Ischaemia–reperfusion injury impairs tissue plasminogen activator release in man

Abstract

AimsIschaemia–reperfusion (IR) injury causes endothelium-dependent vasomotor dysfunction that can be prevented by ischaemic preconditioning. The effects of IR injury and preconditioning on endothelium-dependent tissue plasminogen activator (t-PA) release, an important mediator of endogenous fibrinolysis, remain unknown.Methods and resultsIschaemia–reperfusion injury (limb occlusion at 200 mmHg for 20 min) was induced in 22 healthy subjects. In 12 subjects, IR injury was preceded by local or remote ischaemic preconditioning (three 5 min episodes of ipsilateral or contralateral limb occlusion, respectively) or sham in a randomized, cross-over trial. Forearm blood flow (FBF) and endothelial t-PA release were assessed using venous occlusion plethysmography and venous blood sampling during intra-arterial infusion of acetylcholine (5–20 µg/min) or substance P (2–8 pmol/min). Acetylcholine and substance P caused dose-dependent increases in FBF (P<0.05 for all). Substance P caused a dose-dependent increase in t-PA release (P<0.05 for all). Acetylcholine and substanceP-mediated vasodilatation and substanceP-mediated t-PA release were impaired following IR injury (P<0.05 for all). Neither local nor remote ischaemic preconditioning protected against the impairment of substance P-mediated vasodilatation or t-PA release.ConclusionIschaemia–reperfusion injury induced substanceP-mediated, endothelium-dependent vasomotor and fibrinolytic dysfunction in man that could not be prevented by ischaemic preconditioning.Clinical Trial Registration Information: Reference number: NCT00789243, URL:

Repeated daily dosing with sildenafil provides sustained protection from endothelial dysfunction caused by ischemia and reperfusion: a human in vivo study

“…The mechanisms of I/R-induced endothelial dysfunction remain uncertain; however, previous human studies have implicated ROS, coagulation factors, and inflammatory markers (13,24,31). We examined the effect of forearm I/R on plasma concentrations of MPO, an enzyme with potent oxidant activity that is released from neutrophils upon their activation, as well as the cellular adhesion molecule P-selectin, which is rapidly released from granule storage upon endothelial cell activation (17,25).…”

Ischemia-Reperfusion Injury

“…Preconditioning has resulted in improved microvascular perfusion and reduces leukocyte-EC interaction and cell apoptosis in skeletal muscle as reported by many authors in rat hindlimb, cremaster muscle, and pig latissimus dorsi muscle flaps. 12,44,45 Practical applications may be important in elective surgical procedures. In microsurgery, after the isolation of the tissue transfer flap, before the division of the vascular pedicle, manipulation of the pedicle with intermittent restriction of flow causing conditioned ischemia or remotely restricting blood flow (pressure cuff ) in nonoperated limbs before replantation may provide protection against reperfusion injury.…”

“…Related to this finding, the authors have used streptokinase to reduce myocardial congestion and improve microvascular perfusion in a canine model of IRI. 44,45 Others Many other agents have been examined in an attempt to attenuate IRI. These agents, as listed by Wang et al 6 include recombinant human BCL2 protein, ethyl pyruvate, low-level laser therapy, PARP inhibition, ketamine, recombinant human VEGF165 protein, activated protein C, adenosine A3receptor-selective agonist, bortezomib, MRS2693, hypertonic saline, cariporide, grape seed proanthocyanidin extract, Wisconsin solution, frequency ultrasound, erythropoietin, resveratrol, vitamin E, amino acid peptides, statins, and hyperbaric oxygen.…”

“…It is administered intravenously before arterial occlusion, or shortly after the onset of reperfusion 9 -Substance P releases endothelial t-PA and initiates vasodilation. 44 Its release has been demonstrated to be impaired after IRI. Neither local nor remote ischemic preconditioning protected against the impairment of substance P-mediated vasodilatation or t-PA release induced by IRI.…”

“…Related to this finding authors have used streptokinase to improves microvascular perfusion in a canine model of IRI. 44,45 PRACTICAL IMPLICATIONS By defining the cellular/molecular events occurring with IRI, we can begin to strategize an approach to limit tissue damage. This may well take the form of a multitargeted approach where anticipated sequences of physiological changes are anticipated and modulated.…”