How muscarine weakens heart contractions

Muscarine is a naturally occurring alkaloid best known as the toxic compound in certain Amanita mushrooms. In pharmacology, muscarinic agonists are also used as research tools to study the parasympathetic nervous system. A 2026 paper in Naunyn-Schmiedeberg's Archives of Pharmacology reports something clinically relevant: in isolated human atrial tissue, muscarine can reduce the force of cardiac contractions, but only when cyclic AMP (cAMP) is already elevated by another agent^[1].

This is called an indirect negative inotropic effect. It does not happen when muscarine acts alone on resting tissue. It happens when cAMP levels are raised first, and muscarine then counteracts the resulting increase in contractile force.

What the 2026 study actually tested

Neumann, Hofmann, Hadova, Klimas, and Gergs obtained right atrial muscle strips from patients during cardiac surgery and applied muscarine after first stimulating the tissue with agents known to raise intracellular cAMP. Those agents covered a wide spectrum: the beta-adrenoceptor agonist isoprenaline, serotonin acting at 5-HT4 receptors, histamine at H2 receptors, dopamine at D1 receptors, direct adenylyl cyclase activation with forskolin, cAMP degradation blockade with cilostamide, direct protein kinase A activation with dibutyryl-cAMP, and glucagon-like peptide-1 receptor (GLP-1R) stimulation^[1].

In every case, muscarine reduced the elevated force of contraction. The common thread is cAMP: once the second-messenger pathway is turned on through any of these routes, the M2 muscarinic receptor can oppose it.

Why the M2 receptor dominates in human atrial tissue

Human atrial muscle expresses muscarinic acetylcholine receptors in a highly skewed ratio. The Neumann et al. mRNA data show M2 accounts for roughly 96% of total muscarinic receptor expression, with M1 at under 0.1% and M3 at about 3.6%^[1]. The M2 receptor is the classical cardiac subtype. It couples to Gi proteins, which inhibit adenylyl cyclase and reduce cAMP production.

That coupling logic explains the indirect effect. If cAMP is already elevated, Gi-mediated inhibition of adenylyl cyclase can reduce it. If baseline cAMP is low, there is little for the M2 receptor to inhibit, so the contractile reduction is modest or absent.

Where GLP-1 receptor agonists enter the picture

GLP-1 receptor agonists, including semaglutide, have been shown to produce positive inotropic effects in human atrial tissue through the same cAMP/PKA pathway. A 2024 study in Pharmaceutics found that semaglutide induced a concentration- and time-dependent increase in contractile force in isolated human right atrial muscle, an effect blocked by the protein kinase A inhibitor H89 and attenuated by ryanodine^[2]. Importantly, the effect was absent in mouse atrial preparations, pointing to species differences in GLP-1R distribution that make human tissue studies like these especially informative.

Earlier work with exenatide, another GLP-1R agonist, reached the same conclusion: GLP-1R agonists increase developed force in human atrial trabeculae via GLP-1R/cAMP/PKA signaling, an effect absent in ventricular tissue where GLP-1R expression is much lower^[3]. The atrial selectivity of this inotropic response matters: it suggests the cardiac effects of these drugs are not simply a ventricular concern, and atrial electrophysiology and contractility deserve specific attention in long-term cardiovascular monitoring.

The 2026 Neumann et al. study adds a counterpoint: if a patient using a GLP-1 receptor agonist is simultaneously exposed to elevated muscarinic activity, the positive inotropic signal could be partially offset. The drug class now includes tirzepatide (a dual GIP and GLP-1 receptor agonist) and retatrutide (a triple agonist at GLP-1, GIP, and glucagon receptors), both of which work through overlapping cAMP pathways in cardiac tissue. The muscarinic counterbalance mechanism observed for semaglutide would logically apply to these agents as well, though direct evidence in human tissue is still accumulating^[1].

Clinical context: muscarine intoxication

Muscarine poisoning from wild mushroom ingestion produces the classic cholinergic toxidrome: sweating, salivation, lacrimation, urination, defecation, and bradycardia. Reduced cardiac output is part of that picture. Understanding the mechanism at the receptor level, and specifically why the contractile depression is worse when adrenergic or other cAMP-raising signals are present, matters for treatment decisions in poisoning cases.

The study does not test drug interactions directly. It uses isolated tissue, so the concentrations and timescales are not a one-to-one model of the intact cardiovascular system. What it establishes is a mechanism, not a clinical recommendation.

What we don't yet know

Several questions remain open. The study used isolated atrial strips, not intact hearts or intact patients. Whether the magnitude of indirect negative inotropy is clinically meaningful at therapeutic semaglutide concentrations, alongside physiological levels of parasympathetic tone, has not been studied in humans. The paper also does not address whether the effect differs by sex, age, or underlying cardiac disease, all of which affect receptor expression and downstream signaling.

Longer-term cardiovascular outcomes data on GLP-1 receptor agonists from large trials do not show increased cardiac risk in general, but those trials were not designed to measure inotropic effects directly. The same gap applies to tirzepatide and retatrutide: the phase 3 programmes assess hard endpoints (major adverse cardiac events, hospitalization for heart failure) rather than contractile mechanics in atrial tissue. The mechanistic picture from isolated tissue studies needs to be connected to clinical datasets before firm conclusions are possible.

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