Histamine H-1 receptor activation blocks two classes of potassium current, I-K(rest) and I-AHP to excite ferret vagal afferents

1. Intracellular recordings were made in intact and acutely dissociated vagal afferent neurones (nodose ganalion cells) of the ferret to investigate the membrane effects of histamine. 2. In current-clamp or voltage-clamp recordings, histamine (10 mu M) 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 similar to 80% of the neurones. 3. Histamine (10 mu M) also blocked the post-spike slow after-hyperpolarization (AHP(slow)) present in 80% of these neurones (95 +/- 3.2%; n = 5). All neurones possessing AHP(slow) in ferret nodose were C fibre neurones; all AHP(slow) neurones had conduction velocities less than or equal to 1 m s(-1) (n = 7). 4. Both the histamine-induced inward current and the block of AHP(slow) were concentration dependent and each had an estimated EC50 value of 2 mu M. These histamine-induced effects were mimicked by the histamine H-1 receptor agonist 2-(2-aminoethyl)thiazole dihydrochloride (10 mu M) and blocked by the H-1 antagonists pyrilamine (100 nM) or diphenhydramine (100 nM). Schild plot analysis of the effect of pyrilamine on the histamine-induced inward current revealed a pA(2) value of 9.7, consistent with that expected for an H-1 receptor. Neither impromidine (10 mu M) nor R(-)-alpha-methylhistamine (10 mu M), selective H-2 or H-3 agonists, respectively, significantly affected the membrane potential, input resistance or AHP(slow). 5. The reversal potential (V-rev) for the histamine-induced inward current was -84 +/- 2.1 mV (n = 4). The V-rev 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 V-rev of the histamine response (n = 3). The V-rev for the AHP(slow) was -85 +/- 1.7 mV (n = 4). 6. 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 (I-K(rest)) and the potassium current underlying a post-spike slow after-hyperpolarization (I-AHP). Both these effects can occur in the same neurone and involve activation of the same histamine receptor subtype, the histamine H-1 receptor.