title: Pretreatment with nonselective cationic channel inhibitors blunts the PACAP-induced increase in guinea pig cardiac neuron excitability.
abstract: Calcium influx is required for the pituitary adenylyl cyclase activating polypeptide (PACAP)-induced increase in guinea pig cardiac neuron excitability, noted as a change from a phasic to multiple action potential firing pattern. Intracellular recordings indicated that pretreatment with the nonselective cationic channel inhibitors, 2-aminoethoxydiphenylborate (2-APB), 1-[β-[3-(4-methoxyphenyl)propoxy]-4-methoxyphenethyl]-1H-imidazole HCl (SKF 96365), and flufenamic acid (FFA) reduced the 20-nM PACAP-induced excitability increase. Additional experiments tested whether 2-APB, FFA, and SKF 96365 could suppress the increase in excitability by PACAP once it had developed. The increased action potential firing remained following application of 2-APB but was diminished by FFA. SKF 96365 transiently depressed the PACAP-induced excitability increase. A decrease and recovery of action potential amplitude paralleled the excitability shift. Since semiquantitative PCR indicated that cardiac neurons express TRPC subunit transcripts, we hypothesize that PACAP activates calcium-permeable, nonselective cationic channels, which possibly are members of the TRPC family. Our results are consistent with calcium influx being required for the initiation of the PACAP-induced increase in excitability, but suggest that it may not be required to sustain the peptide effect. The present results also demonstrate that nonselective cationic channel inhibitors could have other actions, which might contribute to the inhibition of the PACAP-induced excitability increase.
authors.affiliation: Department of Anatomy and Neurobiology, College of Medicine, University of Vermont, Burlington, VT 05405, USA.
authors.forename: Laura A
authors.initials: LA
authors.lastname: Merriam
authors.forename: Carolyn W
authors.initials: CW
authors.lastname: Roman
authors.forename: Caitlin N
authors.initials: CN
authors.lastname: Baran
authors.forename: Beatrice M
authors.initials: BM
authors.lastname: Girard
authors.forename: Victor
authors.initials: V
authors.lastname: May
authors.forename: Rodney L
authors.initials: RL
authors.lastname: Parsons
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D001896:Boron Compounds / Q000494:pharmacology*; D002121:Calcium Channel Blockers / Q000494:pharmacology; D020013:Calcium Signaling / Q000187:drug effects* / Q000502:physiology; D005260:Female; D005439:Flufenamic Acid / Q000494:pharmacology*; D006168:Guinea Pigs; D006329:Heart Conduction System / Q000166:cytology / Q000187:drug effects*; D007093:Imidazoles / Q000494:pharmacology*; D007473:Ion Channels / Q000187:drug effects*; D017136:Ion Transport / Q000187:drug effects; D061346:Laser Capture Microdissection; D008297:Male; D049990:Membrane Transport Modulators / Q000494:pharmacology*; D009474:Neurons / Q000187:drug effects* / Q000502:physiology; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D016133:Polymerase Chain Reaction / Q000379:methods; D059010:Single-Cell Analysis; D050052:TRPC Cation Channels / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics
chemical_list: D001896:Boron Compounds; D002121:Calcium Channel Blockers; D007093:Imidazoles; D007473:Ion Channels; D049990:Membrane Transport Modulators; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide; D050052:TRPC Cation Channels; D005439:Flufenamic Acid; C109986:2-aminoethoxydiphenyl borate; C063159:1-(2-(3-(4-methoxyphenyl)propoxy)-4-methoxyphenylethyl)-1H-imidazole