Effects of intravenous diltiazem in a rat model of experimental coronary thrombotic microembolism

Bai,Yupeng; Hu,Liqun; Wu,Jie; Gu,Ye; Li,Lun; Gao,Bo; Jiang,Hong

doi:10.3892/etm.2013.1263

Effects of intravenous diltiazem in a rat model of experimental coronary thrombotic microembolism

Authors:
- Yupeng Bai
- Liqun Hu
- Jie Wu
- Ye Gu
- Lun Li
- Bo Gao
- Hong Jiang
View Affiliations

Affiliations: Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan 430060, P.R. China, Department of Cardiology, Puai Hospital, Huazhong University of Science and Technology, Wuhan 430030, P.R. China
Published online on: August 16, 2013 https://doi.org/10.3892/etm.2013.1263
Pages: 873-882

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

The aim of this study was to assess the feasibility of evaluating the therapeutic effects of intravenous diltiazem in a newly established rat model of coronary thrombotic microembolism (CME). CME was induced by injecting 0.199 ml saline containing 5 mg of automicrothrombotic particulates (~10 µm) into the aorta of Sprague Dawley rats. The injection was carried out over 10 sec using a tuberculin syringe with a 28‑gauge needle. The CME model rats were randomly divided into untreated (CME, n=38) and diltiazem‑treated (CME+DIL, n=38) groups. Diltiazem (1 mg/ml, 50 µg/min/kg) was intravenously injected using an infusion pump through the tail vein for 175 min, 5 min following the injection of the automicrothrombotic particulates. Hemodynamic measurements, echocardiography and pathohistological examinations were performed at various time-points (3 h, 24 h and 7 and 28 days) postoperatively. Arteriolar thrombosis, multifocal myocardial necrosis, inflammatory cell infiltration with markedly increased myocardial tumor necrosis factor α (TNF‑α) and interleukin-6 (IL‑6) expression, reduced left ventricular (LV) systolic function and increased plasma von Willebrand factor (vWF), endothelin-1 (ET-1) and serum c-troponin I (c-TnI) levels (indicating vascular endothelial injury and myocardial necrosis) were observed in the CME model rats. These pathological responses in CME rats were partly attenuated by intravenous diltiazem treatment. The present CME model is suitable for evaluating the therapeutic effects of intravenous diltiazem; intravenous diltiazem treatment significantly improved cardiac function through alleviating inflammatory responses and microvascular thrombotic injury in this rat model of CME.

View Figures

View References

1.	Abdelmeguid AE, Topol EJ, Whitlow PL, Sapp SK and Ellis SG: Significance of mild transient release of creatine kinase-MB fraction after percutaneous coronary interventions. Circulation. 94:1528–1536. 1996. View Article : Google Scholar : PubMed/NCBI
2.	Califf RM, Abdelmeguid AE, Kuntz RE, et al: Myonecrosis after revascularization procedures. J Am Coll Cardiol. 31:241–251. 1998. View Article : Google Scholar : PubMed/NCBI
3.	Herrmann J, Haude M, Lerman A, et al: Abnormal coronary flow velocity reserve after coronary intervention is associated with cardiac marker elevation. Circulation. 103:2339–2345. 2001. View Article : Google Scholar : PubMed/NCBI
4.	Mehran R, Dangas G, Mintz GS, et al: Atherosclerotic plaque burden and CK-MB enzyme elevation after coronary interventions: intravascular ultrasound study of 2256 patients. Circulation. 101:604–610. 2000. View Article : Google Scholar
5.	Erbel R and Heusch G: Coronary microembolization. J Am Coll Cardiol. 36:22–24. 2000. View Article : Google Scholar : PubMed/NCBI
6.	Golino P, Piscione F, Benedict CR, et al: Local effect of serotonin released during coronary angioplasty. N Engl J Med. 330:523–528. 1994. View Article : Google Scholar : PubMed/NCBI
7.	Wilson RF, Laxson DD, Lesser JR and White CW: Intense microvascular constriction after angioplasty of acute thrombotic coronary arterial lesions. Lancet. 1:807–811. 1989. View Article : Google Scholar : PubMed/NCBI
8.	Piana RN, Paik GY, Moscucci M, et al: Incidence and treatment of ‘no-reflow’ after percutaneous coronary intervention. Circulation. 89:2514–2518. 1994.
9.	Gu Y, Bai Y, Wu J, Hu L and Gao B: Establishment and characterization of an experimental model of coronary thrombotic microembolism in rats. Am J Pathol. 177:1122–1130. 2010. View Article : Google Scholar : PubMed/NCBI
10.	Heusch G, Kleinbongard P, Böse D, et al: Coronary micro-embolization: from bedside to bench and back to bedside. Circulation. 120:1822–1836. 2009. View Article : Google Scholar : PubMed/NCBI
11.	Herrmann J: Peri-procedural myocardial injury: 2005 update. Eur Heart J. 26:2493–2519. 2005. View Article : Google Scholar : PubMed/NCBI
12.	Heusch G, Schulz R, Haude M and Erbel R: Coronary microembolization. J Mol Cell Cardiol. 37:23–31. 2004. View Article : Google Scholar : PubMed/NCBI
13.	Lee KW and Norell MS: Management of ‘no-reflow’ complicating reperfusion therapy. Acute Card Care. 10:5–14. 2008.
14.	Pasceri V, Patti G and Di Sciascio G: Prevention of myocardial damage during coronary intervention. Cardiovasc Hematol Disord Drug Targets. 6:77–83. 2006. View Article : Google Scholar : PubMed/NCBI
15.	Valero SJ, Moreno R, Reyes RM, et al: Pharmacological approach of no-reflow phenomenon related with percutaneous coronary interventions. Cardiovasc Hematol Agents Med Chem. 6:125–129. 2008. View Article : Google Scholar : PubMed/NCBI
16.	Kleinbongard P, Konorza T, Böse D, et al: Lessons from human coronary aspirate. J Mol Cell Cardiol. 52:890–896. 2012. View Article : Google Scholar : PubMed/NCBI
17.	Werner GS, Lang K, Kuehnert H and Figulla HR: Intracoronary verapamil for reversal of no-reflow during coronary angioplasty for acute myocardial infarction. Catheter Cardiovasc Interv. 57:444–451. 2002. View Article : Google Scholar : PubMed/NCBI
18.	McIvor ME, Undemir C, Lawson J and Reddinger J: Clinical effects and utility of intracoronary diltiazem. Cathet Cardiovasc Diagn. 35:287–293. 1995. View Article : Google Scholar : PubMed/NCBI
19.	Sütsch G, Oechslin E, Mayer I and Hess OM: Effect of diltiazem on coronary flow reserve in patients with microvascular angina. Int J Cardiol. 52:135–143. 1995.PubMed/NCBI
20.	Zheng ZF, Pu XQ, Yang TL, et al: Effects of intracoronary diltiazem on no-reflow phenomenon after emergent percutaneous coronary intervention in patients with acute myocardial infarction. Zhong Nan Da Xue Xue Bao Yi Xue Ban. 31:917–920. 2006.(In Chinese).
21.	Brown C: Blood collection from the tail of a rat. Lab Anim (NY). 35:24–25. 2006. View Article : Google Scholar : PubMed/NCBI
22.	Kudo M, Aoyama A, Ichimori S and Fukunaga N: An animal model of cerebral infarction. Homologous blood clot emboli in rats. Stroke. 13:505–508. 1982. View Article : Google Scholar : PubMed/NCBI
23.	Grossman W: Pressure measurement. Grossman’s Cardiac Catheterition, Angiography, and Intervention. Baim DS: 7th edition. Lippincott Williams & Wilkins; Philadelphia: pp. 139–141. 2006
24.	Genda S, Miura T, Miki T, Ichikawa Y and Shimamoto K: K(ATP) channel opening is an endogenous mechanism of protection against the no-reflow phenomenon but its function is compromised by hypercholesterolemia. J Am Coll Cardiol. 40:1339–1346. 2002. View Article : Google Scholar : PubMed/NCBI
25.	Eitzman DT, Bodary PF, Shen Y, et al: Fabry disease in mice is associated with age-dependent susceptibility to vascular thrombosis. J Am Soc Nephrol. 14:298–302. 2003. View Article : Google Scholar : PubMed/NCBI
26.	Fujita M, Fujioka Y and Ommura Y: Histopathological diagnosis of early stages of myocardial infarction - applications of the improved hematoxylin basic fuchsin picric acid (HBFP) staining method to human autopsy hearts. Hokkaido Igaku Zasshi. 60:313–320. 1985.(In Japanese).
27.	Goldner J: A modification of the Masson trichrome technique for routine laboratory purposes. Am J Pathol. 14:237–243. 1938.PubMed/NCBI
28.	Blann AD: Plasma von Willebrand factor, thrombosis, and the endothelium: the first 30 years. Thromb Haemost. 95:49–55. 2006.PubMed/NCBI
29.	With Notø AT, Bøgeberg Mathiesen E, Amiral J, Vissac AM and Hansen JB: Endothelial dysfunction and systemic inflammation in persons with echolucent carotid plaques. Thromb Haemost. 96:53–59. 2006.PubMed/NCBI
30.	Stewart DJ, Kubac G, Costello KB and Cernacek P: Increased plasma endothelin-1 in the early hours of acute myocardial infarction. J Am Coll Cardiol. 18:38–43. 1991. View Article : Google Scholar : PubMed/NCBI
31.	Tønnessen T, Giaid A, Saleh D, Naess PA, Yanagisawa M and Christensen G: Increased in vivo expression and production of endothelin-1 by porcine cardiomyocytes subjected to ischemia. Circ Res. 76:767–772. 1995.PubMed/NCBI
32.	Ruggeri ZM: Von Willebrand factor, platelets and endothelial cell interactions. J Thromb Haemost. 1:1335–1342. 2003. View Article : Google Scholar : PubMed/NCBI
33.	Bonvini RF, Hendiri T and Camenzind E: Inflammatory response post-myocardial infarction and reperfusion: a new therapeutic target? Eur Heart J Suppl. 7(Suppl I): I27–I36. 2005. View Article : Google Scholar
34.	Skyschally A, Schulz R, Haude M, Erbel R and Heusch G: Coronary microembolization: perfusion-contraction mismatch secondary to myocardial inflammation. Herz. 29:777–781. 2004.(In German).
35.	Dörge H, Neumann T, Behrends M, et al: Perfusion-contraction mismatch with coronary microvascular obstruction: role of inflammation. Am J Physiol Heart Circ Physiol. 279:H2587–H2592. 2000.PubMed/NCBI
36.	Dörge H, Schulz R, Belosjorow S, et al: Coronary microembolization: the role of TNF-alpha in contractile dysfunction. J Mol Cell Cardiol. 34:51–62. 2002.PubMed/NCBI
37.	Triggle DJ and Swamy VC: Calcium antagonists. Some chemical-pharmacologic aspects. Circ Res. 52:I17–I28. 1983.PubMed/NCBI
38.	Kleinbongard P, Heusch G and Schulz R: TNFalpha in atherosclerosis, myocardial ischemia/reperfusion and heart failure. Pharmacol Ther. 127:295–314. 2010. View Article : Google Scholar : PubMed/NCBI
39.	Fleckenstein A: History of calcium antagonists. Circ Res. 52:I3–I16. 1983.PubMed/NCBI
40.	Beltrame JF, Turner SP, Leslie SL, Solomon P, Freedman SB and Horowitz JD: The angiographic and clinical benefits of mibefradil in the coronary slow flow phenomenon. J Am Coll Cardiol. 44:57–62. 2004. View Article : Google Scholar : PubMed/NCBI
41.	Hamm CW and Opie LH: Protection of infarcting myocardium by slow channel inhibitors. Comparative effects of verapamil, nifedipine, and diltiazem in the coronary-ligated, isolated working rat heart. Circ Res. 52:I129–I138. 1983.
42.	Nayler WG, Ferrari R and Williams A: Protective effect of pretreatment with verapamil, nifedipine and propranolol on mitochondrial function in the ischemic and reperfused myocardium. Am J Cardiol. 46:242–248. 1980. View Article : Google Scholar : PubMed/NCBI
43.	Bourdillon PD and Poole-Wilson PA: The effects of verapamil, quiescence, and cardioplegia on calcium exchange and mechanical function in ischemic rabbit myocardium. Circ Res. 50:360–368. 1982. View Article : Google Scholar : PubMed/NCBI
44.	Przyklenk K and Kloner RA: Effect of verapamil on postischemic ‘stunned’ myocardium: importance of the timing of treatment. J Am Coll Cardiol. 11:614–623. 1988.
45.	Bush LR, Buja LM, Tilton G, et al: Effects of propranolol and diltiazem alone and in combination on the recovery of left ventricular segmental function after temporary coronary occlusion and long-term reperfusion in conscious dogs. Circulation. 72:413–430. 1985. View Article : Google Scholar : PubMed/NCBI
46.	Higgins AJ and Blackburn KJ: Prevention of reperfusion damage in working rat hearts by calcium antagonists and calmodulin antagonists. J Mol Cell Cardiol. 16:427–438. 1984. View Article : Google Scholar : PubMed/NCBI
47.	Galiuto L: Optimal therapeutic strategies in the setting of post-infarct no reflow: the need for a pathogenetic classification. Heart. 90:123–125. 2004. View Article : Google Scholar : PubMed/NCBI
48.	Kleinbongard P, Baars T and Heusch G: Calcium antagonists in myocardial ischemia/reperfusion - update 2012. Wien Med Wochenschr. 162:302–310. 2012. View Article : Google Scholar : PubMed/NCBI
49.	Huang Y, Hunyor S, Jiang L, et al: Remodeling of the chronic severely failing ischemic sheep heart after coronary microembolization: functional, energetic, structural, and cellular responses. Am J Physiol Heart Circ Physiol. 286:2141–2150. 2004. View Article : Google Scholar
50.	Gill RM, Jones BD, Corbly AK, et al: Exhaustion of the Frank-Starling mechanism in conscious dogs with heart failure induced by chronic coronary microembolization. Life Sciences. 79:536–544. 2006. View Article : Google Scholar : PubMed/NCBI