Ionic mechanisms of histamine-induced responses in guinea pig intracardiac neurons.
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.
Hardwick
Jean C
JC
Biology Department, Ithaca College, Ithaca, NY 14850, USA. jhardwick@ithaca.edu
Kotarski
Amy F
AF
Powers
Melanie J
MJ
D000818:Animals; D002118:Calcium / Q000378:metabolism / Q000494:pharmacology; D004963:Estrenes / Q000494:pharmacology; D005260:Female; D006168:Guinea Pigs; D006321:Heart / Q000294:innervation*; D006632:Histamine / Q000494:pharmacology*; D008297:Male; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D026902:Potassium Channel Blockers / Q000494:pharmacology; D011760:Pyrrolidinones / Q000494:pharmacology
D004963:Estrenes; D010726:Phosphodiesterase Inhibitors; D026902:Potassium Channel Blockers; D011760:Pyrrolidinones; C060229:1-(6-((3-methoxyestra-1,3,5(10)-trien-17-yl)amino)hexyl)-1H-pyrrole-2,5-dione; D006632:Histamine; D002118:Calcium