The pulmonary artery pressure and pulmonary congestion are regulated by the reflexes originating from the pulmonary C fibre receptors (J receptors) (Paintal 1973; Roberts et al, 1986). Activation of these receptors reflexly diminishes the accumulation of fluid in the pulmonary interstitium (Paintal, 1973). These reflexes can be elicited by phenyldiguanide (PDG), phenylbiguanide (PBG), 5-hydroxytryptamine (5-HT), capsaicin and lobeline in experimental animals. The reflexes evoked manifest as bradycardia, hypotension and apnoea/tachypnoea. These chemicals involve different types of membrane receptors to produce reflex responses. For example, PBG, PDG and 5-HT mediate their actions via 5-HT3 receptors while capsaicin mediates via TRPV1 receptors. Therefore, this study was undertaken to compare the effects of PBG and capsaicin on cardio-respiratory reflexes. In addition, it was aimed to explore the underlying mechanisms. All the experiments were performed after obtaining the approval from the Institute Ethical Committee for conducting animal experiments. Trachea, jugular vein and femoral artery were cannulated in urethane anaesthetized adult rats. Blood pressure, respiratory excursions and ECG were recorded. In some experiments, vagal afferent activity was also recorded. Jugular venous injection of PBG produced concentration-dependent (0.1-100 µg/kg) hypotensive and bradycardiac responses but in case of respiration, there was tachypnoea at lower concentrations (0.1-3 µg/kg) and apnoea at higher concentrations (10-100 µg/kg). After vagotomy, both tachypnoeic and apnoeic responses induced by PBG were abolished along with cardiovascular responses. Ondansetron (5-HT3 receptor antagonist, 10 µg/kg) abolished the PBG-induced reflex responses at all concentrations but capsazepine (TRPV1 receptor antagonist; 3 mg/kg) failed to antagonize the PBG responses. Bolus injection of capsaicin (0.1-10 µg/kg) also produced concentration-dependent apnoea, hypotension and bradycardia but no tachypnoea was observed at any concentrations of capsaicin. Ondansetron failed to block the capsaicin-induced reflex response while bilateral vagotomy abolished the hypotensive and bradycardiac response and attenuated the apnoeic response. In separate series of experiments, PBG produced a burst of activity in afferents along with cardio-respiratory alterations. However, the afferents which evoked activity with PBG failed to evoke any activity with capsaicin even though bradycardia, hypotension and respiratory changes were observed. The present observations indicate that PBG-induced cardio-respiratory responses involve 5-HT3 receptors on vagal afferents where as capsaicin involve different set of afferents.