The combination of fentanyl and diazepam significantly decreases systemic vascular resistance and blood pressure. We attempted to elucidate the reason the combination of these drugs can reduce blood pressure. In alpha-chloralose-anesthetized dogs, we investigated the effects of fentanyl and diazepam on mean arterial pressure (MAP) and arterial baroreflex control of renal sympathetic nerve activity (RSNA) in both intact (Study 1) and baroreflex-denervated dogs (Study 2). Study 1 included five dogs that received fentanyl 10 micrograms/kg followed by diazepam 0.4 mg/kg after a 10-min interval. Five more received both drugs in reversed sequence. The arterial baroreflex depressor test was performed with sodium nitroprusside before and after administration of each drug. Sensitivity of arterial baroreflex was examined by using the ratio of maximum increase of RSNA to maximum decrease of MAP (delta RSNA/delta MAP). RSNA and MAP significantly decreased only after both drugs had been administered (P < 0.05). Fentanyl alone did not attenuate arterial baroreflex sensitivity. Diazepam after fentanyl and diazepam alone attenuated baroreflex sensitivity to the same extent (P < 0.05). Study 2 comprised 14 dogs that underwent further surgical preparation of bilateral carotid sinus, aortic, and vagal nerve denervations. Seven received fentanyl, 5 and 10 micrograms/kg, and the other seven received diazepam, a total of 0.4 mg/kg. Fentanyl decreased both RSNA and MAP. Diazepam decreased only MAP significantly. The results indicate that fentanyl decreases mainly sympathetic outflow, whereas diazepam attenuates arterial baroreflex. We conclude that these combined effects of fentanyl and diazepam significantly decrease arterial blood pressure.

One reason for the reported conflicting results of the effect of ketamine on hemodynamics and respiration may be variations in afferent inputs from peripheral receptors to the central nervous system. In order to evaluate unmasked direct effects of ketamine on sympathetic nerve and phrenic nerve outflow, totally deafferented (involving vagus, sinus nerve, aortic depressor nerve) rabbits (n = 18), rabbits with vagotomy (n = 21), and neuraxis-intact rabbits (n = 6) were used in this study. The animals were anesthetized with urethane and mechanically ventilated. Ketamine 0.5, 1, or 2 mg/kg was injected intravenously and mean arterial pressure (MAP), heart rate (HR), and integrated renal sympathetic nerve and phrenic nerve activity (IRSNA, IPNA) were recorded before, and 1, 2, 3, 5, and 10 min after injection. MAP and IRSNA were significantly decreased, even by the smallest dose of ketamine, in the totally deafferented group. IPNA was decreased by the largest dose of ketamine only in the totally deafferented group. On the other hand, spontaneous respiratory frequency was decreased in the totally deafferented and vagotomy groups, but more so in the totally deafferented group. In the neuraxis-intact group, the only significant change with the largest dose of ketamine, 2 mg/kg was a slight increase in HR. We conclude that ketamine can suppress vasomotor and respiratory centers directly, and that the suppression is counterbalanced by afferent inputs from peripheral receptors.

Bronchomotor tone is regulated by contraction and relaxation of airway smooth muscle (ASM). A weakened ASM relaxation might be a cause of the airway hyperresponsiveness, a characteristic feature of bronchial asthma. Pituitary adenylyl cyclase-activating polypeptide (PACAP) is known as a mediator that causes ASM relaxation. To date, whether or not the PACAP responsiveness is changed in asthmatic ASM is unknown. The current study examined the hypothesis that relaxation induced by PACAP is reduced in bronchial smooth muscle (BSM) of allergic asthma. The ovalbumin (OA)-sensitized mice were repeatedly challenged with aerosolized OA to induce asthmatic reaction. Twenty-four hours after the last antigen challenge, the main bronchial smooth muscle (BSM) tissues were isolated. Tension study showed a BSM hyperresponsiveness to acetylcholine in the OA-challenged mice. Both quantitative RT-PCR and immunoblot analyses revealed a significant decrease in PAC1 receptor expression in BSMs of the diseased mice. Accordingly, in the antigen-challenged group, the PACAP-induced PAC1 receptor-mediated BSM relaxation was significantly attenuated, whereas the relaxation induced by vasoactive intestinal polypeptide was not changed. These findings suggest that the relaxation induced by PACAP is impaired in BSMs of experimental asthma due to a down-regulation of its binding partner PAC1receptor. Impaired BSM responsiveness to PACAP might contribute to the AHR in asthma.

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