MECHANISM OF CYCLOSPORINE-INDUCED SYMPATHETIC ACTIVATION AND ACUTE HYPERTENSION IN RATS

Although intravenous cyclosporine A (CsA) previously has been shown to cause a robust sympathetically mediated increase in blood pressure in the rat, the underlying mechanism by which CsA increases the activity of the sympathetic nervous system is unknown. To determine the relati ve contributions of central neural versus peripheral reflex mechanisms in causing this sympathetic activation, we recorded efferent renal sy mpathetic nerve activity and blood pressure during intracerebroventric ular or intravenous infusion of CsA, the latter performed in intact ra ts and in those with sinoaortic denervation, cervical or subdiaphragma tic vagotomy, or dorsal rhizotomy (T-10 through L(1)). In intact rats, intravenous CsA (5 mg/kg), as expected, tripled renal sympathetic ner ve activity and increased mean arterial pressure by 27+/-4 mmHg (P<.05 ). The new findings are that this sympathoexcitatory effect of intrave nous CsA (1) was not duplicated by central administration (either into the cerebroventricular system or directly onto the ventrolateral surf ace of the medulla), (2) was unaffected by sinoaortic denervation, but (3) was greatly attenuated by either cervical or subdiaphragmatic vag otomy or by dorsal rhizotomy. In additional experiments, we found that intravenous cyclosporine increased the multiunit activity of subdiaph ragmatic but not cardiopulmonary vagal afferents. From these data, we conclude that in the rat CsA-induced increases in sympathetic activity and blood pressure are caused mainly by activation of excitatory neur al reflexes arising in the subdiaphragmatic region. These reflex mecha nisms use at least two different afferent neural pathways: one involvi ng the subdiaphragmatic vagi and the other involving the low thoracic dorsal spinal roots.