Download PDF
J Reconstr Microsurg 2003; 19(1): 055-060
DOI: 10.1055/s-2003-37192
Copyright © 2002 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel.: +1(212) 584-4662

Role of Nitric Oxide in the Mechanism of Preclamping and Remote Ischemic Preconditioning of Adipocutaneous Flaps in a Rat Model

Markus V. Küntscher1 , Sebastian Juran1 , Jens Altmann1 , Henrik Menke1 , Martha Maria Gebhard2 , Günter Germann1
  • 1Department of Plastic and Hand Surgery-Burn Center, BG Trauma Center, Ludwigshafen, Germany
  • 2Department of Experimental Surgery, University of Heidelberg, Ludwigshafen, Germany
Further Information

Publication History

Publication Date:
12 February 2003 (online)

    Permissions and Reprints

ABSTRACT

The purpose of this study was to determine whether nitric oxide (NO) plays a role in the mechanism of acute ischemic preconditioning (IP). Fifty-eight male Wistar rats were divided into seven experimental groups. An extended epigastric flap was raised in one of the control groups (C, n = 8), and a 3-hr flap ischemia was induced. Another group served as a non-ischemic control (CO, n = 8). The animals of group S (n = 9) received 500 nmol/kg of Spermine/Nitric Oxide Complex (Sper/NO) intravenously 30 min prior to ischemia. The group N+P (L-NAME + preclamping, n = 8) received 10 mg/kg Nω-Nitro-L-Arginine Methyl Ester (L-NAME) intravenously before preclamping of the flap pedicle (10-min cycle length, 30-min reperfusion). Ten mg/kg L-NAME were administered in group N+T (L-NAME + tourniquet, n = 9) before ischemia of the right hindlimb was induced using a tourniquet for 10 min after flap elevation. Flap ischemia was induced after 30 min of limb reperfusion. A similar protocol was used in the groups N+P+S (L-NAME + preclamping+Sper/NO, n = 8) and N+T+S (L-NAME + tourniquet + Sper/NO, n = 8). In both groups Sper/NO was administered 30 min prior to flap ischemia, additionally to the protocol of the groups N+P and N+T. Mean flap necrosis area was assessed on the fifth postoperative day using a planimetry software.

Average flap necrosis area was 67 ± 16 percent in the control group C, 28 ± 13.3 percent in the non-ischemic controls (CO), 10 ± 5.9 percent in group S, 77.5 ± 10.2 percent in group N+P, 76 ± 6.9 percent in group N+T, 71.5 ± 9.4 percent in group N+P+S, and 78 ± 9.9 percent in group N+T+S. The animals of group S and CO demonstrated a significantly lower area of flap necrosis than all other groups (p < 0.001). No significant difference could be shown between the groups C, N+P, N+T, N+P+S and N+T+S. Group S showed a significantly lower flap necrosis area than group CO (p < 0.01).

The data showed, that NO plays an important role in the mechanism of IP since the administration of an NO-donor previous to ischemia simulates the effect of IP, while the unspecific blocking of NO synthesis by L-NAME eliminates the protective effect of flap preconditioning by preclamping as well as by remote IP. Exogenous NO application is insufficient to provide protection once the endogenous NO synthesis is blocked.

KEYWORD

(Remote) ischemic preconditioning - nitric oxide - flap

REFERENCES

  • 1 Murry C E, Jennings R B, Reimer K A. Preconditioning with ischemia: a delay of lethal cell injury in ischemic myocardium.  Circulation . 1986;  74 1124-1136
    CrossrefPubMedGoogle Scholar
  • 2 Mounsey R A, Pang C Y, Forrest C. Preconditioning: a new technique for improved muscle flap survival.  Otolaryngol Head Neck Surg . 1992;  107 549-552
    PubMedGoogle Scholar
  • 3 Küntscher M V, Schirmbeck E U, Menke H, Klar E, Gebhard M M, Germann G. Ischemic preconditioning by brief extremity ischemia prior to flap ischemia in a rat model (in press).  Plast Reconstr Surg . 2002;  109
    PubMedGoogle Scholar
  • 4 Nandagopal K, Dawson T M, Dawson V L. Critical role for nitric oxide signaling in cardiac and neuronal ischemic preconditioning and tolerance.  J Pharmacol Exp Ther . 2001;  297 474-478
    PubMedGoogle Scholar
  • 5 Peralta C, Hotter G, Closa D. Protective effect of preconditioning on the injury associated with hepatic ischemia-reperfusion in the rat: role of nitric oxide and adenosine.  Hepatology . 1997;  25 934-937
    CrossrefPubMedGoogle Scholar
  • 6 Napoli C, Pinto A, Cirino G. Pharmacological modulation, preclinical studies, and new clinical features of myocardial ischemic preconditioning.  Pharmacol Ther . 2000;  88 311-331
    CrossrefPubMedGoogle Scholar
  • 7 Lloris-Carsi J M, Cejalvo D, Toledo-Pereyra L H, Calvo M A, Suzuki S. Preconditioning: effect upon lesion modulation in warm liver ischemia.  Transplant Proc . 1993;  25 3303-3304
    PubMedGoogle Scholar
  • 8 Carroll C M, Carroll S M, Overgoor M L, Tobin G, Barker J H. Acute ischemic preconditioning of skeletal muscle prior to flap elevation augments muscle flap survival.  Plast Reconstr Surg . 1997;  100 58-65
    CrossrefPubMedGoogle Scholar
  • 9 Zahir K S, Syed S A, Zink J R, Restifo R J, Thomson J G. Ischemic preconditioning improves the survival of skin and myocutaneous flaps in a rat model.  Plast Reconstr Surg . 1998;  102 140-152
    CrossrefPubMedGoogle Scholar
  • 10 Wang W Z, Anderson G, Firrell J C, Tsai T M. Ischemic preconditioning versus intermittent reperfusion to improve blood flow to a vascular isolated skeletal muscle flap of rats.  J Trauma . 1998;  45 953-959
    PubMedGoogle Scholar
  • 11 Wang W Z, Anderson G, Maldonado C, Barker J. Attenuation of vasospasm and capillary no-reflow by ischemic preconditioning in skeletal muscle.  Microsurgery . 1996;  17 324-329
    CrossrefPubMedGoogle Scholar
  • 12 Restifo R J, Thomson J G. The preconditioned TRAM flap: preliminary clinical experience.  Ann Plast Surg . 1998;  41 343-347
    CrossrefPubMedGoogle Scholar
  • 13 Dawn B, Bolli R. Toward a better understanding of the metabolic effects of ischemic preconditioning in humans.  J Cardiothorac Vasc Anesth . 2001;  15 409-411
    CrossrefPubMedGoogle Scholar
  • 14 Wang B H, Ye C, Stagg C A. Improved free musculocutaneous flap survival with induction of heat shock protein.  Plast Reconstr Surg . 1998;  101 776-784
    CrossrefPubMedGoogle Scholar
  • 15 Kume M, Yamamoto Y, Saad S. Ischemic preconditioning of the liver in rats: implications of heat shock protein induction to increase tolerance of ischemia-reperfusion injury.  J Lab Clin Med . 1996;  128 251-258
    CrossrefPubMedGoogle Scholar
  • 16 Yokota R, Fujiwara H, Miyamae M. Transient adenosine infusion before ischemia and reperfusion protects against metabolic damage in pig hearts.  Am J Physiol . 1995;  268 H1149-H1157
    PubMedGoogle Scholar
  • 17 Pang C Y, Neligan P, Zhong A, He W, Xu H, Forrest C R. Effector mechanism of adenosine in acute ischemic preconditioning of skeletal muscle against infarction.  Am J Physiol . 1997;  273 R887-R895
    PubMedGoogle Scholar
  • 18 Pang C Y, Neligan P, Xu H. Role of ATP-sensitive K+ channels in ischemic preconditioning of skeletal muscle against infarction.  Am J Physiol . 1997;  273 H44-H51
    PubMedGoogle Scholar
  • 19 Guo Y, Bao W, Wu W J, Shinmura K, Tang X L, Bolli R. Evidence for an essential role of cyclooxygenase-2 as a mediator of the late phase of ischemic preconditioning in mice.  Basic Res Cardiol . 2000;  95 479-484
    CrossrefPubMedGoogle Scholar
  • 20 Schoemaker R G, van Heijningen L C. Bradykinin mediates cardiac preconditioning at a distance.  Am J Physiol Heart Circ Physiol . 2000;  278 H1571-H1576
    PubMedGoogle Scholar
  • 21 Peralta C, Closa D, Hotter G, Gelpí E, Prats N, Roselló-Catafau J. Liver ischemic preconditioning is mediated by the inhibitory action of nitric oxide on endothelin.  Biochem Biophys Res Comm . 1996;  229 271-274
    CrossrefPubMedGoogle Scholar
  • 22 Cordeiro P G, Santamaria E, Hu Q Y. Use of a nitric oxide precursor to protect pig myocutaneous flaps from ischemia-reperfusion injury.  Plast Reconstr Surg . 1998;  102 2040-2051
    PubMedGoogle Scholar
  • 23 Lowenstein C J. NO news is good news.  Proc Natl Acad Sci USA . 1999;  28 96:10953-10954
    PubMedGoogle Scholar
  • 24 Rakhit R D, Edwards R J, Marber M S. Nitric oxide, nitrates and ischaemic preconditioning.  Cardiovasc Res . 1999;  15 43:621-627
    PubMedGoogle Scholar
  • 25 Chen J X, Berry L C, Tanner M, Chang M, Myers R P, Meyrick B. Nitric oxide donors regulate nitric oxide synthase in bovine pulmonary artery endothelium.  J Cell Physiol . 2001;  186 116-123
    CrossrefPubMedGoogle Scholar
  • 26 Jones W K, Flaherty M P, Tang X L. Ischemic preconditioning increases iNOS transcript levels in conscious rabbits via a nitric oxide-dependent mechanism.  J Mol Cell Cardiol . 1999;  31 1469-1481
    CrossrefPubMedGoogle Scholar
  • 27 Ghaleh B, Tissier R, Berdeaux A. Nitric oxide and myocardial ischemic preconditioning.  J Soc Biol . 2000;  194 137-141
    PubMedGoogle Scholar
  • 28 Wang W Z, Anderson G L, Guo S Z, Tsai T M, Miller F N. Initiation of microvascular protection by nitric oxide in late preconditioning.  J Reconstr Microsurg . 2000;  16 621-628
    Article in Thieme ConnectPubMedGoogle Scholar
  • 29 Oshima H. The influence of skin flap ischemia on serum nitric oxide concentrations.  Microsurgery . 1996;  17 191-197
    CrossrefPubMedGoogle Scholar
  • 30 Knox L K, Angel M F, Gamper T, Amiss L R, Morgan R F. Secondary ischemic tolerance improved by administration of L-NAME in rat flaps.  Microsurgery . 1996;  17 425-427
    CrossrefPubMedGoogle Scholar
  • 31 Maragos C M, Morley D, Wink D A. Complexes of NO with nucleophiles as agents for the controlled biological release of nitric oxide. Vasorelaxant effects.  J Med Chem . 1991;  34 3242-3247
    CrossrefPubMedGoogle Scholar
  • 32 Diodati J G, Quyyumi A A, Keefer L K. Complexes of nitric oxide with nucleophiles as agents for the controlled biological release of nitric oxide: hemodynamic effect in the rabbit.  J Cardiovasc Pharmacol . 1993;  22 287-292
    PubMedGoogle Scholar
      >