Acute Adenosine Treatment Is Effective in Augmentation of Ischemic Tolerance in Muscle Flaps in the Pig

Abstract

The objective of the present project was to investigate the efficacy and mechanism of acute (10-minute) adenosine treatment for augmentation of ischemic tolerance in muscle flaps in pigs. Varying doses of adenosine were infused into 28 latissimus dorsi muscle flaps through the axillary artery (0, 0.5, or 2.0 mg per flap) and 22 gracilis muscle flaps through the medial circumflex femoral artery (0, 10, or 20 mg per flap) over 10 minutes. Ten minutes after adenosine infusion, these muscle flaps were subjected to 4 hours of sustained warm global ischemia. In addition, one group of latissimus dorsi muscle flaps (n = 6) received a 10-minute intraarterial adenosine infusion (0.5 mg) at the beginning of reperfusion. Muscle biopsies (n = 4 or 5) for adenosine triphosphate (ATP) analysis were obtained before and after adenosine infusion and at the end of 4 hours of ischemia. The extent of muscle infarction was assessed at 48 hours of reperfusion by the tetrazolium dye staining technique. Muscle blood flow in latissimus dorsi muscle flaps was measured at the end of adenosine infusion (0 or 0.5 mg per flap, n = 8) by the radioactive microsphere (15-microns) technique. It was observed that adenosine, at all doses tested, significantly (p < 0.05) reduced the extent of muscle infarction in latissimus dorsi muscle flaps (control, 40.3 +/- 2.2 percent; 0.5 mg, 20.6 +/- 1.6 percent; 2.0 mg, 18.2 +/- 1 percent) and gracilis muscle flaps (control, 31.0 +/- 1.5 percent; 10 mg, 14.3 +/- 3 percent; 20 mg, 11.6 +/- 1.2 percent). Preischemic adenosine treatment (0.5 mg per flap) was associated with maintenance of a significantly (p < 0.05) higher muscle content of ATP in latissimus dorsi muscle flaps at the end of 4 hours of ischemia compared with saline-treated ischemic controls. Postischemic adenosine treatment did not protect latissimus dorsi muscle flaps against infarction. Furthermore, adenosine treatment did not have any significant effect on mean systemic arterial blood pressure or muscle blood flow in latissimus dorsi muscle flaps. It is concluded that acute (10-minute) preischemic adenosine treatment is effective in augmentation of ischemic tolerance in muscle flaps and that this protective effect of adenosine may be, at least in part, the result of slowing muscle ATP depletion during sustained ischemia. The possible mechanisms of this adenosine-induced energysparing effect are discussed.

Annexin A5 Scintigraphy of Forearm as a Novel In Vivo Model of Skeletal Muscle Preconditioning in Humans

“…These observations were most pronounced in the thenar muscle of the hand but also occurred in the flexor muscle and resemble the effect of ischemic preconditioning and intra-arterial infusion of adenosine on infarct size in skeletal muscle of pigs after a more prolonged ischemic insult. 9,10 Thus, our observations are in accordance with our hypothesis that Annexin A5 scintigraphy validly detects ischemia-reperfusion injury, ischemic preconditioning, and pharmacological modulation of ischemia-reperfusion injury.…”

“…Our interpretation that reactive hyperemia is not significantly involved in targeting of Annexin A5 after ischemic exercise is further supported by the lack of uptake of Tc-99m-albumin. The observed action of ischemic and pharmacological preconditioning on Annexin A5 targeting after ischemic exercise closely resembles the effect of these interventions on infarct size as demonstrated in various animals and organs, including skeletal muscle, 9,10,25 and a clinical trial in the heart. 26 This further indicates that this technique detects relevant early signs of ischemic exercise and reperfusioninduced injury and can be used for future pharmacological research to evaluate agents intended to protect against ischemia-reperfusion injury in humans in vivo.…”

“…In animal models, various drugs that are currently used in clinical practice to prevent or treat acute ischemic events interfere with ischemic preconditioning or modulate ischemia-reperfusion injury. For example, adenosine and opiates mimic ischemic preconditioning (pharmacological preconditioning), 10,11 whereas ATP-sensitive potassium channel blockers and adenosine receptor antagonists inhibit ischemic preconditioning. 12 Insulin and statins reduce ischemia-reperfusion injury by a mechanism that is, at least partially, independent from the signal transduction pathway of ischemic preconditioning.…”

Early Start of the Dangling Procedure in Lower Extremity Free Flap Reconstruction does not Affect the Clinical Outcome

“…19 Increasing free flap tolerance to ischemia was assessed by perfusion washout, caspase inhibition, acute adenosine treatment, or University of Wisconsin (UW) solution, a high-molecular-weight organ preservation solution. [20][21][22][23] Furthermore the secondary ischemic tolerance between pedicled or free skin flaps and the relationship between venous congestion and intraflap venous anatomy in deep inferior epigastric perforator (DIEP) flaps has been compared and investigated. 12,24…”

Adenosine and chronic ischemia of the lower limbs

“…Indeed, ADO in the short course mediates postischemic hyperemia, 6,7,82,83 it may prevent leucocyte and platelet activation during ischemia/reperfusion, [82][83][84][85][86][87]102,103 also eliciting short-term tissue protection against ischemic injury. Over a more prolonged course, ADO, besides dis-Vascular Medicine 2000; 5: 243-250 playing microcirculatory and cytoprotective activities, 28,[57][58][59][60][61][62][63][64]75,79,104 contributes to promote the formation of collaterals by angiogenesis, [51][52][53][54][55] and prevents the vessel wall remodelling process associated with vascular disorders. 56 When all the activities reported above act in concert, it can readily be envisaged why nature has selected ADO as a natural 'drug' to limit ischemic damage (Table 1).…”