Endogenous nitrosyl factors may inhibit the desensitization of 5-HT3 receptors on vagal cardiopulmonary afferents

The pronounced tachyphylaxis to the Bezold-Jarisch reflex (BJR) responses elicited by systemic injections of the 5-HT3 receptor (5-HT3R) agonists such as phenylbiguanide (PBG) may involve desensitization and/or reduced rate of resensitization of 5-HT3Rs on vagal cardiopulmonary afferents. The presence of nitric oxide synthase (NOS) in vagal afferents raises the possibility that endogenous nitrosyl factors regulate the status of 5-HT3Rs in these afferents. Accordingly, the aim of this study was to determine whether the inhibition of NOS alters the development of tachyphylaxis to the BJR responses elicited by PBG in conscious rats. The first injection of PBG (100 μg/kg, i.v.) elicited robust reductions in heart rate (HR), diastolic arterial blood pressure (BPD), and cardiac output (CO) but minor changes in total peripheral resistance in saline-treated rats. Subsequent injections elicited progressively smaller responses such that the sixth injections elicited minor responses only. The first injection of PBG (100 μg/kg, i.v.) in rats treated with the NOS inhibitor, l-NAME (25 μmol/kg, i.v.) elicited similar reductions in HR, BPD, and CO as in saline-treated rats. However, the rate of development of tachyphylaxis to PBG was markedly faster in the l-NAME-treated rats. The BJR responses elicited by 5-HT (40 μg/kg, i.v.) were markedly attenuated after the development of tachyphylaxis to PBG in saline- and in l-NAME-treated rats whereas the BJR responses elicited by the S-nitrosothiol, l-S-nitrosocysteine (5 μmol/kg, i.v.), were not attenuated in either group. These findings suggest that tachyphylaxis to PBG was not due to the loss of central or efferent processing of the BJR. Taken together, these findings suggest NOS exists in vagal cardiopulmonary afferents mediating the BJR and that nitrosyl factors influence 5-HT3R function.