anandamide and Apnea

Anandamide (AEA), an arachidonic acid derivative produced during inflammatory conditions, is an endogenous agonist of both transient receptor potential vanilloid 1 (TRPV1) receptors and cannabinoid CB1 receptors. Sensitization of capsaicin-sensitive lung vagal afferent (CSLVA) fibers by chemical mediators is important in the pathogenesis of hyperreactive airway diseases. We investigated the effect of the intravenous infusion of AEA (2 mg x kg(-1) x ml(-1), 0.5 ml/min for 2 min) on the sensitivity of CSLVA fibers to chemical and mechanical stimulation in anesthetized rats. In artificially ventilated rats, AEA infusion only mildly elevated the baseline activity of CSLVA fibers. However, CSLVA fiber responses to right atrial injection of capsaicin, AEA, or adenosine and to lung inflation (tracheal pressure = 30 cmH(2)O) were all markedly potentiated during AEA infusion, which reverted 20 min after termination of the infusion. The potentiating effect on the sensitivity of CSLVA fibers to adenosine injection or lung inflation was completely blocked by pretreatment with capsazepine (a TRPV1 receptor antagonist) but was unaffected by pretreatment with AM281 (a CB1 receptor antagonist). In spontaneously breathing rats, right atrial injection of adenosine evoked an apneic response that is presumably mediated through CSLVA fibers. Similarly, the adenosine-evoked apneic response was potentiated during AEA infusion, and this potentiating effect was also completely prevented by pretreatment with capsazepine. These results suggest that AEA infusion at the dose tested produces a mild activation of TRPV1 receptors and this nonspecifically increases CSLVA fiber sensitivity to chemical and mechanical stimulation.

Topics: Adenosine; Animals; Apnea; Arachidonic Acids; Blood Pressure; Capsaicin; Endocannabinoids; Heart Rate; Infusions, Intravenous; Lung; Male; Morpholines; Neurons, Afferent; Physical Stimulation; Polyunsaturated Alkamides; Pyrazoles; Rats; Rats, Sprague-Dawley; Receptor, Cannabinoid, CB1; TRPV Cation Channels; Vagus Nerve

Anaesthetized and spontaneously breathing rats were used to study the cardio-respiratory effects of intravenous anandamide administration. To investigate the role of particular levels of the afferent pathway in this response rats were challenged with bolus injection of anandamide (1 mg kg(-1)) into the femoral vein while intact, following bilateral superior laryngeal nerves (SLNs) section and after midcervical vagotomy. To test the hypothesis that the activation of the vanilloid receptors (VR1) as well as cannabinoid receptors (CB1) contributes to the anandamide-induced response administrations of anandamide were preceded by nonselective VR1 antagonist ruthenium red or selective CB1 antagonist AM281. Anandamide evoked apnoea of mean duration of 4.84+/-0.75 s in all animals while intact which was shortened by subsequent neurotomies, after SLNs section to 3.3+/-0.57 s (P<0.05) and after midcervical vagi section to 1.99+/-0.24 s (P<0.01). In post-apnoeic breathing tidal volume (V(T)) was reduced in all neural states. Anandamide evoked hypotension in the intact and SLNs neurotomized rats. Midcervical vagotomy reduced this fall in blood pressure. Both antagonists ruthenium red and AM281 eliminated post-anandamide apnoea and hypotension but had no effect on post-apnoeic depression of V(T). Subsequent SLNs and cervical vagi sections did not eliminate but only reduced post-anandamide depression of breathing. Midcervical vagotomy lessened anandamide-induced hypotension. Apnoeic and hypotensive response to anandamide was mediated by both VR1 and CB1 receptors. Post-anandamide decline of V(T) might depend on different type of receptors.

Topics: Afferent Pathways; Animals; Apnea; Arachidonic Acids; Blood Pressure; Calcium Channel Blockers; Cannabinoid Receptor Modulators; Endocannabinoids; Heart; Hypotension; Injections, Intravenous; Male; Polyunsaturated Alkamides; Rats; Rats, Wistar; Receptor, Cannabinoid, CB1; Respiration; Ruthenium Red; TRPV Cation Channels; Vagotomy; Vagus Nerve

Respiratory effects of an intravenous injection of anandamide were investigated in 19 urethane-chloralose anaesthetised and spontaneously breathing rats. In 10 neurally intact rats the effects of anandamide were checked to establish appropriate dose of the drug. In the second group, nine rats were challenged with anandamide while intact, following bilateral midcervical vagotomy and after subsequent supranodose vagotomy. Bolus injection of 1 mg kg(-1) of anandamide into the right femoral vein pre- and post-midcervical vagotomy induced in all nine rats prompt apnoea of similar duration: 2.97 +/- 0.5 and 3.2 +/- 0.4s, respectively. In post-apnoeic breaths tidal volume decreased below the control level by 25% (P < 0.01) prior to and by 43.4% (P < 0.001) after midcervical vagotomy. Supranodose vagotomy precluded the respiratory response to anandamide. Anandamide-induced decrease in mean arterial blood pressure in nerve-intact and vagotomised rats was abolished by supranodose vagotomy. Results indicate that the cardio-respiratory depression evoked by anandamide administered via the peripheral circulation requires intact supranodose vagi.

Topics: Analysis of Variance; Anesthesia; Animals; Apnea; Arachidonic Acids; Blood Pressure; Calcium Channel Blockers; Dose-Response Relationship, Drug; Endocannabinoids; Hemodynamics; Male; Polyunsaturated Alkamides; Rats; Rats, Wistar; Respiration; Tidal Volume; Time Factors; Vagotomy