Monotherapy of experimental metabolic syndrome: II. Study of cardiovascular effects

Knezl, Vladimír; Sotníková, Ružena; Brnoliaková, Zuzana; Stankovičová, Tatiana; Bauer, Viktor; Bezek, Štefan

doi:10.1515/intox-2017-0014

Abstract

Metabolic syndrome belongs to the most important risk factors of cardiovascular diseases. The aim of this study was to investigate changes in cardiovascular system induced by high cholesterol and high fat diet (HCHF) in HTG rats and their influence by a pyridoindole antioxidant – SMe1EC2 (S). The effects of S were compared with those of atorvastatin (A). Male HTG rats were fed HCHF (1% cholesterol + 7.5% lard) for 4 weeks. S and A were administered p.o., 50 mg/kg b.w. Following experimental groups were used: Wistar rats (W), hypertriglyceridemic rats (HTG), HTG rats fed HCHF (CHOL), HTG+S (S-HTG), CHOL+S (S-CHOL), and CHOL+A (A-CHOL). Values of blood pressure (BP) and selected ECG parameters were monitored in conscious animals, functions of the isolated heart and aorta were analyzed ex vivo. At the end of the experiment, systolic (sBP) and diastolic (dBP) blood pressure was increased in HTG and CHOL. S and A decreased BP in all treated groups. Accordingly with BP changes, the aortic endothelial function of CHOL was damaged. Both S and A administration ameliorated the endothelium-dependent relaxation to values of W. PQ and QTc intervals were prolonged in CHOL, while the treatment with S or A improved ECG findings. Prodysrhythmogenic threshold was decreased significantly in CHOL and both treatments returned it to the control values. In conclusion, HCHF increased BP, impaired endothelial relaxation of the aorta and potentiated susceptibility of myocardium to dysrhythmias. The effect of S on the changes induced by HCHF diet was more pronounced than that of A.

References

Albarado-Ibañez A, Avelino-Cruz JE, Velasco M, Torres-Jácome J, Hiriart M. (2013). Metabolic syndrome remodels electrical activity of the sinoatrial node and produces arrhythmias in rats. PLoS One8: e76534.
Search in Google Scholar Back to article
Alberti KG, Eckel RH, Grungy SM, Zimmet PZ, Cleeman JI, Donato KA, Fruchart JC, James WP, Loria CM, Smith SC Jr. (2009). Harmonizing the Metabolic Syndrome. A Joint Interim Statement of the International Diabetes Federation Task Force on Epidemiology and Prevention; National Heart, Lung, and Blood Institute; American Heart Association; World Heart Federation; International Atherosclerosis Society; and International Association for the Study of Obesity. Circulation120: 1640–1645.
Search in Google Scholar Back to article
Allesie MA, Lammers WJEP, Bonke IM, Hollen J. (1984). Intra-atrial reentry as a mechanism for atrial flutter induced by acetylcholine and rapid pacing in dog. Circulation70: 123–135.10.1161/01.CIR.70.1.123
Open DOI Search in Google Scholar Back to article
Bacharova L, Krivosikova Z, Wsolova L, Gajdos M. (2012). Alterations in the QRS complex in the offspring of patients with metabolic syndrome and diabetes mellitus: early evidence of cardiovascular pathology. J Electrocardiol45: 244–251.10.1016/j.jelectrocard.2012.02.004
Open DOI Search in Google Scholar Back to article
Benova T, Knezl V, Viczenczova C, Bacova BS, Radosinska J, Tribulova N. (2015). Acute anti-fibrillating and defibrillating potential of atorvastatin, melatonin, eicosapentaenoic acid and docosahexaenoic acid demonstrated in isolated heart model. J Physiol Pharmacol66: 83–89.
Search in Google Scholar Back to article
Bezek Š, Brnoliaková Z, Sotníková R, Knezl V, Paulovičová E, Navarová J, Bauer V. (2017). Monotherapy of experimental metabolic syndrome: I. Efficacy and safety. Interdiscip Toxicol10(3): 100–105.
Search in Google Scholar Back to article
Broskova Z and Knezl V. (2011). Protective effect of novel pyridoindole derivatives on ischemia/reperfusion injury of the isolated rat heart. Pharmacol Rep63: 967–974.10.1016/S1734-1140(11)70612-0
Open DOI Search in Google Scholar Back to article
Dougherty PJ and Arora RR. (2012). Utility of early high dose statins in acute coronary syndrome. Am J Ther19: 369–376.10.1097/MJT.0b013e31823735aa22964560
Open DOI Search in Google Scholar Back to article
Duflou J, Virmani R, Rabi I, et al. (1995). Sudden death as a result of heart disease in morbid obese. Am Heart J130: 306–313.
Search in Google Scholar Back to article
Du Toit EF, Nabben M, Lochner A. (2005). A potential role of angiotensin II in obesity induced hypertrophy and ischaemic/reperfusion injury. Basic Res Cardiol100: 346–354.10.1007/s00395-005-0528-515821998
Open DOI Search in Google Scholar Back to article
Galajda P, Mokáň M, Prídavková D, Tomásková V, Sutarík L, Krucinská L, Bukovská A, Rusnáková G. (2007). Prevalencia metabolického syndrómu na Slovensku. (Prevalence of metabolic syndrome in Slovakia. In Slovak). Int med7: 325–331.
Search in Google Scholar Back to article
Gray RA, Pertsov AM, Jalife J. (1998). Spatial and temporal organization during cardiac fibrillation. Nature392: 75–78.
Search in Google Scholar Back to article
Grundy SM. (2007). Controversy in Clinical Endocrinology. Metabolic Syndrome: A Multiplex Cardiovascular Risk Factor. J Clin Endocr Met92: 399–404.10.1210/jc.2006-051317284640
Open DOI Search in Google Scholar Back to article
Horwich TB, MacLellan WR. (2007). Atorvastatin and statins in the treatment of heart failure. Expert Opin Pharmacother17: 3061–3068.
Search in Google Scholar Back to article
Huang JV, Lu L, Ye S, Bergman BC, Sparagna GC, Sarraf M, Reusch JE, Greyson CR, Schwartz GG. (2013.) Impaired contractile recovery after low-flow myocardial ischemia in a porcine model of metabolic syndrome. Am J Physiol Heart C304: H861–873.10.1152/ajpheart.00535.2012360277023335793
Search in Google Scholar Back to article
Jain KS, Kulkarni RR, Jain DP. (2010). Current drug targets for antihyperlipidemic therapy. Mini Rev Med Chem10: 232–262.
Search in Google Scholar Back to article
Jouven X, Charles MA, Desnos M, Ducimetière P. (2001). Circulating nonesterified fatty acid levels as a predictive risk factor for sudden death in the population. Circulation104: 756–761.10.1161/hc3201.09415111502698
Open DOI Search in Google Scholar Back to article
Liptak B, Knezl V, Gasparova Z. (2017). Metabolic disturbances induce malignant heart arrhythmias in rats. Bratisl Med J118: 539–543.10.4149/BLL_2017_10329061061
Open DOI Search in Google Scholar Back to article
Liu C, Zhou M-S, Li Y, Wang A, Chadipiralla K, Tian R, Tian R, Raij L. (2017). Oral nicotine aggravates endothelial dysfunction and vascular inflammation in diet-induced obese rats: Role of macrophage TNFα. PLoS ONE12: e0188439.
Search in Google Scholar Back to article
Kihara Y and Morgan JP. (1991). Intracellular calcium and ventricular fibrillation. Circ Res 68: 1378–1389.10.1161/01.RES.68.5.13782018996
Open DOI Search in Google Scholar Back to article
Kurl S, Laaksonen DE, Jae SY, Mäkikallio TH, Zaccardi F, Kauhanen J, Ronkainen K, Laukkanen JA. (2015). Metabolic syndrome and the risk of sudden cardiac death in middle-aged men. Int J Cardiol203: 792–797.
Search in Google Scholar Back to article
Lew EA and Garfinkel L. (1979). Variations in mortality by weight among 750 000 men and woman. J Chron Dis32: 563–576.
Search in Google Scholar Back to article
Luscher TF, Creager MA, Beckman JA, Cosentino F. (2003). Diabetes and vascular disease: patophysiology, clinical consequences, and medical therapy: part II. Circulation108: 1655–1661.
Search in Google Scholar Back to article
Luu M, Stevenson WG, Stevenson LW, Baron K, Walden J. (1989). Diverse mechanisms of unexpected cardiac arrest in advanced heart failure. Circulation. 80: 1675–80.10.1161/01.CIR.80.6.1675
Open DOI Search in Google Scholar Back to article
Merrilat JC, Lakatta EG, Hano O, Guarnieri T. (1990): Role of calcium and the calcium channel in the initiation and maintenance of ventricular fibrillation. Circ Res67: 115–1123.10.1161/01.RES.67.5.11152171799
Search in Google Scholar Back to article
Mikhin VP, Zhilyaeva YA, Gromnaky NI. (2016). Pleotropic effects of atorvastatin in patients with chronic ischemic heart disease. Kardiologiia56: 42–46.
Search in Google Scholar Back to article
Nduhirabandi F, Du Toit EF, Blackhurst D, et al. (2011). Chronic melatonin consumption prevents obesity-related metabolic abnormalities and protects the heart against myocardial ischemia and reperfusion injury in a prediabetic model of diet-induced obesity. J Pineal Res50: 171–182.
Search in Google Scholar Back to article
Niedrig D, Maechler S, Hoppe L, Corti N, Kovari H, Russmann S. (2016). Drug safety of macrolide and quinolone antibiotics in a tertiary care hospital: administration of interacting co-medication and QT prolongation. Eur J Clin Pharmacol72: 859–867.10.1007/s00228-016-2043-z27023463
Open DOI Search in Google Scholar Back to article
Ooie T, Kajimoto M, Takahashi N, Shinohara T, Taniguchi Y, Kouno H, Wakisaka O, Yoshimatsu H, Saikawa T. (2005). Effects of insulin resistance on geranylgeranylacetone-induced expression of heart shock protein 72 and cardioprotection in high-fat diet rats. Life Sciences77: 869–881.
Search in Google Scholar Back to article
Plourde B, Sarrazin J-F, Nault I, Poirier P. (2014). Sudden cardiac death and obesity. Expert Rev Cardiovasc Ther12: 1099–1110.10.1586/14779072.2014.95228325160995
Open DOI Search in Google Scholar Back to article
Raal FJ. (2009). Pathogenesis and managenemt of the dyslipidaemia of the metabolic syndrome. Metab Syndr Relat Disord7: 83–88.
Search in Google Scholar Back to article
Reule CA, Goyvaerts B, Schoen C. (2017). Effects of an L-arginine-based multi ingredient product on endothelial function in subjects with mild to moderate hypertension and hyperhomocysteinemia - a randomized, double-blind, placebo-controlled, cross-over trial. BMC Complement Altern Med17: 92.10.1186/s12906-017-1603-9529065428153005
Open DOI Search in Google Scholar Back to article
Silva MT, Ribeiro FP, Medeiros MA, Sampaio PA, Silva YM, Silva MT, Quintans JS, Quintans-Júnior LJ, Ribeiro LA. (2015). The vasorelaxant effect of p-cymene in rat aorta involves potassium channels. Sci World J2015: 458080.
Search in Google Scholar Back to article
Simões FV, de Batista PR, Botelho T, Ribeiro-Júnior RF, Padilha AS, Vassallo DV. (2016). Treatment with high dose of atorvastatin reduces vascular injury in diabetic rats. Pharmacol Rep68: 865–873.10.1016/j.pharep.2016.04.02227351941
Open DOI Search in Google Scholar Back to article
Simor T, Lorand T, Gaszner B, Elgavish GA. (1997). The modulation of pacing-induced changes in intracellular sodium levels by extracellular Ca in isolated perfused rat hearts. J Mol Cell Cardiol29: 1225–1235.10.1006/jmcc.1996.03599160874
Open DOI Search in Google Scholar Back to article
Sotnikova R, Bacova B, Vlkovicova J, Navarova J, Tribulova N. (2012). Sex differences in endothelial function of aged hypertriglyceridemic rats – effect of atorvastatin treatment. Interdiscip Toxicol5: 155–158.
Search in Google Scholar Back to article
Soydinc S, Davutoglu V, Akcay M. (2006). Uncomplicated metabolic syndrome is associated with prolonged electrocardiographic QTc interval and QTc dispersion. Ann Noninvasive Electrocardiol11: 313–317.
Search in Google Scholar Back to article
Štolc S, Šnirc V, Májeková M, Gáspárová Z, Gajdošíková A, Štvrtina S. (2006). Development of the new group of indole-derived neuroprotective drugs affecting oxidative stress. Cell Mol Neurobiol26: 1493–1502.10.1007/s10571-006-9037-916705480
Open DOI Search in Google Scholar Back to article
Tadic M, Ivanovic B, Cuspidi C. (2013) What do we currently know about metabolic syndrome and atrial fibrillation? Clin Cardiol36: 654–662.10.1002/clc.22163664936523788255
Open DOI Search in Google Scholar Back to article
Tribulová N, Okruhlicová Ľ, Nováková S, Pancza D, Bernátová I, Pechanová O, Weismann P, Manoach M, Seki S, Mochizuki M. (2002). Hypertension-related intermyocyte junction remodeling is associated with higher incidence of low K+-induced lethal arrhythmias in isolated rat heart. Exp Physiol87: 195–205.
Search in Google Scholar Back to article
Tribulová N, Fialová M, Dlugošová K, Knezl V, Okruhlicová L, Kristek F, Zicha J, Kuneš J. (2006). Myocardial gap junction remodelling in hypetriglyceridemic rat heart is associated with increased vulnerability to ventricular fibrillation. Cardiology15: 32S–33S.
Search in Google Scholar Back to article
Tribulova N, Knezl V, Okruhlicova L, Slezak J. (2008). Myocardial gap junctions: targets for novel approaches in the prevention of life-threatening cardiac arrhythmias. Physiol Res57: S1–S13.
Search in Google Scholar Back to article
Watanabe H., Tanabe N, Watanabe T, Roden D M, Sasaki S. (2008). Aizawa Y. Metabolic syndrome and risk of development of atrial fibrillation. Circulation117: 1255–1260.
Search in Google Scholar Back to article
Wensley I, Salaveria K, Bulmer AC, Donner DG, du Toit EF. (2013). Myocardial structure, function, and ischaemic tolerance in a rodent model of obesity with insulin resistance. Exp Physiol98: 1552–1564.10.1113/expphysiol.2013.07494823851919
Open DOI Search in Google Scholar Back to article
Witkowski FX, Leon LJ, Penkoske PA, Giles WR, Spano ML, Ditto WL, Wintre AT. (1998). Spatiotemporal evolution of ventricular fibrillation. Nature392: 78–82.
Search in Google Scholar Back to article
Xu XR, Li KB, Wang P, Xu L, Liu Y, Yang ZS, Yang XC. (2016). The impact of different doses of atorvastatin on plasma endothelin and platelet function in acute ST-segment elevation myocardial infarction after emergency percutaneous coronary intervention. Zhonghua Nei Ke Za Zhi55: 932–936.
Search in Google Scholar Back to article
Yilmaz H, Özcan KS, Sayar N, Kemaloglu T, Gungor B, Erer B, Yilmaz M, Gurkan U, Cakmak N, Oz D, Calik AN, Bolca O. (2015). Metabolic syndrome is associated with atrial electrical and mechanical dysfunction. Med Princ Pract24: 147–152.
Search in Google Scholar Back to article
Zhang WL, Yan WJ, Sun B, Zou ZP. (2014). Synergistic effects of atorvastatin and rosiglitazone on endothelium protection in rats with dyslipidemia. Lipids Health Dis13: 168.10.1186/1476-511X-13-168423267225361814
Open DOI Search in Google Scholar Back to article
Zúrová-Nedelčevová J, Navarová J, Drábiková K, Jančinová V, Petríková M, Bernátová I, Kristová V, Šnirc V, Nosáľová V, Sotníková R. (2006). Participation of reactive oxygen species in diabetes induced endothelial dysfunction. Neuroendocrinol Lett27: 168–171.
Search in Google Scholar Back to article

Monotherapy of experimental metabolic syndrome: II. Study of cardiovascular effects

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