Cholinergic Mechanisms

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Synaptic transmission in autonomic ganglia principally involves the release of acetylcholine by presynaptic terminals and subsequent binding of that neurotransmit-ter to nicotinic cholinergic receptors on postganglionic neurons. In mammals this synaptic junction is not obligatory, indicating that a significant convergence of inputs may be necessary to evoke postganglionic neuronal activity (115,119,135,138). Thus the potential for synaptic integration exists within intrathoracic autonomic ganglia (15). Nicotinic and muscarinic cholinergic receptors have been associated with intrathoracic autonomic neurons (2,14,55, 68,119,135). Furthermore, the blockade of nicotinic receptors attenuates, but does not eliminate, activity generated by intrinsic cardiac neurons (20, 21, 53). Muscarinic blockade attenuates excitatory and inhibitory synaptic function within intrinsic cardiac ganglia as well (135). These data indicate that acetylcholine exerts both mediator and modulator effects at synapses within intrathoracic autonomic ganglia.

Application of nicotine to intrathoracic autonomic neurons can alter their activity (68) and induce concomitant changes in regional cardiac function, whether the neurons are located in extracardiac or intrinsic cardiac ganglia (68,140). Nicotinic activation of intrinsic cardiac neurons evokes a biphasic cardiac response, with initial suppression in regional cardiac function being followed by augmentation (Fig. 6). Nicotinic activation of atrial intrinsic cardiac neurons modifies primarily, but not exclusively, atrial function, whereas nicotinic activation of ventricular intrinsic cardiac neurons modifies primarily,

FIGURE 6 Chronotropic and atrial inotropic effects elicited by injecting nicotine into a locus of the dorsal right atrial ganglionated plexus (RAGP) before (control) and following sequential selective muscarinic (atropine) and then ft-adrenergic (propranolol + atropine) blockade. The dorsal right atrial ganglionated plexus is primarily associated with the control of right atrial function (4,120). Before administration of blocking agents, nicotine injected into the RAGP evoked a biphasic response with an initial negative chronotropic and atrial inotropic response followed by increases in both cardiac indices. Atropine prevented the neurally evoked suppressive effects, whereas pro-pranolol blocked the neurally evoked augmentation in atrial function. Adapted from Yuan et al. (140).

FIGURE 6 Chronotropic and atrial inotropic effects elicited by injecting nicotine into a locus of the dorsal right atrial ganglionated plexus (RAGP) before (control) and following sequential selective muscarinic (atropine) and then ft-adrenergic (propranolol + atropine) blockade. The dorsal right atrial ganglionated plexus is primarily associated with the control of right atrial function (4,120). Before administration of blocking agents, nicotine injected into the RAGP evoked a biphasic response with an initial negative chronotropic and atrial inotropic response followed by increases in both cardiac indices. Atropine prevented the neurally evoked suppressive effects, whereas pro-pranolol blocked the neurally evoked augmentation in atrial function. Adapted from Yuan et al. (140).

133). Direct application of various neurotransmitters adjacent to neurons in intrinsic cardiac ganglia modifies the activities they generated, often resulting in concomitant changes in cardiac pacemaker and/or contractile behavior (25, 67-69). Subsequent transection of all extrinsic nerve inputs to the heart (acute decentralization) markedly attenuates, but does not eliminate, neuro-chemical modulation of intrinsic cardiac neuronal activity (67-69); however, it does eliminate most changes induced in regional cardiac function (25).

In summary, intrinsic cardiac ganglia contain a heterogeneous population of neurons that utilize cholin-ergic and noncholinergic synapses to control intragan-glionic, interganglionic, and nerve effector organ cell activities. Some of these neurotransmitters subserve short duration synaptic actions (e.g., acetylcholine), whereas others modulate pre- and/or postsynaptic function over longer periods of time [e.g., neuropeptide Y (95, 129, 130)]. Although studies have indicated the presence and potential effects of various putative neurotransmitters within the intrinsic cardiac nervous system, the physiological function of most of these substances in overall cardiac regulation remains to be determined.

but not exclusively, ventricular function (140). Acute decentralization of intrathoracic ganglia from the CNS attenuates, but does not eliminate, such effects (140). In time, following chronic decentralization of intrathoracic ganglia, including those on the heart as with cardiac transplantation, peripheral nerve networks remodel to sustain cardiac function (123).

B. Noncholinergic Mechanisms

Blockade of nicotinic cholinergic receptors attenuates, but does not eliminate, the activity generated by neurons within intrathoracic autonomic ganglia (5, 14). These data indicate that non-nicotinic putative neuro-transmitters act as mediators for synaptic transmission within the intrathoracic neuronal system. Anatomical and physiological studies have identified multiple putative neurotransmitters in association with the mammalian intrinsic cardiac ganglia, which include purinergic agonists (3, 40, 47, 69), catecholamines (27, 45, 71,110), angiotensin II (64), calcitonin gene-related peptide (79, 132, 133), neuropeptide Y (41, 54, 56-58, 91, 120, 132), substance P (26, 41, 60, 61, 79, 126, 131-134), neurokinins (124), endothelin (17), and vasoactive intestinal peptide (42, 56, 120, 131,-133). Many of these putative neurochemicals arise from neurons whose cell bodies are located in stellate, middle cervical, or mediastinal ganglia, whereas others may be synthesized by neurons intrinsic to the heart (40-42, 56-58, 72, 79, 126, 131,

X. INTERACTIONS BETWEEN CNS AND INTRATHORACIC NEURONAL NETWORKS: IMPLICATIONS FOR TREATMENT OF ANGINA PECTORIS

Myocardial ischemia reflects an imbalance in the supply:demand balance within the heart with resultant activation of cardiac afferent neurons and, as a consequence, the perception of symptoms (i.e., angina pectoris) (49). In addition to such nociceptive responses, activating cardiac afferent neurons can elicit autonomic and somatic reflexes (18, 49). Pharmacological, surgical, and angioplasty therapies are commonly used to improve symptoms and cardiac function in patients exhibiting angina pectoris. Despite the fact that these treatments are usually successful, some patients still suffer from pain of cardiac origin following these procedures (74, 114). Epidural stimulation of the spinal cord (SCS) has been suggested as an alternative to bypass surgery in high-risk patients (81). With SCS, high-frequency, low-intensity electrical stimuli are delivered to the dorsal aspect of the T1-T2 segments of the thoracic spinal cord. This therapy decreases the frequency and intensity of anginal episodes (43, 59,112). SCS reduces the magnitude and duration of ST segment alteration during exercise stress in patients with cardiac disease (111), improves myocardial lactate metabolism (80), and increases workload tolerance (111). The mechanisms whereby this mode of therapy produces such beneficial effects are poorly understood.

Because intrathoracic cardiac neurons have been found to play important modulatory roles in cardiac regulation, we have begun to study SCS and its effects on the activity generated by intrinsic cardiac neurons (50). Transient cardiac ventricular ischemia increases the activities generated by intrathoracic ganglia, including those on the heart (18,65). Excessive focal activation of intrathoracic neural circuits can induce cardiac dys-rhythmias, even in normally perfused hearts (70). SCS resulted in an immediate suppression in intrinsic cardiac neuronal activity. A neurosuppressor effect imposed in the intrinsic cardiac nervous system occurs whether SCS is applied immediately before, during, or after coronary artery occlusion (50). Furthermore, the suppression of intrinsic cardiac neuronal activity persists even after cessation of SCS. That transection of the ansae subclavia eliminated these effects suggests that they primarily involve the sympathetic nervous system (50).

The synaptic mechanisms and specific pathways mediating these responses have yet to be determined. They likely involve both sympathetic afferent and efferent neurons. For instance, spinal cord stimulation may activate sensory afferent fibers antidromically such that en-dorphins (44) or neuropeptides such as calcitonin gene-related peptide or substance P (23, 25, 39) are locally released in the myocardium. It is known that opiates and neuropeptides can influence cardiac function of intrinsic cardiac neurons (see earlier discussion). Spinal cord stimulation may also suppress intrinsic cardiac adrener-gic as well as local circuit neurons as the result of altered sympathetic efferent preganglionic neuronal activity. It is known that the activation of sympathetic efferent preganglionic axons can suppress many intrathoracic reflexes that are involved in cardiac regulation (4, 15). Thus these neurosuppressor effects may be due, in part, to the activation of inhibitory synapses within intratho-racic ganglia (36,88). Clinical experience with SCS highlights the dynamic interactions that can occur between central and intrathoracic neurons, demonstrating the potential for effective clinical treatment of cardiac pathology via modulation of the intrathoracic nervous system.

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