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 relative contributions of central neural versus peripheral reflex mechanisms in causing this sympathetic activation, we recorded efferent renal sympathetic nerve activity and blood pressure during intracerebroventricular or intravenous infusion of CsA, the latter performed in intact rats and in those with sinoaortic denervation, cervical or subdiaphragmatic vagotomy, or dorsal rhizotomy (T10 through L1). In intact rats, intravenous CsA (5 mg/kg), as expected, tripled renal sympathetic nerve activity and increased mean arterial pressure by 27 +/- 4 mm Hg (P < .05). The new findings are that this sympathoexcitatory effect of intravenous CsA (1) was not duplicated by central administration (either into the cerebroventricular system or directly onto the ventrolateral surface of the medulla), (2) was unaffected by sinoaortic denervation, but (3) was greatly attenuated by either cervical or subdiaphragmatic vagotomy or by dorsal rhizotomy. In additional experiments, we found that intravenous cyclosporine increased the multiunit activity of subdiaphragmatic 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 neural reflexes arising in the subdiaphragmatic region. These reflex mechanisms use at least two different afferent neural pathways: one involving the subdiaphragmatic vagi and the other involving the low thoracic dorsal spinal roots.
Lyson
T
T
Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas 75235-9034.
McMullan
D M
DM
Ermel
L D
LD
Morgan
B J
BJ
Victor
R G
RG
D000208:Acute Disease; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects*; D016572:Cyclosporine / Q000494:pharmacology*; D005260:Female; D006973:Hypertension / Q000139:chemically induced; D051381:Rats; D017207:Rats, Sprague-Dawley; D012018:Reflex / Q000187:drug effects; D013564:Sympathetic Nervous System / Q000187:drug effects*; D014630:Vagus Nerve / Q000502:physiology
D016572:Cyclosporine