BACKGROUND: Although in vitro studies suggest that cyclosporine (CSA) reduces endothelium-dependent relaxation (EDR), controversy still remains regarding the effects of in vivo CSA treatment. The lack of correlation between CSA dosages and therapeutic efficacy has led to an increased emphasis on the monitoring of CSA blood levels in clinical immunosuppression. We therefore studied the effects of in vivo administration to rats of a therapeutic level of CSA on endothelium-dependent vascular reactivity using isolated vascular rings obtained from these animals. METHODS AND RESULTS: Thoracic aorta vascular rings from adult Sprague-Dawley rats treated with subcutaneous injections of CSA (5 mg/kg/day) for 7 and 21 days were suspended in Krebs buffer containing indomethacin and tested for EDR to methacholine (1 x 10(-7) to 5 x 10(-5) M) and for endothelium-independent relaxation (EIR) to nitroprusside (5 x 10(-6) M). Mean whole blood CSA trough levels were 978 +/- 287 and 2,865 +/- 379 ng/ml for the 7- and 21-day groups, respectively. No differences were noted in both EDR and EIR between untreated control rats and the treated groups. Maximal EDR (mean +/- SEM) was 83 +/- 3%, 79 +/- 2%, and 81 +/- 3% for control rats and 7- and 21-day treatment groups, respectively. Relative developed tension (grams) to 5 x 10(-6) M phenylephrine was significantly (p < 0.05) increased in the CSA-treated groups (1.03 +/- 0.01 and 1.08 +/- 0.01 g at 7 and 21 days, respectively, versus 0.73 +/- 0.01 g (p = NS) for untreated controls). Minimal endothelial disruption was evident on scanning electron microscopy in the CSA-treated animals. CONCLUSIONS: We conclude that CSA-induced vascular dysfunction may be in part a result of an increased sensitivity to direct vasoconstriction rather than of an attenuation of endothelium-dependent relaxation.
BACKGROUND: Although in vitro studies suggest that cyclosporine (CSA) reduces endothelium-dependent relaxation (EDR), controversy still remains regarding the effects of in vivo CSA treatment. The lack of correlation between CSA dosages and therapeutic efficacy has led to an increased emphasis on the monitoring of CSA blood levels in clinical immunosuppression. We therefore studied the effects of in vivo administration to rats of a therapeutic level of CSA on endothelium-dependent vascular reactivity using isolated vascular rings obtained from these animals. METHODS AND RESULTS: Thoracic aorta vascular rings from adult Sprague-Dawley rats treated with subcutaneous injections of CSA (5 mg/kg/day) for 7 and 21 days were suspended in Krebs buffer containing indomethacin and tested for EDR to methacholine (1 x 10(-7) to 5 x 10(-5) M) and for endothelium-independent relaxation (EIR) to nitroprusside (5 x 10(-6) M). Mean whole blood CSA trough levels were 978 +/- 287 and 2,865 +/- 379 ng/ml for the 7- and 21-day groups, respectively. No differences were noted in both EDR and EIR between untreated control rats and the treated groups. Maximal EDR (mean +/- SEM) was 83 +/- 3%, 79 +/- 2%, and 81 +/- 3% for control rats and 7- and 21-day treatment groups, respectively. Relative developed tension (grams) to 5 x 10(-6) M phenylephrine was significantly (p < 0.05) increased in the CSA-treated groups (1.03 +/- 0.01 and 1.08 +/- 0.01 g at 7 and 21 days, respectively, versus 0.73 +/- 0.01 g (p = NS) for untreated controls). Minimal endothelial disruption was evident on scanning electron microscopy in the CSA-treated animals. CONCLUSIONS: We conclude that CSA-induced vascular dysfunction may be in part a result of an increased sensitivity to direct vasoconstriction rather than of an attenuation of endothelium-dependent relaxation.