SYMPATHOEXCITATORY RESPONSE TO CYCLOSPORINE-A AND BAROREFLEX RESETTING

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 n erve electrodes. In intact rabbits, cyclosporin A (20 mg/kg IV, 30 min utes) produced significant increases in renal sympathetic nerve activi ty (100% to 269+/-74%, P<.05) but did not increase mean arterial press ure. In intact rabbits, we determined arterial baroreflex curves relat ing renal sympathetic nerve activity and heart rate to mean arterial p ressure by producing ramp increases (intravenous phenylephrine) and de creases (intravenous nitroprusside) in mean arterial pressure. Cyclosp orin A treatment produced a shift of the midrange of the baroreflex co ntrol of heart rate (78.0+/-4.1 to 84.6+/0 4.7 mm Hg, P<.05) and renal sympathetic nerve activity (74.6+/-3.9 to 87.0+/-4.8 mm Hg, P<.05). V ehicle administration produced no effects on arterial baroreflex curve s relating renal sympathetic nerve activity and heart rate to mean art erial pressure. Compared with vehicle treatment, cyclosporin A reduced the maximum gain of heart rate (-5.6+/-0.6 versus -3.1+/-0.8 beats pe r minute per millimeter of mercury, P<.05) but had no effect on the ma ximum gain of renal sympathetic nerve activity. In conscious sinoaorti c-denervate rabbits, cyclosporin A had no effect on mean arterial pres sure (95.7+/-7.3 to 91.8+/-10.8 mm Hg), renal sympathetic nerve activi ty (100% to 110+/-6%), and heart rate (287+/-10 to 279+/-8 beats per m inute). However, when the same sinoaortic-denervated rabbits were anes thetized with sodium pentobarbital, cyclosporin A (20 mg/kg IV) produc ed increases in renal sympathetic nerve activity (100% to 189+/-27%). These data indicate (1) that the sympathoexcitatory response to cyclos porin A depends on baroreceptor afferent input in the conscious state and (2) that this response involves an upward resetting of the arteria l baroreflex.