Ischaemia-reperfusion injury impairs tissue plasminogen activator release in man

Christian M Pedersen, Gareth Barnes, Michael R Schmidt, Hans Erik Bøtker, Rajesh K Kharbanda, David E Newby, Nicholas L Cruden, Christian M Pedersen, Gareth Barnes, Michael R Schmidt, Hans Erik Bøtker, Rajesh K Kharbanda, David E Newby, Nicholas L Cruden

Abstract

Aims: Ischaemia-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 results: Ischaemia-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.

Conclusion: Ischaemia-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: https://ichgcp.net/clinical-trials-registry/NCT00789243?term=NCT00789243&rank=1.

Figures

Figure 1
Figure 1
Study protocols.
Figure 2
Figure 2
Effect of ischaemia–reperfusion injury on acetylcholine-mediated vasodilatation. IR indicates ischaemia–reperfusion (Protocol 1). Data analysed using two-way ANOVA with repeated measures.
Figure 3
Figure 3
Effect of ischaemia–reperfusion injury alone and ischaemia–reperfusion injury preceded by local or remote ischaemic preconditioning on substanceP-induced vasodilatation (Protocol 2). IR indicates ischaemia–reperfusion; IPC, local ischaemic preconditioning; and RIPC, remote ischaemic preconditioning. Data analysed using two-way ANOVA with repeated measures.
Figure 4
Figure 4
Effect of ischaemia–reperfusion injury alone and ischaemia–reperfusion injury preceded by local or remote ischaemic preconditioning on substanceP-induced net release of tissue plasminogen activator antigen and activity (Protocol 2). IR indicates ischaemia–reperfusion; IPC, local ischaemic preconditioning; RIPC, remote ischaemic preconditioning; and t-PA, tissue-plasminogen activator. Data analysed using two-way ANOVA with repeated measures.

References

    1. Tiefenbacher CP, Chilian WM, Mitchell M, DeFily DV. Restoration of endothelium-dependent vasodilation after reperfusion injury by tetrahydrobiopterin. Circulation. 1996;94:1423–1429.
    1. Kharbanda RK, Peters M, Walton B, Kattenhorn M, Mullen M, Klein N, Vallance P, Deanfield J, MacAllister R. Ischemic preconditioning prevents endothelial injury and systemic neutrophil activation during ischemia-reperfusion in humans in vivo. Circulation. 2001;103:1624–1630.
    1. Kharbanda RK, Mortensen UM, White PA, Kristiansen SB, Schmidt MR, Hoschtitzky JA, Vogel M, Sorensen K, Redington AN, MacAllister R. Transient limb ischemia induces remote ischemic preconditioning in vivo. Circulation. 2002;106:2881–2883. .
    1. Oliver JJ, Webb DJ, Newby DE. Stimulated tissue plasminogen activator release as a marker of endothelial function in humans. Arterioscler Thromb VascBiol. 2005;25:2470–2479. .
    1. Rosenberg RD, Aird WC. Vascular-bed-specific hemostasis and hypercoagulable states. N Engl J Med. 1999;340:1555–1564. .
    1. Newby DE, Wright RA, Labinjoh C, Ludlam CA, Fox KA, Boon NA, Webb DJ. Endothelial dysfunction, impaired endogenous fibrinolysis, and cigarette smoking: a mechanism for arterial thrombosis and myocardial infarction. Circulation. 1999;99:1411–1415.
    1. Robinson SD, Ludlam CA, Boon NA, Newby DE. Endothelial fibrinolytic capacity predicts future adverse cardiovascular events in patients with coronary heart disease. Arterioscler Thromb Vasc Biol. 2007;27:1651–1656. .
    1. Newby DE, McLeod AL, Uren NG, Flint L, Ludlam CA, Webb DJ, Fox KA, Boon NA. Impaired coronary tissue plasminogen activator release is associated with coronary atherosclerosis and cigarette smoking: direct link between endothelial dysfunction and atherothrombosis. Circulation. 2001;103:1936–1941.
    1. Aspelin T, Eriksen M, Lindgaard AK, Lyberg T, Ilebekk A. Cardiac fibrinolytic capacity is markedly increased after brief periods of local myocardial ischemia, but declines following successive periods in anesthetized pigs. J Thromb Haemost. 2005;3:1947–1954.
    1. Valen G, Eriksson E, Risberg B, Vaage J. Reactive oxygen intermediates and ischemia-reperfusion injury release tissue plasminogen activator from isolated rat hearts. Thromb Res. 1993;71:113–121. .
    1. Winnerkvist A, Wiman B, Valen G, Vaage J. Release of tissue plasminogen activator during reperfusion after different times of ischaemia in isolated, perfused rat hearts. Thromb Res. 1996;82:533–542. .
    1. Schoots IG, Levi M, van Vliet AK, Declerck PJ, Maas AM, van Gulik TM. Enhancement of endogenous fibrinolysis does not reduce local fibrin deposition, but modulates inflammation upon intestinal ischemia and reperfusion. Thromb Haemost. 2004;91:497–505.
    1. Roelofs JJ, Rouschop KM, Leemans JC, Claessen N, de Boer AM, Frederiks WM, Lijnen HR, Weening JJ, Florquin S. Tissue-type plasminogen activator modulates inflammatory responses and renal function in ischemia reperfusion injury. J Am Soc Nephrol. 2006;17:131–140. .
    1. Treska V, Valenta J, Pecen L, Topolcan O. Endogenous fibrinolysis in patients with lower extremity ischemia. Ann Vasc Surg. 2000;14:356–359. .
    1. Killewich LA, Gardner AW, Macko RF, Hanna DJ, Goldberg AP, Cox DK, Flinn WR. Progressive intermittent claudication is associated with impaired fibrinolysis. J Vasc Surg. 1998;27:645–650. .
    1. Newby DE, Wright RA, Ludlam CA, Fox KA, Boon NA, Webb DJ. An in vivo model for the assessment of acute fibrinolytic capacity of the endothelium. Thromb Haemost. 1997;78:1242–1248.
    1. Garlid KD, Paucek P, Yarov-Yarovoy V, Murray HN, Darbenzio RB, D'Alonzo AJ, Lodge NJ, Smith MA, Grover GJ. Cardioprotective effect of diazoxide and its interaction with mitochondrial ATP-sensitive K+ channels. Possible mechanism of cardioprotection. Circ Res. 1997;81:1072–1082.
    1. Broadhead MW, Kharbanda RK, Peters MJ, MacAllister RJ. KATP channel activation induces ischemic preconditioning of the endothelium in humans in vivo. Circulation. 2004;110:2077–2082. .
    1. Muldowney JA, III, Painter CA, Sanders-Bush E, Brown NJ, Vaughan DE. Acute tissue-type plasminogen activator release in human microvascular endothelial cells: the roles of Galphaq, PLC-beta, IP3 and 5,6-epoxyeicosatrienoic acid. Thromb Haemost. 2007;97:263–271.
    1. Gudmundsdottir IJ, Lang NN, Boon NA, Ludlam CA, Webb DJ, Fox KA, Newby DE. Role of the endothelium in the vascular effects of the thrombin receptor (protease-activated receptor type 1) in humans. J Am Coll Cardiol. 2008;51:1749–1756. .
    1. Zhong B, Wang DH. TRPV1 gene knockout impairs preconditioning protection against myocardial injury in isolated perfused hearts in mice. Am J Physiol Heart Circ Physiol. 2007;293:H1791–H1798. .
    1. Newby DE, Sciberras DG, Mendel CM, Gertz BJ, Boon NA, Webb DJ. Intra-arterial substance P mediated vasodilatation in the human forearm: pharmacology, reproducibility and tolerability. Br J Clin Pharmacol. 1997;43:493–499. .
    1. Jaffe R, Dick A, Strauss BH. Prevention and treatment of microvascular obstruction-related myocardial injury and coronary no-reflow following percutaneous coronary intervention: a systematic approach. JACC Cardiovasc Interv. 2010;3:695–704. .
    1. Gibson CM, Karha J, Murphy SA, James D, Morrow DA, Cannon CP, Giugliano RP, Antman EM, Braunwald E. Early and long-term clinical outcomes associated with reinfarction following fibrinolytic administration in the Thrombolysis in Myocardial Infarction trials. J Am Coll Cardiol. 2003;42:7–16. .
    1. Grines C, Patel A, Zijlstra F, Weaver WD, Granger C, Simes RJ. Primary coronary angioplasty compared with intravenous thrombolytic therapy for acute myocardial infarction: six-month follow up and analysis of individual patient data from randomized trials. Am Heart J. 2003;145:47–57. .
    1. Keeley EC, Boura JA, Grines CL. Primary angioplasty vs. intravenous thrombolytic therapy for acute myocardial infarction: a quantitative review of 23 randomised trials. Lancet. 2003;361:13–20. .
    1. Nanobashvili J, Neumayer C, Fuegl A, Blumer R, Prager M, Sporn E, Polterauer P, Malinski T, Huk I. Development of ‘no-reflow’ phenomenon in ischemia/reperfusion injury: failure of active vasomotility and not simply passive vasoconstriction. Eur Surg Res. 2003;35:417–424. .
    1. Heusch G, Kleinbongard P, Bose D, Levkau B, Haude M, Schulz R, Erbel R. Coronary microembolization: from bedside to bench and back to bedside. Circulation. 2009;120:1822–1836. .
    1. Reffelmann T, Kloner RA. The no-reflow phenomenon: a basic mechanism of myocardial ischemia and reperfusion. Basic Res Cardiol. 2006;101:359–372. .
    1. Woo KS, Armiger LC, White HD, Norris RM. Can streptokinase produce beneficial effects additional to coronary recanalization? Quantitative microvascular analysis of critically injured reperfused myocardium. Microvasc Res. 2000;60:8–20. .
    1. Sezer M, Oflaz H, Goren T, Okcular I, Umman B, Nisanci Y, Bilge AK, Sanli Y, Meric M, Umman S. Intracoronary streptokinase after primary percutaneous coronary intervention. N Engl J Med. 2007;356:1823–1834. .
    1. Okorie MI, Bhavsar DD, Ridout D, Charakida M, Deanfield JE, Loukogeorgakis SP, Macallister RJ. Postconditioning protects against human endothelial ischaemia-reperfusion injury via subtype-specific KATP channel activation and is mimicked by inhibition of the mitochondrial permeability transition pore. Eur Heart J. 2011;32:1266–1274. .
    1. Richard V, Kaeffer N, Tron C, Thuillez C. Ischemic preconditioning protects against coronary endothelial dysfunction induced by ischemia and reperfusion. Circulation. 1994;89:1254–1261.
    1. Laskey WK, Yoon S, Calzada N, Ricciardi MJ. Concordant improvements in coronary flow reserve and ST-segment resolution during percutaneous coronary intervention for acute myocardial infarction: a benefit of postconditioning. Catheter Cardiovasc Interv. 2008;72:212–220. .
    1. Heusch G, Schulz R. Preservation of peripheral vasodilation as a surrogate of cardioprotection? The mechanistic role of ATP-dependent potassium channels and the mitochondrial permeability transition pore. Eur Heart J. 2011;32:1184–1186. .
    1. Brown NJ, Gainer JV, Murphey LJ, Vaughan DE. Bradykinin stimulates tissue plasminogen activator release from human forearm vasculature through B(2) receptor-dependent, NO synthase-independent, and cyclooxygenase-independent pathway. Circulation. 2000;102:2190–2196.
    1. Pedersen CM, Cruden NL, Schmidt MR, Lau C, Botker HE, Kharbanda RK, Newby DE. Remote ischemic preconditioning prevents systemic platelet activation associated with ischemia-reperfusion injury in humans. J Thromb Haemost. 2011;9:404–407. .

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