Phentolamine, a non-selective α-adrenoreceptor antagonist, is widely used in clinical settings to reverse local anaesthesia by promoting vasodilation and drug clearance. While generally well tolerated, it has been associated with adverse effects such as tachycardia and, paradoxically, pain relief in some cases. Previous studies have suggested that phentolamine may interact with molecular targets involved in cardiac excitability and nociception, raising the possibility that it influences voltage-gated sodium channels (NaV). However, this interaction had not been fully explored.

A recent study from the Angelika Lampert Group demonstrates that phentolamine inhibits NaV1.7 and NaV1.5 channels through the local anaesthetic receptor site, a mechanism that may conflict with its intended use as an antidote for local anaesthetic toxicity. Using manual and automated patch clamp (the SyncroPatch 384), the researchers determined IC50 values of 57–72 μM for NaV1.7 and 27 μM for NaV1.5, indicating a potent blocking effect, particularly on cardiac sodium channels. Furthermore, phentolamine enhanced the tonic block induced by the local anaesthetic mexiletine, raising concerns about its potential impact on cardiac excitability.

Molecular docking studies confirmed that phentolamine binds to the same receptor site as local anaesthetics, reinforcing the hypothesis that it acts as a sodium channel inhibitor. Comparative analyses with other α-adrenoreceptor antagonists revealed that alternatives such as alfuzosin and urapidil exhibit weaker sodium channel blockade, suggesting they may be better suited for reversing local anaesthesia without interfering with sodium channel function.

These findings challenge the current clinical indication of phentolamine and highlight the need for a careful reassessment of its safety profile. The study underscores the importance of selecting alternative α-adrenoreceptor antagonists with minimal sodium channel interaction to ensure effective and safe local anaesthetic reversal.

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Find the full article here: α-Adrenoreceptor blocker phentolamine inhibits voltage-gated sodium channels via the local anaesthetic binding site

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