Acute inhalation of airborne pollutants alters cardiovascular function and has been shown to have its greatest affects on individuals with pre-existing cardiovascular disease. Evidence suggests that pollutant-induced activation of airway sensory nerves via the gating of ion channels is critical to these systemic responses. Here, we have investigated the cardiovascular responses evoked by inhalation of AITC (TRPA1 agonist) and capsaicin (TRPV1 agonist) in healthy Sprague Dawley (SD) and Wistar Kyoto (WKY) rats, and cardiovascular diseased Spontaneously Hypertensive (SH) rats. Inhalation of the agonists by healthy SD and WKY rats caused significant bradycardia, atrio-ventricular (AV) block and prolonged PR-Intervals. Inhalation of TRP agonists caused differential cardiovascular responses in the cardiovascular diseased SH rats, such that the TRP agonists evoked brady-tachy with AV block and premature ventricular contractions (PVCs). Bradycardic responses to AITC were inhibited by the TRP channel blocker ruthenium red and the muscarinic antagonist atropine, but atropine did not prevent the tachycardic responses seen in the SH rats. Adrenergic inhibition with atenolol prevented the tachycardic responses, but did not prevent the bradycardic responses evoked by AITC in the SH rats. In healthy rats, AITC inhalation also caused a biphasic blood pressure response: a brief hypertensive phase followed by a hypotensive phase, while evoking hypertension in the SH rats. Atropine accentuated the hypertensive phase in all animals, while preventing the hypotension in the healthy animals. In all animals, AITC-evoked heart rate responses were not abolished by terazosin, the [U+F061]1 adrenoceptor inhibitor, which prevented the hypertensive responses. Anesthetics had profound effects on AITC-evoked bradycardia and AV block, which was abolished by urethane, ketamine and isoflurane. Nevertheless, AITC inhalation caused bradycardia and AV block in paralyzed and ventilated rats following pre-collicular decerebration. In conclusion, we provide evidence that activation of TRP channels expressed on nociceptive airway sensory nerves causes significant cardiovascular effects in healthy rats via reflex modulation of the autonomic nervous system (ANS), and that these effects are exacerbated in cardiovascular diseased rats.

CoordenaÃÃo de AperfeiÃoamento de Pessoal de NÃvel Superior / INTRODUÃÃO: A amifostina (WR-2721) tem sido largamente estudada como agente citoprotetor em diferentes ÃrgÃos e contra os mais diversos agressores do organismo humano. Recentemente, um efeito gastroprotetor deste fÃrmaco foi observado em modelo de lesÃo gÃstrica induzida por indometacina (MOTA et al., 2007). OBJETIVOS: Este trabalho investigou o efeito da amifostina na lesÃo gÃstrica por etanol e o papel dos neurÃnios sensoriais aferentes, grupos sulfidrÃlicos nÃo-protÃicos, Ãxido nÃtrico, canais de potÃssio sensÃveis ao ATP e ciclooxigenase-2 nesse processo. MÃTODOS: Ratos Wistar foram tratados com amifostina (22,5, 45, 90 ou 180 mg/kg, v.o. ou s.c.). ApÃs 30 minutos, os animais receberam etanol absoluto (5 ml/kg v.o.). Decorridos 60 minutos da administraÃÃo de etanol, os animais foram sacrificados. Foram realizados estudos macroscÃpicos e histolÃgicos, bem como dosagem de grupos sulfidrÃlicos nÃo-protÃicos e de hemoglobina em fragmentos de estÃmago. Outros grupos foram prÃ-tratados com L-NAME (10 mg/kg i.p.), glibenclamida (10 mg/kg v.o.), celecoxibe (10 mg/kg v.o.) ou salina. ApÃs 30 minutos os ratos receberam amifostina (90 mg/kg v.o. ou s.c.) e depois de mais 30 minutos etanol absoluto (5 ml/kg), com sacrifÃcio ocorrendo 60 minutos depois. Um grupo de animais foi desensibilizado com capsaicina (125 mg/kg s.c.) entre 10 a 14 dias antes do protocolo de tratamento com amifostina. RESULTADOS: A amifostina preveniu de forma significativa o dano macroscÃpico causado por etanol no estÃmago nas doses de 45, 90 e 180 mg/kg quando administrada por via oral e 90 e 180 mg/kg quando utilizada por via subcutÃnea. Os parÃmetros histolÃgicos, edema, hemorragia e perda de cÃlulas epiteliais, tambÃm foram reduzidos (p<0,05) com o uso de amifostina. Os animais que receberam apenas etanol apresentaram nÃveis reduzidos de GSH no estÃmago. A amifostina reverteu esse efeito atravÃs de um estÃmulo à produÃÃo de novo de GSH ou pela prevenÃÃo do consumo destes grupos. A gastroproteÃÃo da amifostina na lesÃo induzida pelo etanol foi revertida pela administraÃÃo prÃvia de doses neurotÃxicas de capsaicina, mas nÃo pelo uso de L-NAME, glibenclamida ou celecoxibe. CONCLUSÃES: A amifostina protege a mucosa gÃstrica contra a injÃria induzida pelo etanol atravÃs de um aumento dos nÃveis de GSH e estimulaÃÃo de neurÃnios sensoriais aferentes no estÃmago. Esse efeito parece ser independente da ativaÃÃo de canais de potÃssio sensÃveis ao ATP e da atividade de Ãxido nÃtrico sintase e ciclooxigenase-2 / INTRODUCTION: Amifostine (WR-2721) has been widely tested as a cytoprotective agent against a number of aggressors in different organs. Recently, a gastroprotective effect was observed for this drug in a model of indomethacin-induced gastric injury (MOTA et al., 2007). OBJECTIVES: We investigated the effect of amifostine on ethanol-induced gastric injury and the role played by afferent sensory nerves, non-protein sulfhydryl groups, nitric oxide, ATP-sensitive potassium channels and cyclooxygenase-2 in the mechanism. METHODS: Wistar rats were treated with amifostine (22.5, 45, 90 or 180 mg/kg, p.o. or s.c.). Thirty minutes after amifostine administration, the animals were given 100% ethanol (5 ml/kg p.o.). Sixty minutes after ethanol administration the animals were euthanized. Macroscopic and histological studies were carried out and stomach fragments were retrieved and submitted to analysis for non-protein sulfhydryl groups and hemoglobin. Some animals were pretreated with L-NAME (10 mg/kg i.p.), glibenclamide (10 mg/kg p.o.), celecoxib (10 mg/kg p.o.) or saline solution. Thirty minutes after pretreatment the animals were given amifostine (90 mg/kg p.o. or s.c.) and, after another 30 minutes, 100% ethanol (5 ml/kg). The animals were euthanized 60 minutes later. Other rats were desensitized with capsaicin (125 mg/kg s.c.) 10-14 days before amifostine treatment. RESULTS: Amifostine treatment significantly reduced ethanol-induced macroscopic stomach injury at 45, 90 and 180 mg/kg p.o. and at 90 and 180 mg/kg s.c. The histological parameters (edema, hemorrhage and epithelial cell loss) were also reduced (p<0.05) when the animals were treated with amifostine. Animals receiving ethanol only presented reduced GSH levels in the stomach. Amifostine reverted this effect either by stimulating de novo GSH production or by preventing the consumption of GSH. Amifostine-promoted gastroprotection against ethanol-induced stomach injury was reversed by pretreatment with neurotoxic doses of capsaicin, but not by L-NAME, glibenclamide or celecoxib. CONCLUSIONS: Amifostine protects against ethanol-induced gastric injury by increasing GSH levels and stimulating the afferent sensory nerves in the stomach independently of ATP-sensitive potassium channels activation, nitric oxide synthase and cyclooxygenase-2 activity