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.


RESULTS
Male S-D rats were pretreated twice with FK506 (0.2 mg/kg), CsA (10 mg/kg) or only saline solution (0.5 mL). The tissue microcirculation in the control was reduced after I/R (29% +/- 10%) accompanied by hypotension, increased tissue ET-1 expression (25.0% +/- 6.4% to 67.9% +/- 5.0% 60 minutes after reperfusion), and increased ET-1 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 performed with BQ485Na (BQ), an ETA receptor antagonist, to evaluate the genuine role 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.
Soda
Y
Y
Second Department of Surgery, Shimane Medical University, Izumo, Japan.
el-Assal
O N
ON
Yu
L
L
Nagasue
N
N
D000818:Animals; D001381:Azepines / Q000494:pharmacology; D001794:Blood Pressure; D016572:Cyclosporine / Q000494:pharmacology*; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000097:blood; D007022:Hypotension / Q000503:physiopathology; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007421:Intestine, Small / Q000098:blood supply* / Q000187:drug effects / Q000502:physiology*; D007511:Ischemia / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D008297:Male; D008833:Microcirculation / Q000187:drug effects / Q000502:physiology*; D009842:Oligopeptides / Q000494:pharmacology; D011168:Portal System; D051381:Rats; D017207:Rats, Sprague-Dawley; D044022:Receptor, Endothelin A; D017466:Receptors, Endothelin / Q000502:physiology*; D015427:Reperfusion Injury / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D015996:Survival Rate; D016559:Tacrolimus / Q000494:pharmacology*; D013997:Time Factors
D001381:Azepines; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D007166:Immunosuppressive Agents; D009842:Oligopeptides; D044022:Receptor, Endothelin A; D017466:Receptors, Endothelin; C083116:BQ 485; D016572:Cyclosporine; D016559:Tacrolimus