Pharmacologic preconditioning of random-pattern skin flap in rats using local cyclosporine and FK-506: interaction with nitric oxide system.
It has been suggested that immunophilin ligands such as cyclosporine and FK-506 (tacrolimus) affect the survival of ischemic tissues. Our objective was to show an acute effect of local cyclosporin-A (CsA) and FK-506 on ischemic protection in a random-pattern skin-flap model in rats and investigate the effect of nitric oxide (NO) pathways as a modulator of protection of these agents. Ninety male Sprague-Dawley rats were randomly assigned to treatment groups. Bipedicled dorsal flaps (2 x 8 cm) were elevated at midline. Prior to cutting the cranial pedicle to induce permanent ischemia, pharmacologic preconditioning groups received local injection of CsA (0.3, 1, or 3 nmol/flap) or FK-506 (0.01, 0.03, or 0.1 pmol/flap), and the ischemic preconditioning (IPC) group underwent temporary clamping of the cranial pedicle. At the seventh day postoperatively, the survival of the flaps was measured. In other groups, nitric oxide synthase inhibitor N omega-nitro-l-arginine methyl ester hydrochloride (L-NAME) was administered with effective CsA and FK-506, and ischemic preconditioning. Nitric oxide precursor L-arginine doses were also studied, and a systemic subeffective dose (100 mg/kg) was coadministered with subeffective CsA and FK-506. Significant increase in flap survival was obtained with CsA (1 nmol/flap), FK-506 (0.1 pmol/flap), and IPC. These protections were abolished by systemic administration of L-NAME (10 mg/kg). Coadministration of subeffective doses of CsA (0.3 nmol/flap) and FK-506 (0.03 pmol/flap), with subeffective systemic l-arginine, significantly improved flap survival.Pharmacologic preconditioning with local, single, low doses of CsA or FK-506 is shown to be even more effective than IPC. Administration of the NOS substrate l-arginine potentiates these effects.
Nezami
Behtash Ghazi
BG
Basic Medical Sciences Research Center, Imam Khomeini Hospital, Tehran University of Medical Sciences, Tehran, Iran.
Ghazinezami
Behtash
B
Rahimpour
Sina
S
Gholipour
Taha
T
Ghasemi
Mehdi
M
Sadeghipour
Hamed
H
Mehr
Shahram Ejtemaie
SE
Emami-Razavi
Seyed Hassan
SH
Dehpour
Ahmad Reza
AR
D000818:Animals; D016572:Cyclosporine / Q000008:administration & dosage*; D004357:Drug Synergism; D007166:Immunosuppressive Agents / Q000008:administration & dosage*; D019194:Ischemic Preconditioning / Q000379:methods*; D008297:Male; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013524:Surgical Flaps; D016559:Tacrolimus / Q000008:administration & dosage*; D014022:Tissue Survival / Q000187:drug effects* / Q000502:physiology
D007166:Immunosuppressive Agents; D009569:Nitric Oxide; D016572:Cyclosporine; D019331:NG-Nitroarginine Methyl Ester; D016559:Tacrolimus