Cyclosporine induces progressive attenuation of baroreceptor heart rate response and cumulative pressor response in conscious unrestrained rats.

Abstract

Cyclosporine A (CsA) use is associated with hypertension and reduced baroreceptor sensitivity (BRS), but the underlying mechanisms remain unresolved. In this study, we investigated whether CsA attenuation of BRS is 1) dependent on treatment regimen, and 2) causative of the pressor response. Furthermore, we investigated whether a reduction in plasma testosterone contributes to BRS attenuation caused by short-term CsA administration. The effects of the clinically used CsA formulation (15 mg/kg/day i.v. for 5 days) on mean arterial pressure (MAP), heart rate, BRS, and body weight were investigated in conscious rats. CsA caused reproducible pressor responses (15.1 +/- 3.0 mm Hg) starting after the first dose and continuing through the 5 days of the study. BRS and baseline MAP were inversely related in the CsA group because of a progressive reduction in BRS, which started on day 2 and reached approximately 50% of baseline on day 5 and a cumulative elevation in MAP. The inverse BRS and MAP responses required daily administration of CsA because neither response was evident throughout the 5-day observation period after a single dose of CsA. Plasma testosterone levels were similar in all groups, whereas the body weight decreased approximately 10% in the CsA group on day 5. These findings suggest 1) CsA attenuation of BRS is relatively rapid and cumulative; 2) the attenuation of BRS may contribute to the delayed, but not to the acute, pressor elicited by CsA; and 3) the cumulative reduction in BRS caused by short-term (5-day) CsA treatment is not testosterone-related.