Histamine H1 receptor activation blocks two classes of potassium current, IK(rest) and IAHP to excite ferret vagal afferents

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Abstract
Intracellular recordings were made in intact and acutely dissociated vagal afferent neurones (nodose ganglion cells) of the ferret to investigate the membrane effects of histamine. In current‐clamp or voltage‐clamp recordings, histamine (10 μm) depolarized the membrane potential (10 ± 0.8 mV; mean ±s.e.m.; n= 27) or produced an inward current of 1.6 ± 0.35 nA (n= 27) in ∼80% of the neurones. Histamine (10 μm) also blocked the post‐spike slow after‐hyperpolarization (AHPslow) present in 80% of these neurones (95 ± 3.2%; n= 5). All neurones possessing AHPslow in ferret nodose were C fibre neurones; all AHPslow neurones had conduction velocities ≤ 1 m s−1(n= 7). Both the histamine‐induced inward current and the block of AHPslow were concentration dependent and each had an estimated EC50 value of 2 μm. These histamine‐induced effects were mimicked by the histamine H1 receptor agonist 2‐(2‐aminoethyl)thiazole dihydrochloride (10 μm) and blocked by the H1 antagonists pyrilamine (100 nm) or diphenhydramine (100 nm). Schild plot analysis of the effect of pyrilamine on the histamine‐induced inward current revealed a pA2 value of 9.7, consistent with that expected for an H1 receptor. Neither impromidine (10 μm) nor R(−)‐α‐methylhistamine (10 μm), selective H2 or H3 agonists, respectively, significantly affected the membrane potential, input resistance or AHPslow. The reversal potential (Vrev) for the histamine‐induced inward current was −84 ± 2.1 mV (n= 4). The Vrev for the histamine response shifted in a Nernstian manner with changes in the extracellular potassium concentration. Alterations in the extracellular chloride concentration had no significant effect on the Vrev of the histamine response (n= 3). The Vrev for the AHPslow was –85 ± 1.7 mV (n= 4). These results indicate that histamine increases the excitability of ferret vagal afferent somata by interfering with two classes of potassium current: the resting or ‘leak’ potassium current (IK(rest)) and the potassium current underlying a post‐spike slow after‐hyper‐polarization (IAHP). Both these effects can occur in the same neurone and involve activation of the same histamine receptor subtype, the histamine H1 receptor.