Cyclosporine Adversely Affects Baroreflexes via Inhibition of Testosterone Modulation of Cardiac Vagal Control

Abstract

Previous studies have shown that the immunosuppressant drug cyclosporine A attenuates arterial baroreceptor function. This study investigated whether the modulatory effect of cyclosporine on baroreceptor function involves inhibition of the baroreflex-facilitatory effect of testosterone. The role of cardiac autonomic control in cyclosporine-testosterone baroreflex interaction was also investigated. Baroreflex curves relating bradycardic responses to increments in blood pressure evoked by phenylephrine were constructed in conscious, sham-operated, castrated rats and in testosterone-replaced castrated (CAS ϩ T) rats in the absence and presence of cyclosporine. The slopes of the curves were taken as an index of the baroreflex sensitivity (BRS). Short-term (11-13 days) cyclosporine treatment or castration reduced plasma testosterone levels and caused similar attenuation of the reflex bradycardia, as indicated by the significantly smaller BRS compared with sham-operated values (Ϫ0.97 Ϯ 0.07, Ϫ0.86 Ϯ 0.06, and Ϫ1.47 Ϯ 0.10 beats/min/mm Hg, respectively). The notion that androgens facilitate baroreflexes is further confirmed by the observation that testosterone replacement of castrated rats restored plasma testosterone and BRS to sham-operated levels. Cyclosporine had no effect on BRS in castrated rats but caused a significant reduction in CAS ϩ T rats. Muscarinic blockade by atropine caused approximately 60% reduction in the BRS in sham-operated rats, an effect that was significantly and similarly diminished by castration, cyclosporine, or their combination. ␤-Adrenergic blockade by propranolol caused no significant changes in BRS. These findings suggest that cyclosporine attenuates baroreflex responsiveness via, at least partly, inhibition of the testosteroneinduced facilitation of cardiomotor vagal control.

Cyclosporine Induces Progressive Attenuation of Baroreceptor Heart Rate Response and Cumulative Pressor Response in Conscious Unrestrained Rats

“…MAP, HR, and BRS were measured only at the conclusion of the study (El-Mas et al, 2002), and in some instances, blood pressure was measured by the tail cuff method (Oriji and Keiser, 1999). Even when the i.v.…”

“…Nonetheless, whether a rapid inhibitory effect of CsA on BRS occurs in rodents and whether such effect is secondary to a reduction in serum testosterone has not been investigated. Furthermore, the reported findings on the effects of a single dose (Ryuzaki et al, 1997) or multiple doses (Ͼ10 days) of CsA (El-Mas et al, 2002) on mean arterial pressure (MAP) were based on the use of doses, formulation, and route of administration that are not relevant to the clinical use of CsA.…”

“…Recent evidence suggests that a reduction in serum testosterone level contributes to the inhibition of BRS caused by chronic CsA administration (El-Mas et al, 2002). This conclusion is based on the findings that chronic CsA causes a reduction in serum testosterone (Rajfer et al, 1987;Krueger et al, 1991) and the ability of testosterone to enhance BRS (El-Mas et al, 2001).…”

Sinus bradycardia associated with cyclosporine following allogeneic hematopoietic stem cell transplantation

“…As an alternative possibility, cyclosporine might have stimulated the parasympathetic nervous system and led to bradycardia; with diaphoresis being the result of compensatory increase in the sympathetic nervous system activity. However, cyclosporine has been reported to suppress the parasympathetic nervous function such as baroreflex, 5 suggesting that the second possibility is less likely.…”

Uso crônico de decanoato de nandrolona como fator de risco para hipertensão arterial pulmonar em ratos Wistar

“…Estudos prévios de nosso grupo demonstraram que o reflexo de bradicardia (BezoldJarish) não foi modificado pela administração do EAA, decanoato de nandrolona (16) . Por outro lado, relatos na literatura sugerem que os androgênios poderiam promover o controle direto da FC pela bradicardia reflexa via barorreflexo (25) , aumentando a atividade eferente vagal cardíaca ou interferindo no drive parassimpático (26)(27)(28) . Ou, ainda, modificando a função diastólica, por mecanismos ainda não completamente elucidados, os quais poderiam influenciar de forma estrutural e/ou funcional o miocárdio, modulando seu controle intrínseco e/ou interferindo na ação dos reflexos cardiovasculares (28 ).…”