Suppressed endothelin-1 production by FK506 and cyclosporin A in ischemia/reperfusion of rat small intestine

Background. Endothelin-1 (ET-1), a novel vasoconstrictor, possibly plays a role in the mediation of ischemia/reperfusion (I/R) injury. Tacrolimus (FK506) and cyclosporin A (CsA) were reported to maintain tissue microcirculation of the liver subjected to I/R This study investigated the effects of these immunosuppressants on intestinal I/R in terms of intestinal tissue microcirculation associated with ET-1. Methods and Results. Male S-D rats were pretreated twice with FK506 (0.2 mg/kg), CsA (10 mg/kg) or only saline solution (0.5 mt). The tissue microcirculation in the control was reduced after I/R (29% +/- 10%) accompanied by hypotension increased tissue ET-I expression (25.0% +/- 6.4% to 67.9% +/- 5.0% 60 minutes after reperfusion), and increased ET-I level in the portal blood (3.4 +/- 0.9 to 23.6 +/- 6.1 pg/mL). FK506 suppressed ET-1 expression (27.3% +/- 5.2%, 4.1 +/- 2.2 pg/mL) maintained microcirculation (96% +/- 16%), and blood pressure, reduced histologic damage, and improved survival. CsA had a similar but weaker effect compared with FK506. An additional experiment was per formed with BQ485Na (BQ), an ETA receptor antagonist, to evaluate the genuine rob of ET-1. BQ showed almost the same effects as FK506. Conclusions, FK506 and CsA, particularly the former, maintain microcirculation and protect the tissue from I/R injury by suppressing the production and release of ET-1.