Ryuzaki M, Stahl L K, Lyson T, Victor R G, Bishop V S
Kidney Disease Medical Center, Saitama (Japan) Medical School.
Hypertension. 1997 Feb;29(2):576-82. doi: 10.1161/01.hyp.29.2.576.
We postulate that the sympathoexcitatory response associated with the immunosuppressive agent cyclosporin A is due to an upward resetting of the arterial baroreflex. We performed studies in conscious intact and sinoaortic-denervated rabbits instrumented with catheters and renal nerve electrodes. In intact rabbits, cyclosporin A (20 mg/kg i.v., 30 minutes) produced significant increases in renal sympathetic nerve activity (100% to 269 +/- 74%, P < .05) but did not increase mean arterial pressure. In intact rabbits, we determined arterial baroreflex curves relating renal sympathetic nerve activity and heart rate to mean arterial pressure by producing ramp increases (intravenous phenylephrine) and decreases (intravenous nitroprusside) in mean arterial pressure. Cyclosporin A treatment produced a shift of the midrange of the baroreflex control of heart rate (78.0 +/- 4.1 to 84.6 +/- 4.7 mm Hg, P < .05) and renal sympathetic nerve activity (74.6 +/- 3.9 to 87.0 +/- 4.8 mm Hg, P < .05). Vehicle administration produced no effects on arterial baroreflex curves relating renal sympathetic nerve activity and heart rate to mean arterial pressure. Compared with vehicle treatment, cyclosporin A reduced the maximum gain of heart rate (-5.6 +/- 0.6 versus -3.1 +/- 0.8 beats per minute per millimeter of mercury, P < .05) but had no effect on the maximum gain of renal sympathetic nerve activity. In conscious sinoaortic-denervated rabbits, cyclosporin A had no effect on mean arterial pressure (95.7 +/- 7.3 to 91.8 +/- 10.8 mm Hg), renal sympathetic nerve activity (100% to 110 +/- 6%). and heart rate (287 +/- 10 to 279 +/- 8 beats per minute). However, when the same sinoaortic-denervated rabbits were anesthetized with sodium pentobarbital, cyclosporin A (20 mg/kg i.v.) produced increases in renal sympathetic nerve activity (100% to 189 +/- 27%). These data indicate (1) that the sympathoexcitatory response to cyclosporin A depends on baroreceptor afferent input in the conscious state and (2) that this response involves an upward resetting of the arterial baroreflex.
我们推测，与免疫抑制剂环孢素A相关的交感神经兴奋反应是由于动脉压力反射的向上重置。我们对有意识的完整和去窦主动脉神经支配的兔子进行了研究，这些兔子通过导管和肾神经电极进行监测。在完整的兔子中，静脉注射环孢素A（20mg/kg，30分钟）可使肾交感神经活动显著增加（100%至269±74%，P<.05），但不会增加平均动脉压。在完整的兔子中，我们通过使平均动脉压呈斜坡式升高（静脉注射去氧肾上腺素）和降低（静脉注射硝普钠）来确定将肾交感神经活动和心率与平均动脉压相关联的动脉压力反射曲线。环孢素A治疗使心率的压力反射控制的中间范围发生了偏移（从78.0±4.1至84.6±4.7mmHg，P<.05）以及肾交感神经活动的中间范围发生了偏移（从74.6±3.9至87.0±4.8mmHg，P<.05）。给予赋形剂对将肾交感神经活动和心率与平均动脉压相关联的动脉压力反射曲线没有影响。与赋形剂治疗相比，环孢素A降低了心率的最大增益（-5.6±0.6对-3.1±0.8次/分钟/毫米汞柱，P<.05），但对肾交感神经活动的最大增益没有影响。在有意识的去窦主动脉神经支配的兔子中，环孢素A对平均动脉压（从95.7±7.3至91.8±10.8mmHg）、肾交感神经活动（100%至110±6%）和心率（从287±10至279±8次/分钟）没有影响。然而，当用戊巴比妥钠麻醉相同的去窦主动脉神经支配的兔子时，环孢素A（20mg/kg静脉注射）可使肾交感神经活动增加（100%至189±27%）。这些数据表明：（1）对环孢素A的交感神经兴奋反应在清醒状态下依赖于压力感受器传入输入；（2）这种反应涉及动脉压力反射的向上重置。
