Tachyphylaxis to 5-HT3-receptor-mediated activation of vagal afferents is prevented by co-activation of 5-HT2 receptors.
Functional studies have provided evidence that 5-HT(3) ion-channel receptors (5-HT(3)Rs) on vagal cardiopulmonary afferents mediating the Bezold-Jarisch reflex (BJR) rapidly desensitize upon repeated exposure to selective 5-HT(3)R agonists. G-protein-coupled 5-HT(2) receptors (5-HT(2)Rs) also exist on vagal afferents, although activation of these receptors does not elicit the BJR. However, there is in vivo evidence that 5-HT(2)Rs may regulate the activity of 5-HT(3)Rs. The aim of this study was to determine whether co-activation of 5-HT(2)Rs prevents desensitization of 5-HT(3)Rs mediating the BJR in conscious rats. The principal findings were that (1) tachyphylaxis rapidly developed to the BJR-mediated hemodynamic responses elicited by successive injections of 5-HT(3)R agonists and (2) co-injection of the selective 5-HT(2)R agonist, alpha-methyl-5-HT, prevented tachyphylaxis to the BJR-mediated hemodynamic responses elicited by the 5-HT(3)R agonists. Additional studies provided evidence that (1) tachyphylaxis to the 5-HT(3)R agonists was not due to impairment of the central or efferent processing of the BJR, and (2) the pressor responses elicited by alpha-methyl-5-HT were not responsible for preventing tachyphylaxis to the BJR reflex responses elicited by 5-HT(3)R agonists. These results suggest that the loss of response to 5-HT(3)R agonists is due to desensitization of 5-HT(3)Rs on vagal afferents mediating the BJR and that co-activation of 5-HT(2)Rs prevents the desensitization of these 5-HT(3)Rs.
Lacolley
Patrick J
PJ
Department of Pharmacology, University of Iowa, Iowa City, IA 52242, USA. Patrick.Lacolley@nancy.inserm.fr
Owen
Joy R
JR
Bates
James N
JN
Johnson
Alan Kim
AK
Lewis
Stephen J
SJ
D000818:Animals; D006439:Hemodynamics / Q000187:drug effects / Q000502:physiology; D008297:Male; D009475:Neurons, Afferent / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D044348:Receptors, Serotonin, 5-HT2 / Q000187:drug effects / Q000378:metabolism; D044406:Receptors, Serotonin, 5-HT3 / Q000187:drug effects / Q000378:metabolism*; D012018:Reflex / Q000187:drug effects / Q000502:physiology; D017366:Serotonin Receptor Agonists / Q000494:pharmacology*; D013618:Tachyphylaxis / Q000502:physiology*; D014630:Vagus Nerve / Q000187:drug effects / Q000378:metabolism*
D044348:Receptors, Serotonin, 5-HT2; D044406:Receptors, Serotonin, 5-HT3; D017366:Serotonin Receptor Agonists