THE EFFECTS OF CYCLOOXIGENASE INHIBITORS - DICLOFENAC AND IBUPROFEN - ON CARDIAC CONTRACTILITY, CORONARY FLOW, AND OXIDATIVE STRESS MARKERS IN ISOLATED RAT HEART
Abstract
ABSTRACT
Eicosanoids lead to promotion of inflammation, cause fever, pain and have many other effects to the organism. NSAIDs block the action of cyclooxigenase (COX) in the process of converting arachidonic acid into inflammatory mediators, thus reducing symptoms of inflammation. Investigations focusing on nonselective COX inhibitors, used in high doses, showed harmful effects on myocardial function. Aim of our study was to assess the effects of nonselective NSAIDs, diclofenac and ibuprofen, on cardiodinamic parameters, coronary flow and oxidative stress biomarkers in isolated rat heart. The hearts of male Wistar albino rats were excised and retrogradely perfused according to Langendorff technique at gradually increased coronary perfusion pressure (40–120 cm H2O). The experiments were performed during control conditions (Krebs–Henseleit physiological solution), and after that hearts were perfused with: diclofenac 10 μmol/l and ibuprofen 10 μmol/l. The next parameters of heart function: maximum rate of pressure development (dp/dt max), minimum rate of pressure development (dp/dt min), systolic left ventricular pressure (SLVP), diastolic left ventricular pressure (DLVP), mean perfusion pressure (MBP) and heart rate (HR) were continuously registered. Coronary flow (CF) was measured flowmetrically. Oxidative stress markers: index of lipid peroxidation measured as TBARS, nitric oxide measured through nitrites (NO2-), superoxide anion radical (O2-), and hydrogen peroxide (H2O2) in the coronary venous effluent assessed spectrophotometrically. Our results showed that diclofenac affect cardiodynamic parameters more significantly compared to ibuprofen. Furthermore, present data indicate that, both estimated COX inhibitors, do not promote production of reactive oxygen species.
References
Vane JR, Botting RM. Mechanism of action of antiinflammatory drugs. Int J Tissue React. 1998;20(1):3-15. Review.
Masferrer JL, Zweifel BS, Manning PT, Hauser SD, Leahy KM, Smith WG, Isakson
Pawlosky N. Cardiovascular risk: Are all NSAIDs alike? Can Pharm J (Ott). 2013 Mar;146(2):80-3.
Santos M, Kunkar V, García-Iturralde P, Tendillo FJ. Meloxicam, a specific
Fosbøl EL, Folke F, Jacobsen S, Rasmussen JN, Sørensen R, Schramm TK, Andersen
Huerta C, Varas-Lorenzo C, Castellsague J, García Rodríguez LA. Non-steroidal
Gottlieb S. COX 2 inhibitors may increase risk of heart attack. BMJ. 2001 Sep
Straino S, Salloum FN, Baldi A et al (2007) Protective effects of parecoxib, a cyclo-oxygenase-2 inhibitor, in postinfarction remodeling in the rat. J Cardiovasc Pharmacol 50:571–577.
Förstermann U and Münzel T (2006) Endothelial nitric oxide synthase in vascular disease: from marvel to menace. Circulation 113: 1708-1714.
Griendling KK and FitzGerald GA (2003) Oxidative stress and cardiovascular injury: Part II: animal and human studies. Circulation 108: 2034-2040.
Li H, Hortmann M, Daiber A, Oelze M, Ostad MA, Schwarz PM, Xu H, Xia N, Kleschyov AL, Mang C, Warnholtz A, Münzel T, Förstermann U. Cyclooxygenase 2-selective and nonselective nonsteroidal anti-inflammatory drugs induce oxidative stress by up-regulating vascular NADPH oxidases. J Pharmacol Exp Ther. 2008 Sep;326(3):745-53.
Barudzic N, Turjacanin-Pantelic D, Zivkovic V, Selakovic D, Srejovic I,
Yarishkin OV, Hwang EM, Kim D, Yoo JC, Kang SS, Kim DR, Shin JH, Chung HJ, Jeong HS, Kang D, Han J, Park JY, Hong SG. Diclofenac, a Non-steroidal Anti-inflammatory Drug, Inhibits L-type Ca Channels in Neonatal Rat Ventricular Cardiomyocytes. Korean J Physiol Pharmacol. 2009 Dec;13(6):437-42.
McGettigan P, Henry D. Cardiovascular risk and inhibition of cyclooxygenase: a
de Vries F, Setakis E, van Staa TP. Concomitant use of ibuprofen and
Hernandez-Diaz S, Garcia-Rodriguez LA. Epidemiologic assessment of the safety of conventional nonsteroidal anti-inflammatory drugs. Am J Med. 2001;110:20S–27S.
Yang ZF, Wang HW, Zheng YQ, Zhang Y, Liu YM, Li CZ. Possible arrhythmiogenic
Jakovljević V, Savić M, Kučević I, Djurić A, Ranković A, Radisavljević M, Azanjac A, Djurić DM (2005) The effects of dipyridamole on coronary flow, nitrite outflow and oxidative stress during coronary autoregulation in isolated rat heart. Medicus; 6(2): 57-61.
Ohkawa H, Ohishi N, Yagi K (1979) Assay for lipid peroxides in animal tissues by thiobarbituric acid reaction. Anal Biochem 95:351–358.
Auclair C, Voisin E (1985) Nitroblue tetrazolium reduction. In: Greenvvald RA (ed) Handbook of methods for oxygen radical research. CRC Press, Boca Raton, pp 123–132.
Pick E, Keisari Y (1980) A simple colorimetric method for the measurement of hydrogen peroxide produced by cells in culture. J Immunol Methods 38:161–170.
Green LC, Wagner DA, Glogowski J, Skipper PL, Wishnok JS,Tannenbaum SR (1982) Analysis of nitrate, nitrite and [15 N] nitrate in biological fluids. Anal Biochem 126:131–138.
Zivkovic V, Djuric D, Turjacanin-Pantelic D, Marinkovic Z, Stefanovic D,
Herbertson MJ, Werner HA, Studer W, Russell JA, Walley KR. Decreased left
Beamer KC, Daly T, Vargish T. Hemodynamic evaluation of ibuprofen in canine
Kristóf A, Husti Z, Koncz I, Kohajda Z, Szél T, Juhász V, Biliczki P, Jost N,
Kristóf A, Husti Z, Koncz I, Kohajda Z, Szél T, et al. (2012) Diclofenac Prolongs Repolarization in Ventricular Muscle with Impaired Repolarization Reserve. PLoS ONE 7(12): e53255.
Takayama F, Egashira T, Yamanaka Y. Effect of diclofenac, a non-steroidal
Hermann M, Camici G, Fratton A, Hurlimann D, Tanner FC, Hellermann JP, Fiedler
Wilkinson BL, Cramer PE, Varvel NH, Reed-Geaghan E, Jiang Q, Szabo A, Herrup
Zhao Y, McLaughlin D, Robinson E, Harvey AP, Hookham MB, Shah AM, McDermott