Secondary ischemic tolerance improved by administration of L-NAME in rat flaps

Knox, Laura K.; Angel, Michael; Gamper, Thomas; Amiss, L. R.; Morgan, Raymond F.

doi:10.1002/(sici)1098-2752(1996)17:8<425::aid-micr1>3.0.co;2-d

Cited by 18 publications

(4 citation statements)

References 29 publications

(20 reference statements)

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“…Other studies report a possible cytotoxic action of NO producing damaging hydroxyl free radicals in models of venous flap obstruction. 30 However, these findings can neither be confirmed nor be disproved by our results, since our model did not focus on venous ischemia.…”

Section: Discussioncontrasting

confidence: 67%

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

Küntscher

Juran²,

Altmann³

et al. 2003

J reconstr Microsurg

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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 Nomega-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.

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Section: Discussioncontrasting

confidence: 67%

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

Küntscher

Juran²,

Altmann³

et al. 2003

J reconstr Microsurg

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“…44 Treatment with L-arginine in the drinking water and autologous bone marrow cells increased perfusion in a hind-limb ischemia model. 45 Nonselectively inhibiting NOS using L-NAME decreased tissue preservation under ischemic conditions, 46 and eNOS-null mice have defective recovery of blood flow following hind-limb ischemia. 47 These results are consistent with the effects of L-NAME to decrease and ISDN to increase tissue survival in our ischemic flap model.…”

Section: Discussioncontrasting

confidence: 64%

Thrombospondin-1 limits ischemic tissue survival by inhibiting nitric oxide–mediated vascular smooth muscle relaxation

Isenberg¹,

Hyodo

Matsumoto

et al. 2006

Blood

106

129

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The nitric oxide (NO)/cGMP pathway, by relaxing vascular smooth muscle cells, is a major physiologic regulator of tissue perfusion. We now identify thrombospondin-1 as a potent antagonist of NO for regulating IntroductionTissue ischemia is a major cause of morbidity and mortality associated with cardiovascular disease and diabetes. 1,2 Despite advances in wound closure based on surgical restorations with complex tissue units, 3 many surgical patients experience wound healing complications involving tissue ischemia and necrosis. 4 Patient morbidity resulting from surgical flap necrosis remains a substantial health problem. 5 Resolution of acute and chronic ischemia requires restoration of tissue perfusion as well as suppressing the inflammatory response triggered by reperfusion. If ischemia is secondary to vascular insufficiency or thrombosis, induction of an angiogenic response may also be required. Treatments to address these factors, including hyperbaric oxygen, intravenous thrombolytics, anti-inflammatory agents, and local application of angiogenesis promoters, have been developed but have yielded only limited success. [6][7][8][9][10] Nitric oxide (NO) is a key signaling molecule in ischemia. NO stimulates vascular smooth muscle cell (VSMC) relaxation to increase blood flow and tissue perfusion. [11][12][13] Low-dose NO also has proangiogenic and anti-inflammatory activities. [14][15][16] Consistent with these activities, elevating NO levels increases tissue survival in situations of ischemic insult. 17 To improve the effectiveness of NO and other agents for treating ischemia and to understand why such treatments may fail, endogenous inhibitors that may antagonize their activity must be identified. Increased thrombospondin-1 (TSP1) expression during wound healing and following ischemic injury in the heart, kidney, and diabetic limbs suggests a potential role for this protein in the pathogenesis of ischemia. [18][19][20][21][22] The potent antiangiogenic activity of TSP1 could aggravate ischemia, whereas its anti-inflammatory activity may be beneficial. 23,24 We recently reported that TSP1 potently inhibits NO/cGMP signaling in endothelial cells and VSMCs. 25,26 Given the central role that this pathway plays in controlling vascular tone, 13,27 these findings suggested that TSP1 may also regulate VSMC contractility, blood vessel diameter, and flow.Here, we demonstrate that TSP1 antagonizes NO signals to regulate the actin/myosin cytoskeleton and contraction of VSMCs in vitro. We show that endogenous TSP1 modulates acute effects of NO in vivo on tissue perfusion and blood oxygen levels in healthy muscle and in ischemic tissues following surgery. We further show that soft-tissue survival in ischemic myocutaneous flaps is increased in the absence of endogenous TSP1 and that this negative effect of endogenous TSP1 on tissue survival is NO dependent. Materials and methods AnimalsC57/Bl6 wild-type (WT) and TSP1-null mice were housed in a pathogenfree environment and had ad libitum access to filtered water and stand...

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“…Other studies reported a possible cytotoxic action of NO in producing damaging hydroxyl free radicals in models of venous flap obstruction. 73 However, these findings can be neither confirmed nor disproved by our results, since our model did not focus on venous ischemia.…”

Section: The Role Of Nitric Oxide In the Preconditioning Mechanismcontrasting

confidence: 70%

Remote ischemic preconditioning of flaps: A review

2005

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Ischemic preconditioning (IP) is defined as a brief period of ischemia ("preclamping") followed by tissue reperfusion, thereby increasing ischemic tolerance for a subsequent longer ischemic period. Several studies showed the effectiveness of classic local IP by preclamping the flap pedicle. There are two temporally and mechanically different types of IP: acute preconditioning, which is induced by preclamping the flap pedicle briefly before flap ischemia, and late preconditioning, induced by a preclamping procedure 24-48 h before flap ischemia. However, both types of local ischemic preconditioning are rarely used clinically, most likely since they can be applied only by invasive means, significantly increase operation time, or even require a second surgical procedure. Several studies from our laboratory showed, in different experimental models, that acute IP, enhancement of flap survival, and improvement of reperfusion microcirculation can be achieved not only by preclamping the flap pedicle, but also by induction of an ischemia/reperfusion event in a body area distant from the flap prior to elevation. This new acute remote IP procedure can be applied without invasive means, using limb tourniquet ischemia briefly before flap ischemia. The effectiveness of acute remote IP was confirmed by other authors in large animal models. Another of our studies showed that late remote IP using a limb tourniquet 24 h before flap ischemia attenuates ischemia/reperfusion in muscle flaps, whereas it was ineffective in adipocutaneous flaps. The exact mechanism of "classic" as well as remote IP is not yet finally determined, although several studies demonstrated that endogenous nitric oxide plays an important role. In summary, the use of a tourniquet to induce limb ischemia before flap ischemia could provide a new, alternative, noninvasive remote IP protocol, although late remote IP might be effective only in muscle flaps. However, the possible future clinical application for late IP is elective flap surgery, whereas acute remote IP could even be used in emergency flaps.

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Secondary ischemic tolerance improved by administration of L-NAME in rat flaps

Cited by 18 publications

References 29 publications

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

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

Thrombospondin-1 limits ischemic tissue survival by inhibiting nitric oxide–mediated vascular smooth muscle relaxation

Remote ischemic preconditioning of flaps: A review

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