Ionic mechanisms of histamine-induced responses in guinea pig intracardiac neurons

Abstract

Histamine, released from mast cells, can modulate the activity of intrinsic neurons in the guinea pig cardiac plexus. The present study examined the ionic mechanisms underlying the histamine-induced responses in these cells. Histamine evokes a small membrane depolarization and an increase in neuronal excitability. Using intracellular voltage recording from individual intracardiac neurons, we were able to demonstrate that removal of extracellular sodium reduced the membrane depolarization, whereas inhibition of K+ channels by 1 mM Ba2+, 2 mM Cs+, or 5 mM tetraethylammonium had no effect. The depolarization was also not inhibited by either 10 microM Gd3+ or a reduced Cl- solution. The histamine-induced increase in excitability was unaffected by K+ channel inhibitors; however, it was reduced by either blockage of voltage-gated Ca2+ channels with 200 microM Cd2+ or replacement of extracellular Ca2+ with Mg2+. Conversely, alterations in intracellular calcium with thapsigargin or caffeine did not inhibit the histamine-induced effects. However, in cells treated with both thapsigargin and caffeine to deplete internal calcium stores, the histamine-induced increase in excitability was decreased. Treatment with the phospholipase C inhibitor U73122 also prevented both the depolarization and the increase in excitability. From these data, we conclude that histamine, via activation of H1 receptors, activates phospholipase C, which results in 1) the opening of a nonspecific cation channel, such as a transient receptor potential channel 4 or 5; and 2) in combination with either the influx of Ca2+ through voltage-gated channels or the release of internal calcium stores leads to an increase in excitability.

Chronic myocardial infarction induces phenotypic and functional remodeling in the guinea pig cardiac plexus

“…The PACAP-induced change appears to be due, in large part, to modulation of the hyperpolarization-activated (I h ) current (19). Conversely, the histamine-induced response does not involve I h (12). The facilitatory effect of PACAP is maintained in the neurons derived from animals with CMI, but in contradistinction to the histamine response, it does not functionally upregulate in either phasic or tonic neurons.…”

“…In animals with CMI, the increases in AP frequency observed with histamine were differentially enhanced in phasic neurons, which represent the majority of the cells recorded in vitro. Prior studies have shown that the histamine-induced increase in AP frequency is dependent on an influx of extracellular Ca 2ϩ through voltage-gated Ca 2ϩ channels (12). One of the changes that has been observed in other cells in response to ischemia is a change in Ca 2ϩ channels.…”

“…Each was applied by local pressure injection, immediately adjacent (ϳ50 -100 m) to the recorded neuron, and doses were chosen that produce maximal or near-maximal responses (12,28). Induced changes in AP frequency vs. stimulus amplitude were determined to assess relative druginduced changes in excitability for both phasic and tonic intrinsic cardiac neurons derived from control animals compared with animals with CMI.…”

Histamine regulates activities of neurons in the ventrolateral preoptic nucleus

“…These effects are accompanied by changes in the action potential parameters (amplitude, width and AHP). A membrane depolarization can potentially increase the excitability of these neurons by bringing the membrane potential closer to the action potential threshold and increasing the responsiveness of the neuron to depolarizing stimuli (Hardwick et al 2006). Histamine‐induced changes in the action potential parameters are most likely to be caused by Na + channel inactivation due to membrane depolarization, since this can result in reduced activation of K + channels (both voltage‐gated and Ca 2+ ‐gated) during action potentials.…”

Histamine facilitates GABAergic transmission in the rat entorhinal cortex: Roles of H1 and H2 receptors, Na+‐permeable cation channels, and inward rectifier K+ channels

“…Neuromodulatory actions of HA typically involve enhancement of neuronal excitability via H 1 and/or H 2 and both receptors influence a variety of different ionic conductances. The H 1 is implicated in the inhibition of background K + channels (McCormick and Williamson, ; Reiner and Kamondi, ; Whyment et al, ) and inward rectifier K + channels (Kirs) (Gorelova and Reiner, ; He et al, ), activation of a TTX‐insensitive Na + channels (Gorelova and Reiner, ; Bell et al, ), nonselective cation channels (Hardwick et al, ), and Na + ‐Ca 2+ exchanger (Zhang et al, ). Activation of H 2 results in inhibition of K + conductances (Munakata and Akaike, ; Starodub and Wood, ) including the voltage‐gated (Atzori et al, ) and Ca 2+ ‐activated (Haas, ) K + channels, and activation of hyperpolarization‐activated cation channels (Ih) (McCormick and Williamson, ; Zhang et al, ).…”