From node to myocyte: meta-analysis of atropine sulfate effects on muscarinic M2 pathways in atrioventricular block of varying degrees

Excess vagal cholinergic tone acting on the muscarinic type-2 receptor (M2 receptor, M2R) slows atrioventricular (AV) nodal conduction through G-inhibitory protein (Gi) signalling that lowers cyclic adenosine monophosphate (cAMP) and reduces the L-type calcium current (ICaL).

To synthesise evidence—from intact humans to cellular systems—on atropine sulfate effects on (i) clinical reversal of bradyarrhythmia/AVB and PR-interval shortening, and (ii) inhibition of the M2R–Gi–cAMP–ICaL pathway, with stratification by AVB degree and aetiology (vagally mediated versus non-vagal).

We conducted a systematic review and meta-analysis (protocol registered on the International Prospective Register of Systematic Reviews [PROSPERO]: [ID]) of studies published 2015–2025 in PubMed, Embase, Cochrane CENTRAL, and Web of Science. Eligible designs included randomised, crossover, observational, ex-vivo and in-vitro studies assessing atropine sulfate with AV conduction or M2R–Gi–cAMP–ICaL outcomes. Primary clinical endpoint: reversal to sinus rhythm or a lower AVB grade within 30–60 minutes. Secondary endpoints: PR-interval change, need for temporary pacing, and adverse events (tachyarrhythmia, myocardial ischaemia)

Mechanistic and electrophysiologic evidence establishes that atropine acts as a competitive antagonist at cardiac M2 muscarinic receptors, blocking ACh-mediated activation of IKACh and Gi-dependent suppression of cAMP, thereby producing a net positive dromotropic effect at the AV node. Human and animal electrophysiology studies consistently demonstrate shortening of AV nodal conduction times (AH/PR) and reduced nodal refractory periods after IV atropine.

Atropine sulfate was generally well tolerated, with adverse events such as tachyarrhythmia or myocardial ischemia occurring infrequently and requiring close monitoring, especially in vulnerable patient groups. These findings support guideline-concordant use of atropine sulfate as an initial diagnostic–therapeutic trial in suspected cholinergic AVB while expediting escalation when higher-grade block persists. Further investigations are warranted to optimize dosage strategies and to better identify patient subgroups most likely to benefit from atropine, as well as to refine combined therapeutic approaches for advanced AV block. Integration of these findings into AV block management protocols is recommended to further improve clinical outcomes.