Modulation of TRPV-1 by prostaglandin-E and bradykinin changes cough sensitivity and autonomic regulation of cardiac rhythm in healthy subjects.

A neurogenic pathway, involving airway TRPV-1, has been implicated in acute cardiovascular events occurring after peaks of air pollution. We tested whether inhaled prostaglandin-E (PGE) and bradykinin (BK) regulate TRPV-1 activity in vivo by changing cough response to capsaicin (CPS) and affecting heart rate variability (HRV), while also taking into account the influence of TRPV-1 polymorphisms (SNPs). Moreover, we assessed the molecular mechanism of TRPV-1 modulation in vitro. Seventeen healthy volunteers inhaled 100 μg PGE, 200 μg BK or diluent in a randomized double-blind fashion. Subsequently, the response to CPS was assessed by cough challenge and the sympathetic activity by HRV, expressed by low (nLF) and high (nHF) normalized frequency components, as well as nLF/nHF ratio. Intracellular [Ca] was measured in HeLa cells, transfected with wild-type TRPV-1, pre-treated with increasing doses of PGE, BK or diesel exhaust particulate (DEP), after CPS stimulation. Six functional TRPV-1 SNPs were characterized in DNA from each subject. Inhalation of PGE and BK was associated with significant increases in cough response induced by 30 μM of CPS (cough number after PGE = 4.20 ± 0.42; p < 0.001, and after BK = 3.64 ± 0.37; p < 0.01), compared to diluent (2.77 ± 0.29) and in sympathetic activity (nLF/nHF ratio after PGE = 6.1; p < 0.01, and after BK = 4.2; p < 0.05), compared to diluent (2.5-3.3). No influence of SNPs was observed on autonomic regulation and cough sensitivity. Unlike PGE and BK, DEP directly activated TRPV-1. Inhalation of PGE and BK sensitizes TRPV-1 and is associated with autonomic dysregulation of cardiac rhythm in healthy subjects.