Sympathoexcitatory Response to Cyclosporin A and Baroreflex Resetting

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Abstract
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 IV, 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 IV) 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.