Ultrasound Improves Tissue Perfusion in Ischemic Tissue through a Nitric Oxide Dependent Mechanism

Valentina N. Suchkova; Raymond B. Baggs; Sanjeev K. Sahni; Charles W. Francis

doi:10.1055/s-0037-1613315

Thrombosis and Haemostasis, Inhaltsverzeichnis

Thromb Haemost 2002; 88(05): 865-870
DOI: 10.1055/s-0037-1613315

Review Article

Schattauer GmbH

Ultrasound Improves Tissue Perfusion in Ischemic Tissue through a Nitric Oxide Dependent Mechanism

Valentina N. Suchkova

¹Hematology/Oncology Unit, Department of Medicine, University of Rochester School of Medicine & Dentistry, Rochester, NY, USA

,

Raymond B. Baggs

¹Hematology/Oncology Unit, Department of Medicine, University of Rochester School of Medicine & Dentistry, Rochester, NY, USA

^*Division of Laboratory Animal Medicine, University of Rochester School of Medicine & Dentistry, Rochester, NY, USA

¹Hematology/Oncology Unit, Department of Medicine, University of Rochester School of Medicine & Dentistry, Rochester, NY, USA

,

Sanjeev K. Sahni

¹Hematology/Oncology Unit, Department of Medicine, University of Rochester School of Medicine & Dentistry, Rochester, NY, USA

,

Charles W. Francis

¹Hematology/Oncology Unit, Department of Medicine, University of Rochester School of Medicine & Dentistry, Rochester, NY, USA

› Institutsangaben

Abstract

Summary

Ultrasound accelerates enzymatic fibrinolysis in vitro and in animal models and may be used as an adjunct to thrombolytic therapy. Ultrasound can also affect vascular tone directly, and we have now investigated the effect of ultrasound on tissue perfusion in a rabbit model of acute muscle ischemia to characterize the magnitude and temporal course of vasodilation and determine its mechanism. After ligation of the femoral artery of rabbits, tissue perfusion in the gracilis muscle as determined using a laser Doppler probe declined by 53% from 13.7 ± 0.3 U to 6.4 ± 0.2 U. The tissue became acidotic as pH declined from normal to 7.05 ± 0.2. Application of 40 kHz ultrasound at intensities from 0.25 to 0.75 W/cm² progressively improved perfusion over 60 min and reversed acidosis, but these effects were both completely blocked by pre-treatment with the nitric oxide synthase inhibitor LNAME. Nitric oxide synthase activity in muscle was measured using an assay based on the conversion of radiolabeled L-arginine to L-citrulline and demonstrated an increase of 3.6-fold following ultrasound exposure. This effect was greatest at locations close to the transducer and declined progressively away from it. Histologic examination showed greater capillary circumference in ultrasound exposed muscle compared to unexposed tissue with no other histologic changes. We conclude that the application of 40 kHz at low intensity improves perfusion and reverses acidosis in acutely ischemic muscle through a nitric oxide dependent mechanism.

Keywords

Ultrasound - nitric oxide - nitric oxide synthase - ischemia

Volltext

Referenzen

References
1 Furchgott RF, Zawadzki JV. The obligatory role of endothelial cells in the reaxation of arterial smooth muscle by acetylcholine. Nature 1980; 288: 373-6.
2 Stuehr DJ. Mammalian nitric oxide synthases. Biochem Biophys Acta 1999; 1411: 217-30.
3 Radomski MW, Palmer RMJ, Moncada S. The role of nitric oxide and cGMP in platelet adhesion molecules to vascular endothelium. Biochem Biophys Res Commun 1987; 148: 1482-9.
4 Tsao PS, Lewis N, Alpert S, Cooke JP. Exposure to shear stress alters endothelial adhesiveness: role of nitric oxide. Circulation 1995; 92: 3513-9.
5 Zeiher AH, Fisslthaler B, Schray-Utz B, Busse R. Nitric oxide modulates the expression of monocyte chemoattractant protein 1 in cultured human endothelial cells. Circ Res 1995; 76: 980-6.
6 Garg UC, Hassid A. Nitric oxide-generating vasodilators and 8-bromocyclic guanosine monophosphate inhibit mitogenesis and proliferation of cultured rat vascular smooth muscle cells. J Clin Invest 1989; 83: 1774-7.
7 Sarkar R, Meinberg EG, Stanley JC. et al. Nitric oxide reversibly inhibits the migration of cultured vascular smooth muscle cells. Circ Res 1996; 78: 225-30.
8 Hogg N, Kalyanaraman B, Joseph J. et al. Inhibition of low-density lipoprotein oxidation by nitric oxide: potential role in atherogenesis. FEBS Lett 1993; 334: 170-4.
9 Traub O, Berk BC. Laminar shear stress: mechanisms by which endothelial cells can transduce an atheroprotective force. Arterioscler Thromb Vasc Biol 1998; 18: 677-85.
10 Fleming I, Busse R. Signal transduction of eNOS activation. Cardiovasc Res 1999; 43: 532-41.
11 Oemar BS, Tshudi MR, Godoy N. et al. Reduced endothelial nitric oxide synthase expression and production in human atherosclerosis. Circulation 1998; 97: 2494-8.
12 Zeiher AM, Drexler H, Saurbier B, Just H. Endothelium-mediated coronary blood flow modulation in humans: effects of age, atherosclerosis, hypercholesterolemia, and hypertension. J Clin Invest 1993; 92: 652-62.
13 Creager MA, Cooke JP, Mendelsohn ME. et al. Impaired vasodilation of forearm resistance vessels in hypercholesterolemic humans. J Clin Invest 1990; 86: 228-34.
14 Channon KM, Qian H, George SE. Nitric oxide synthase in atherosclerosis and vascular injury. Insights from experimental gene therapy. Arterioscler Thromb Vasc Biol 2000; 20: 1873-81.
15 Akiyama K, Kimura A, Suzuki H. et al. Production of oxidative products of nitric oxide in infarcted human heart. J Am Coll Cardiol 1998; 32: 373-9.
16 Huk I, Nanabashvili J, Christoph N. et al. L-arginine treatment alters the kinetics of nitric oxide and superoxide release and reduced ischemia/reperfusion injury in skeletal muscle. Circulation 1997; 96: 667-82.
17 Hillegass WB, Dean NA, Liao L. et al. Treatment of no-reflow and impaired flow with the nitric oxide donor nitroprusside following percutaneous coronary interventions: initial human clinical experience. J Am Coll Cardiol 2001; 37: 1335-43.
18 Luo H, Steffen W, Cercek B. et al. Enhancement of thrombolysis by external ultrasound. Am Heart J 1993; 1125: 1564-9.
19 Tachibana K. Enhancement of fibrinolysis with ultrasound energy. J Vasc Interv Radiol 1992; 03: 299-303.
20 Suchkova V, Siddiqi FN, Carstensen EL. et al. Enhancement of fibrinolysis with 40-kHz ultrasound. Circulation 1998; 98: 1030-5.
21 Suckhova VN, Baggs RB, Francis CW. Effect of 40-kHz ultrasound on acute thrombotic ischemia in a rabbit femoral artery thrombosis model. Enhancement of thrombolysis and improvement in capillary muscle perfusion. Circulation 2000; 101: 2296-301.
22 Riggs PN, Francis CW, Bartos RS. et al. Ultrasound enhancement of rabbit femoral artery thrombolysis. Cardiovasc Surg 1997; 05: 201-7.
23 Kornowski R, Meltzer RS, Chernine A. et al. Does external ultrasound accelerate thrombolysis? Results from a rabbit model. Circulation 1994; 89: 339-44.
24 Siegel RJ, Atar S, Fishbein MC. et al. Noninvasive, transthoracic, lowfrequency ultrasound augments thrombolysis in a canine model of acute myocardial infarction. Circulation 2000; 101: 2026-9.
25 Haberl RL, Heizer ML, Marmarou A. et al. Laser-Doppler assessment of brain microcirculation: effect of systemic alterations. Am J Physiol 1989; 256: 1247-54.
26 Liu P, Hock CE, Nagele R, Wong PY. Formation of nitric oxide, superoxide, and peroxynitrite in myocardial ischemia-reperfusion injury in rats. Am J Physiol 1997; 272: 2327-36.
27 Vergnani L, Hatrik S, Ricci F. et al. Effect of native and oxidized lowdensity lipoprotein on endothelial nitric oxide and superoxide production: key role of L-arginine availability. Circulation 2000; 101 (11) 1261-6.
28 Pritchard KA, Ackerman AW, Gross ER. et al. Heat shock protein 90 mediates the balance of nitric oxide and superoxide anion. J Bio Chem 2001; 276 (21) 17621-4.
29 Davies PF. Flow-mediated endothelial mechanotransduction. Physiol Rev 1995; 75: 519-60.
30 Ingber D. Integrins as mechanochemical transducers. Curr Opin Cell Biol 1991; 03: 841-8.
31 Garcia-Cardena G, Oh P, Liu J. et al. Targeting of nitric oxide synthase to endothelial cell caveolae via palmitoylation: implications for nitric oxide signaling. Proc Natl Acad Sci USA 1996; 93: 6448-53.
32 Gudi SRP, Clark CB, Frangos JA. Fluid flow rapidly activates G proteins in human endothelial cells. Involvement of G protein in mechanochemical signal transduction. Circ Res 1996; 79: 834-9.
33 Uematsu M, Ohara Y, Navas JP. et al. Regulation of endothelial cell nitric oxide synthase mRNA expression by shear stress. Am J Physiol 1995; 269: C1371-8.
34 Francis CW. Ultrasound-enhanced thrombolysis. Echocardiography 2001; 18: 239-46.
35 Fischell TA, Maher A, Abbas BS. et al. Ultrasonic energy. Effects on vascular function and integrity. Circulation 1991; 84: 1783-95.
36 Steffen D, Cumberland P, Gaines H. et al. Catheter-delivered high intensity, low frequency ultrasound induced vasodilation in vivo . Am Heart J 1994; 15: 369-76.
37 Siegel RJ, Gaines P, Procter A. et al. Clinical demonstration that catheterdelivered ultrasound energy reverses arterial vasoconstriction. J Am Coll Cardiol 1992; 20: 732-5.
38 Fitzgerald PJ, Takagi A, Moore MP. et al. Intravascular sonotherapy decreases neointimal hyperplasia after stent implantation in swine. Circulation 2001; 103: 1828-31.
39 Young SR, Dyson M. The effect of therapeutic ultrasound on angiogenesis. Ultrasound Med Biol 1990; 16: 261-9.
40 Reher P, Doan N, Bradnock B. et al. Effect of ultrasound on the production of IL-8, basic FGF and VEGF. Cytokine 1999; 11: 416-23.