Mechanisms of Vascular Responses
The decrease in blood pressure following intravenous acetylcholine administration is a complex physiological process. Its key feature is that the drug acts not directly on smooth muscle, but on the vascular endothelium.
Endothelial cell membranes contain $M_3$ cholinergic receptors. Their stimulation triggers the release of endothelium-derived relaxing factor, nitric oxide (NO). It is this factor that diffuses into the smooth muscle cells of the vessel wall and causes their relaxation. A crucial nuance for differential diagnosis: if the endothelium were absent, direct stimulation of smooth muscle $M_3$ receptors would lead to vasoconstriction. However, under normal physiological conditions, endothelium-dependent relaxation always predominates.
Effect of Denervation on Drug Action
The pharmacological efficacy of a drug on a denervated organ (e.g., when studying the circular muscle of the iris) strictly depends on whether the drug has a direct or indirect mechanism of action.
- Indirect mimetics (anticholinesterase agents: neostigmine, physostigmine, armine). Their role is to inhibit the enzyme acetylcholinesterase to prevent the breakdown of the endogenous neurotransmitter. However, in denervation, nerve impulses are absent, and acetylcholine is not released. Consequently, there is nothing to protect from degradation, and the drug effect is completely absent.
- Direct M-cholinomimetics (pilocarpine, as well as carbachol, which possesses a direct component). They bind to receptors independently. On a denervated organ, their effect is preserved: they can induce sustained pupillary constriction (miosis). In some cases, denervation supersensitivity of receptors to such agonists is observed.
Interactions and Differences in Spectrum of Action
The main difference between M-cholinomimetics and anticholinesterase agents lies in their effect on skeletal muscle. Skeletal muscles are controlled via $N_M$ cholinergic receptors at the neuromuscular junctions.
M-cholinomimetics act extremely selectively: exclusively on M-receptors of smooth muscle, glands, heart, and endothelium. They do not affect skeletal muscle. Anticholinesterase agents, by contrast, increase the overall concentration of acetylcholine, which stimulates both receptor types (M and N), leading to facilitated neuromuscular transmission and increased skeletal muscle tone.
This difference is clearly demonstrated by the pharmacological antagonism between neostigmine and atropine. Atropine is a selective M-cholinergic receptor blocker. It successfully eliminates neostigmine-induced bronchospasm, bradycardia, miosis, and glandular hypersecretion. However, atropine cannot eliminate the increase in skeletal muscle tone because this process occurs via $N$-cholinergic receptors, which are outside its control.
Paradoxical Pressor Effect
A classic example of an interaction that reverses the direction of a response is the combination of acetylcholine and atropine. Under normal conditions, acetylcholine lowers blood pressure. However, if atropine is administered beforehand to block M-cholinergic receptors, subsequent administration of acetylcholine leads to an increase in blood pressure.
The mechanism behind this phenomenon lies in the activation of unblocked $N$-cholinergic receptors (nicotinic receptors). When M-receptors are blocked, acetylcholine actively excites:
- Sympathetic ganglia (stimulating postganglionic sympathetic fibers).
- The adrenal medulla (triggering a massive release of epinephrine and norepinephrine).
As a result, a powerful pressor response occurs.
Clinical Application: Blood-Brain Barrier Penetration and Selectivity
The choice of a cholinotropic drug for treating specific pathologies relies on its ability to cross the blood-brain barrier (BBB) and its receptor subtype selectivity.
- Alzheimer's Disease: Central-acting agents capable of crossing the BBB and replenishing brain acetylcholine deficits are required (donepezil, rivastigmine, galantamine). Peripheral-acting drugs (quaternary ammonium compounds: neostigmine, edrophonium, pyridostigmine) cross the barrier poorly and are not used.
- Motion Sickness (Kinetosis): Scopolamine easily crosses the BBB. It blocks M-cholinergic receptors in the vestibular nuclei and the vomiting center, providing a potent antiemetic effect for seasickness and airsickness.
- Gastroenterology: Pirenzepine selectively blocks $M_1$ cholinergic receptors (in the intramural gastric ganglia and enterochromaffin-like cells), inhibiting hydrochloric acid secretion more strongly than non-selective atropine. This selectivity provides a safer profile: general adverse effects (dry mouth, tachycardia) are significantly less pronounced.