Inhibitory effect of the tricyclic antidepressant amitriptyline on voltage‐dependent K⁺ channels in rabbit coronary arterial smooth muscle cells

Abstract

Amitriptyline, a tricyclic antidepressant (TCA) drug, is widely used in treatment of psychiatric disorders. However, the side effects of amitriptyline on vascular K channels remain to be determined. Therefore, we investigated the effect of the tricyclic antidepressant and serotonin reuptake inhibitor amitriptyline on voltage-dependent K (Kv) channels in freshly isolated rabbit coronary arterial smooth muscle cells, using the whole-cell patch clamp technique. The Kv current amplitudes were inhibited by amitriptyline in a concentration-dependent manner, with an apparent IC value of 2.2 ± 0.14 μmol/L and a Hill coefficient of 0.87 ± 0.03. Amitriptyline shifted the activation curve to a more positive potential, but had no significant effect on the inactivation curve, suggesting that amitriptyline altered the voltage sensitivity of Kv channels. Pretreatment with Kv1.5 and Kv1.2 channel inhibitors did not alter the inhibitory effect of amitriptyline on Kv channels. Additionally, application of train pulses (1 and 2 Hz) did not affect amitriptyline-induced inhibition of Kv currents, which suggested that the action of amitriptyline on Kv channels was not use (state)-dependent. From these results, we concluded that amitriptyline inhibited the channels in a concentration-dependent, but state-independent manner.

Modulation of nociception by amitriptyline hydrochloride in the Speke’s hinge‐back tortoise (Kiniskys spekii)

“…This drug has considerable affinity for serotonin and norepinephrine reuptake transporters, 5‐HT 1A and 5‐HT 2A receptors, alpha‐adrenergic receptors, muscarinic acetylcholine receptors and histamine receptors (Park et al., 2018). Amitriptyline hydrochloride is also a known voltage‐gated Na + and K + channel blocker (Dick et al., 2007; Li et al., 2018; Song et al., 2000; Wang et al., 2004; Wolff et al., 2016). Some of its antinociceptive effects are as a result of inhibition of these voltage gated ion channels which impairs excitability of sensory neurons (Wolff et al., 2016).…”

Adverse drug reactions associated with amitriptyline — protocol for a systematic multiple-indication review and meta-analysis

“…In order to prioritize the symptoms on the list, an experienced clinical pharmacologist (SH) first rated them for specificity with regard to anticholinergic ADRs by differentiating between symptoms that are unequivocally caused by the inhibition of muscarinergic signaling [35,36], and those that are not. Amitriptyline can also cause potassium channel blockades [37], peripheral alpha blockades [38], norepinephrine reuptake blockades [39], and inhibit histamine receptors [40], and sodium channels [41], all of which potentially cloud the clinical presentation of anticholinergic ADRs. The items on the list also needed to be distinguished from intoxication [42,43].…”