HISTAMINE H-1 RECEPTOR ACTIVATION BLOCKS 2 CLASSES OF POTASSIUM CURRENT, I-K(REST) AND I-AHP TO EXCITE FERRET VAGAL AFFERENTS

1. Intracellular recordings were made in intact and acutely dissociate d vagal afferent neurones (nodose ganalion cells) of the ferret to inv estigate the membrane effects of histamine. 2. In current-clamp or vol tage-clamp recordings, histamine (10 mu M) depolarized the membrane po tential (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-hyperp olarization (AHP(slow)) present in 80% of these neurones (95 +/- 3.2%; n = 5). All neurones possessing AHP(slow) in ferret nodose were C fib re neurones; all AHP(slow) neurones had conduction velocities less tha n 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 ea ch had an estimated EC50 value of 2 mu M. These histamine-induced effe cts were mimicked by the histamine H-1 receptor agonist 2-(2-aminoethy l)thiazole dihydrochloride (10 mu M) and blocked by the H-1 antagonist s pyrilamine (100 nM) or diphenhydramine (100 nM). Schild plot analysi s 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-methylhistami ne (10 mu M), selective H-2 or H-3 agonists, respectively, significant ly affected the membrane potential, input resistance or AHP(slow). 5. The reversal potential (V-rev) for the histamine-induced inward curren t was -84 +/- 2.1 mV (n = 4). The V-rev for the histamine response shi fted in a Nernstian manner with changes in the extracellular potassium concentration. Alterations in the extracellular chloride concentratio n 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 cur rent: the resting or 'leak' potassium current (I-K(rest)) and the pota ssium current underlying a post-spike slow after-hyperpolarization (I- AHP). Both these effects can occur in the same neurone and involve act ivation of the same histamine receptor subtype, the histamine H-1 rece ptor.