title: Attenuation of autonomic reflexes by A803467 may not be solely caused by blockade of NaV 1.8 channels.
abstract: In decerebrated rats, we determined the dose of A803467, a NaV 1.8 antagonist, needed to attenuate the reflex pressor responses to femoral arterial injections of lactic acid (24 mM; ~0.1 ml) and capsaicin (0.1 μg), agents which stimulate thin fiber afferents having NaV 1.8 channels. We also determined whether the dose of A803467 needed to attenuate these reflex responses affected the responses of muscle spindle afferents to tendon stretch and succinylcholine (200 μg). Spindle afferents are not supplied with NaV 1.8 channels, and consequently their responses to these stimuli should not be influenced by A803467. Pressor responses to lactic acid and capsaicin were not altered by 500 μg of A803467 (n=6). A803467 in a dose of 1mg, however, significantly reduced (p<0.05; n=12) the pressor responses to lactic acid (23 ± 5 to 7 ± 3 Δmm Hg) and capsaicin (47 ± 5 to 31 ± 5 ΔmmHg). Surprisingly, we also found that 1mg of A803467 reduced the responses of 10 spindle afferents to succinylcholine (34 ± 11 to 4 ± 3 Δimp/s; p<0.05) and stretch (83 ± 17 to 0.4 ± 1 Δimp/s; p<0.05). We conclude that A803467 reduces the reflex response to lactic acid and capsaicin; however, it may be working on multiple channels, including NaV 1.8, other NaVs as well as voltage-gated calcium channels.
authors.affiliation: Heart and Vascular Institute, Penn State College of Medicine, Hershey, PA 17033, United States. astone1@hmc.psu.edu
authors.forename: Audrey J
authors.initials: AJ
authors.lastname: Stone
authors.forename: Joyce S
authors.initials: JS
authors.lastname: Kim
authors.forename: Katsuya
authors.initials: K
authors.lastname: Yamauchi
authors.forename: Victor
authors.initials: V
authors.lastname: Ruiz-Velasco
authors.forename: Marc P
authors.initials: MP
authors.lastname: Kaufman
mesh_terms: D000344:Afferent Pathways / Q000187:drug effects / Q000502:physiology; D000814:Aniline Compounds / Q000494:pharmacology*; D000818:Animals; D001341:Autonomic Nervous System / Q000187:drug effects* / Q000502:physiology; D017704:Baroreflex / Q000187:drug effects; D002211:Capsaicin / Q000494:pharmacology; D003655:Decerebrate State; D005663:Furans / Q000494:pharmacology*; D006614:Hindlimb; D019344:Lactic Acid / Q000494:pharmacology; D008297:Male; D018482:Muscle, Skeletal / Q000187:drug effects / Q000294:innervation; D062559:NAV1.8 Voltage-Gated Sodium Channel / Q000502:physiology*; D009412:Nerve Fibers / Q000187:drug effects / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012018:Reflex / Q000187:drug effects*; D012026:Reflex, Stretch / Q000187:drug effects; D061567:Voltage-Gated Sodium Channel Blockers / Q000494:pharmacology*
chemical_list: C520740:A 803467; D000814:Aniline Compounds; D005663:Furans; D062559:NAV1.8 Voltage-Gated Sodium Channel; C568319:Scn10a protein, rat; D061567:Voltage-Gated Sodium Channel Blockers; D019344:Lactic Acid; D002211:Capsaicin