acetylcholine. Norepinephrine and acetylcholine both bind to seven-transmembrane-spanning G protein-coupled receptors to transduce their intracellular signals and effect their functional responses ( Fig. 18-15 ).^[41] At rest, the heart has a tonic level of parasympathetic cardiac nerve firing and little, if any sympathetic activity. Therefore, the major influence on the heart is parasympathetic at rest. During exercise or stress, however, the sympathetic neural influence becomes more prominent.

Parasympathetic innervation of the heart is through the vagal nerve. Supraventricular tissue receives much greater vagal innervation than the ventricles do. The principal parasympathetic target neuroeffectors are the muscarinic receptors in the heart.^{[42] [43]} Activation of muscarinic receptors reduces pacemaker activity, slows AV conduction, decreases the atrial contractile force directly, and exerts inhibitory modulation of ventricular contractile force. A total of five muscarinic receptors have been cloned.^[44] The M₂ receptors are the predominant subtype found in the mammalian heart. In the coronary circulation, M₃ receptors have been identified. Moreover, non-M₂ receptors have also been reported to exist in the heart. In general, for intracellular signaling, M₁ , M₃ , and M₅ receptors couple to G_q/11 protein and activate the phospholipase C-diacylglycerol-inositol phosphate system. On the other hand, the M₂ and M₄ receptors couple to the pertussis toxin-sensitive G protein G_i/o to inhibit adenylyl cyclase. M₂ receptors can couple to certain K⁺ channels and can influence the activity of calcium channels, I_f current, phospholipase A₂ , phospholipase D, and tyrosine kinases.

Figure 18-15 A general scheme for a G protein-coupled receptor consisting of receptor, the heterotrimeric G protein, and the effector unit is shown. (Reprinted by permission from Bers DM: Cardiac excitation-contraction coupling. Nature 415:198–205, 2002. Copyright © MacMillan Magazines Ltd.)

In contrast to vagal innervation, sympathetic innervation of the heart is more predominant in the ventricle than the atrium. Norepinephrine released from sympathetic nerve terminals stimulates adrenergic receptors (adrenoreceptors [ARs]) located in the heart. The two major classes of adrenoceptors are α and β, both of which are G protein-coupled receptors that transduce their intracellular signals by means of specific signaling cascades ( Fig. 18-16 ).

β-ARs can be further divided into subpopulations of β₁ , β₂ , and β₃ .^{[43] [45]} Although most mammalian hearts contain β₁ - and β₂ -ARs, β₃ -ARs have also been demonstrated in many mammalian ventricular tissues. The relative contribution of each β-AR subtype to the modulation of cardiac function varies among species. In humans, β₁ -ARs are the predominant subtype in both the atria and ventricle, but a substantial proportion of β₂ -ARs are located in the atria and approximately 20% β₂ -ARs are found in the LV. Much less is known about β₃ -ARs, but their existence has been documented in the human ventricle. Despite the fact that the β₁ -AR population is greater than the β₂ -AR population, the cardiostimulant effect is not proportional to the relative densities of these two subpopulations, which is largely attributable to the tighter coupling of β₂ -AR to the cyclic adenosine monophosphate (cAMP) signaling pathway in comparison to β₁ -ARs. Both β₁ - and β₂ -ARs activate a pathway that involves the stimulatory G protein (G_s ), activation of adenylyl cyclase, accumulation of cAMP, stimulation of cAMP-dependent protein kinase A, and phosphorylation of key target proteins, including L-type calcium channels, phospholamban, and TnI.

Although traditional teaching is that both β₁ - and β₂ -ARs are coupled to the G_s -cAMP pathway, more recent experimental evidence has indicated that β₂ -ARs also couple to the inhibitory G protein G_i to activate non-cAMP-dependent signaling pathways. Additionally, β₂ -ARs can also couple to G protein-independent pathways to modulate cardiac function. β-AR stimulation increases both contraction and relaxation, as summarized in Figure 18-17 .

The two major subpopulations of α-ARs are α₁ and α₂ . The α₁ - and α₂ -ARs can be further subdivided into different subtypes. α₁ -ARs are G protein-coupled receptors and include the α₁ A, α₁ B, and α₁ D subtypes. The α₁ -AR subtypes are products of separate genes and differ in structure, G protein coupling, tissue distribution, signaling, regulation, and function. Both α₁ A and α₁ B ARs mediate positive inotropic responses. However, the positive inotropic effect mediated by α₁ -ARs is believed to be of minor importance in the heart. α₁ -ARs are coupled to phospholipase C, phospholipase D, and phospholipase A₂ ; they increase intracellular Ca²⁺ and myofibrillar sensitivity to Ca²⁺ .

Cardiac hypertrophy is primarily mediated by α₁ A ARs.^{[46] [47]} Cardiac hypertrophic responses to α₁ -AR agonists involve activation of protein kinase C and mitogen-activated protein kinase through G_q signaling mechanisms. Three subtypes of α₂ -ARs are recognized: α₂ A, α₂ B, and α₂ C ARs. In the mammalian heart, α₂ -ARs in the atrium play a role in the presynaptic inhibition of norepinephrine release. These prejunctional α₂ -ARs are believed to belong to the α₂ C subtype.

Neural regulation of cardiac function involves a complex interaction between the different classes and

736

Figure 18-16 Adrenoceptor signaling cascades. G proteins and effectors (AC, adenylyl cyclase; iCA_L , L-type calcium current; PLC-β, phospholipase β) are the primary G protein and effectors in the heart. The intracellular signals are DAG (diacylglycerol), IP₃ (inositol triphosphate), PKC (protein kinase C), cAMP (cyclic adenosine monophosphate), PKA (protein kinase A), and MAPK (mitogen-activated protein kinase).

Figure 18-17 The β-adrenoceptor signaling system leads to an increased rate and force of contraction and increased relaxation. SL, sarcolemma; SR, sarcoplasmic reticulum. (From Opie LH: Receptors and signal transduction. In The Heart. Physiology from Cell to Circulation, 3rd ed. Philadelphia, Lippincott-Raven, 1998, p 195.)

737