Do cholinergic drugs cause vasoconstriction or vasodilation?

October 10, 2025 •

3 min read

Contrary to a simple classification, the effect of cholinergic drugs on blood vessels is not uniform and can be paradoxical, depending on the state of the vascular endothelium. The intricate interplay between acetylcholine, endothelial health, and different receptor subtypes determines whether cholinergic drugs cause vasoconstriction or vasodilation.

Quick Summary

The effect of cholinergic drugs is complex, primarily causing vasodilation in healthy blood vessels but potentially causing vasoconstriction in those with damaged endothelium.

Key Points

Dual Effect: Cholinergic drugs can cause both vasodilation and vasoconstriction, depending on the health of the vascular endothelium.
Vasodilation in Healthy Vessels: In vessels with a healthy endothelium, cholinergic drugs bind to M3 muscarinic receptors on endothelial cells, stimulating nitric oxide (NO) release, which relaxes the underlying smooth muscle.
Vasoconstriction in Diseased Vessels: In vessels with endothelial damage or dysfunction, the NO-releasing pathway is impaired. The drug then acts directly on M3 receptors on the vascular smooth muscle, causing it to contract and resulting in vasoconstriction.
Diagnostic Application: This paradoxical effect is used in medical procedures, such as acetylcholine challenge tests during angiograms, to diagnose coronary artery endothelial dysfunction.
Receptor Subtypes Matter: The specific muscarinic receptor subtype and its location (endothelial vs. smooth muscle) dictate the ultimate vascular response.
Dependence on Drug Concentration: The concentration of the cholinergic drug can influence the outcome, with higher concentrations sometimes favoring vasoconstriction.
Balance of Autonomic Systems: The cholinergic system and its effects on vasodilation are in constant interplay with the sympathetic system, which primarily causes vasoconstriction.

Understanding the Cholinergic System and Vascular Function

To understand the effect of cholinergic drugs on blood vessels, one must first grasp the role of the body's natural cholinergic system. The cholinergic system is part of the autonomic nervous system, which controls involuntary bodily functions. The primary neurotransmitter of this system is acetylcholine (ACh). Cholinergic drugs are designed to mimic or modulate the effects of ACh, either by directly stimulating its receptors or by inhibiting the enzyme (acetylcholinesterase) that breaks it down.

The autonomic nervous system is divided into the sympathetic ('fight or flight') and parasympathetic ('rest and digest') branches. While sympathetic stimulation typically causes vasoconstriction, parasympathetic stimulation, mediated by ACh, often leads to vasodilation. However, the effect of ACh on blood vessels is not as simple as its effect on heart rate. The final outcome is highly dependent on the specific receptors and the health of the vessel's inner lining, the endothelium.

The Standard Response: Endothelium-Dependent Vasodilation

In a healthy blood vessel, cholinergic drugs primarily cause vasodilation, the widening of the vessel's diameter. This process is dependent on the endothelium and involves acetylcholine binding to muscarinic receptors (particularly M3) on endothelial cells. This triggers the release of nitric oxide (NO), a potent vasodilator, which then causes the underlying smooth muscle cells to relax, resulting in vasodilation.

The Paradoxical Response: Endothelium-Independent Vasoconstriction

Cholinergic drugs can cause vasoconstriction when the endothelium is damaged or dysfunctional, a phenomenon known as paradoxical vasoconstriction. This is particularly relevant in conditions like coronary artery disease. In a damaged endothelium, the ability to produce NO is impaired. Consequently, the cholinergic drug acts directly on muscarinic receptors (primarily M3) on the vascular smooth muscle, causing contraction and vasoconstriction. This effect can be used diagnostically during procedures like coronary angiograms to identify endothelial dysfunction.

Factors Influencing the Vascular Response

Several factors influence the vascular response to cholinergic drugs:

Health of the Endothelium: Healthy endothelium promotes vasodilation, while damaged endothelium can lead to vasoconstriction.
Receptor Subtype and Location: M3 receptors on the endothelium mediate vasodilation via NO, while M3 receptors on smooth muscle can cause vasoconstriction.
Drug Concentration: The concentration of the cholinergic drug can affect the outcome; for example, higher concentrations of acetylcholine have been observed to cause vasoconstriction in some cases.
Vascular Bed: The response can differ depending on the specific blood vessel or vascular bed.
Balance with Adrenergic System: The interplay between the cholinergic and adrenergic systems also affects the net vascular tone.

Comparison of Cholinergic Effects on Healthy vs. Diseased Endothelium


Feature	Healthy Endothelium	Diseased Endothelium (e.g., Atherosclerosis)
Effect on Blood Vessels	Vasodilation	Vasoconstriction (paradoxical)
Mechanism	Endothelium-dependent via Nitric Oxide (NO) release	Endothelium-independent; direct action on vascular smooth muscle
Key Receptor Role	M3 receptors on endothelial cells trigger NO production	M3 receptors on vascular smooth muscle cause contraction
Clinical Observation	Increased blood flow and lower vascular resistance	Reduced blood flow, increased vascular resistance, potential for vasospasm
Diagnostic Use	Not relevant as a diagnostic tool for endothelial damage	Used to test for endothelial dysfunction in coronary artery disease

Clinical Significance of the Paradoxical Effect

The dual effect of cholinergic drugs is clinically significant. The acetylcholine challenge test is used diagnostically to assess coronary artery endothelial function; vasoconstriction in response to acetylcholine indicates dysfunction. Furthermore, understanding this complex pharmacology is crucial for managing potential cardiovascular side effects of cholinergic medications, such as cholinesterase inhibitors used for Alzheimer's disease. Careful monitoring is necessary to avoid unexpected vasoconstrictive effects in patients with underlying vascular conditions.

Conclusion

In conclusion, cholinergic drugs have a complex effect on blood vessels, typically causing vasodilation in healthy vessels but paradoxical vasoconstriction in those with damaged endothelium. This response is influenced by factors like receptor subtypes, drug concentration, and vascular bed. This complexity is important for diagnosis and safe medication use in patients with cardiovascular issues. For more details, consult resources like {Link: CV Physiology cvphysiology.com}.

Frequently Asked Questions

The primary effect of acetylcholine (ACh) on healthy blood vessels is vasodilation, or the widening of the vessels. This is triggered by the release of nitric oxide from the endothelial cells lining the vessels.

Cholinergic drugs cause vasoconstriction when the vascular endothelium is damaged or dysfunctional. In this case, the drug bypasses the nitric oxide-releasing pathway and acts directly on muscarinic receptors on the vascular smooth muscle, causing it to contract.

The M3 muscarinic receptor subtype is primarily involved in the vascular response to cholinergic drugs. When on endothelial cells, it triggers vasodilation, but when acting directly on smooth muscle, it causes vasoconstriction.

In a procedure called an acetylcholine challenge test, a cholinergic drug is administered into a coronary artery. If the artery constricts instead of dilating, it indicates the presence of endothelial dysfunction associated with atherosclerosis.

Yes, the effect can vary depending on the vascular bed. For instance, the response of cerebral arteries may involve different receptor subtypes (like M5), and some vascular beds might respond differently than others.

The concentration can be a factor. Some studies show that low concentrations of acetylcholine can cause vasodilation, while higher concentrations might lead to vasoconstriction, particularly in diseased vessels.

The cholinergic (parasympathetic) system and the adrenergic (sympathetic) system have a balanced and often opposing effect on vascular tone. The cholinergic system typically promotes vasodilation, while the adrenergic system primarily causes vasoconstriction.