COPD: chronic obstructive pulmonary disease
eNOS: endothelial NO synthase
HCN: hyperpolarization-activated, cyclic nucleotide-gated (channels)
ICa-L: L-type Ca2+ current
If: cardiac pacemaker current
IK-ACh: ACh-activated K+ current
M1, M2, M3: muscarinic receptor subclasses
NO: nitric oxide
ACETYLCHOLINE AND ITS MUSCARINIC RECEPTOR TARGET
Muscarinic acetylcholine receptors in the peripheral nervous system are found primarily on autonomic effector cells innervated by postganglionic parasympathetic nerves. Muscarinic receptors are also present in autonomic ganglia and on some cells (e.g., vascular endothelial cells) that, paradoxically, receive little or no cholinergic innervation. Within the CNS, the hippocampus, cortex, and thalamus have high densities of muscarinic receptors.
Acetylcholine, the naturally occurring neurotransmitter for these receptors, has virtually no systemic therapeutic applications because its actions are diffuse, and its hydrolysis, catalyzed by both AChE and plasma butyrylcholinesterase, is rapid. Muscarinic agonists mimic the effects of ACh at these sites. These agonists typically are longer-acting congeners of ACh or natural alkaloids, some of which stimulate nicotinic as well as muscarinic receptors.
The mechanisms of action of endogenous ACh at the postjunctional membranes of the effector cells and neurons that represent different types of cholinergic synapses are discussed in Chapter 8. Cholinergic synapses occur at:
autonomic effector sites innervated by postganglionic parasympathetic nerves (or, in the sweat glands, by postganglionic sympathetic nerves)
sympathetic and parasympathetic ganglia and the adrenal medulla, innervated by preganglionic autonomic nerves
motor end plates on skeletal muscle, innervated by somatic motor nerves
certain synapses in the CNS (Krnjevíc, 2004) where ACh can have either pre- or postsynaptic actions
When ACh is administered systemically, it can potentially act at all of these sites; however, as a quaternary ammonium compound, its penetration to the CNS is limited, and the amount of ACh that reaches peripheral areas with low blood flow is limited due to hydrolysis by plasma butyrylcholinesterase.
The actions of ACh and related drugs at autonomic effector sites are referred to as muscarinic, based on the observation that the alkaloid muscarine acts selectively at those sites and produces the same qualitative effects as ACh. The muscarinic, or parasympathomimetic, actions of the drugs considered in this chapter are practically equivalent to the parasympathetic effects of ACh listed in Table 8–1. Muscarinic receptors are present in autonomic ganglia and the adrenal medulla but primarily function to modulate the nicotinic actions of ACh at these sites (Chapter 11). In the CNS, muscarinic receptors are widely distributed and have a role in mediating many important responses. The differences between the actions of ACh and other muscarinic agonists are largely quantitative, with limited selectivity for one organ system or another. All of the actions of ACh and its congeners at muscarinic ...