Advances in Clinical and Experimental Medicine

Title abbreviation: Adv Clin Exp Med
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ISSN 1899–5276 (print)
ISSN 2451-2680 (online)
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Advances in Clinical and Experimental Medicine

2011, vol. 20, nr 1, January-February, p. 39–45

Publication type: original article

Language: English

The Influence of Concomitant Administration of Simvastatin at Different Doses with Metoprolol on Heart Rate and Blood Pressure in Normocholesterolemic and Hypercholesterolemic Rats

Wpływ łącznego podania simwastatyny w różnych dawkach z metoprololem na częstość rytmu serca oraz ciśnienie tętnicze u szczurów z zaburzeniami i bez zaburzeń lipidowych

Jacek Owczarek1,, Magdalena Jasińska1,, Urszula Kurczewska1,, Daria Orszulak-Michalak1,

1 Department of Biopharmacy, Medical University of Lodz, Poland

Abstract

Background. β1-adrenergic blocking drugs and inhibitors of HMGCo-A reductase (statins) are widely used by a lot of patients in the prevention of cardiovascular events. Previous studies have shown that the administration of statins influences β adrenergic signaling.
Objectives. The aim of the study was to evaluate the influence of a chronic 4-week administration of simvastatin given at different doses with concomitant metoprolol on heart rate and blood pressure.
Material and Methods. The experiments were performed in normotensive Wistar rats. The animals were divided into 2 groups: normocholesterolemic and hypercholesterolemic. During the 4 weeks, hypercholesterolemic rats received a diet with 5% cholesterol and 2,5% cholic acid. Drugs: metoprolol 30 mg × kg–1 b.w.; simvastatin 1 mg × × kg–1 b.w.; simvastatin 20 mg × kg–1 b.w.; simvastatin 1 mg × kg–1 b.w. + metoprolol 30 mg × kg–1 b.w., or simvastatin 20 mg × kg–1 b.w. + metoprolol 30 mg kg–1 b.w. were given intragastrically over the 4-week period. For the evaluation of heart rate and blood pressure, the signals were provided by an Isotec pressure transducer.
Results. Concomitant administration of simvastatin at 1 and 20 mg × kg–1 b.w with metoprolol in normocholesterolemic rats statistically decreased heart rate as compared to the control group and the group receiving simvastatin alone. No statistical differences between the groups receiving simvastatin at dose 1 mg/kg–1 with metoprolol and simvastatin at dose 20 mg/kg–1 with metoprolol (381.64 ± 7.90 vs. 388.21 ± 5,15 1/min p = 0.05) were observed. In the hypercholesterolemic animals, the heart rate evaluation after concomitant administration of simvastatin given at different doses with metoprolol showed comparable statistical implications as compared to normocholesterolemic rats. Concomitant administration of simvastatin in different doses on normoand hypercholesterolemic rats did not significantly influence blood pressure.
Conclusion. No significant impact of chronic administration of simvastatin given at different doses to normoand hypercholesterolemic Wistar rats receiving metoprolol on the heart rate was observed.

Streszczenie

Wprowadzenie. Leki blokujące receptory β1-adrenergiczne oraz inhibitory reduktazy 3-hydroksy 3-metyloglutarylokoenzymu A (statyny) są powszechnie stosowane u pacjentów w zapobieganiu incydentom sercowo-naczyniowym. Wcześniejsze badania wykazały, że podawanie statyn wpływa na sygnalizację β-adrenergiczną.
Cel pracy. Ocena wpływu podawania simwastatyny w różnych dawkach na wartości rytmu serca i ciśnienia tętniczego po łącznym 4-tygodniowym podawaniu z metoprololem.
Materiał i metody. Badanie zostało przeprowadzone na szczurach Wistar o prawidłowym ciśnieniu krwi. Zwierzęta measurebyły podzielone na 2 grupy: z prawidłowym stężeniem cholesterolu i podwyższonym stężeniem cholesterolu. Szczury z grupy z podwyższonym stężeniem cholesterolu otrzymywały dietę wzbogaconą 5% zawartością cholesterolu i 2,5% zawartością kwasu cholowego. Leki: metoprolol 30 mg × kg–1 m.c.; simwastatyna 1 mg × kg–1 m.c.; simwastatyna 20 mg × kg–1 m.c.; simwastatyna 1 mg × kg–1 m.c. + metoprolol 30 mg × kg–1 m.c., simwastatyna 20 mg × kg–1 m.c. + metoprolol 30 mg × kg–1 m.c. były podawane dożołądkowo przez okres 4 tygodni.
Wyniki. Łączne podanie simwastatyny w dawkach: 1 i 20 mg × kg–1 m.c. z metoprololem szczurom z grupy z prawidłowym stężeniem cholesterolu znacząco statystycznie zwalniało rytm serca w porównaniu z grupą kontrolną oraz grupy otrzymującej samą simwastatynę. Nie odnotowano istotnej statystycznie różnicy w zakresie rytmu serca między osobnikami z grup z prawidłowym stężeniem cholesterolu otrzymującymi różne dawki simwastatyny (1 i 20 mg × kg–1 m.c.) łącznie z metoprololem (381,64 ± 7.90 vs 388,21 ± 5,15 1/min p = 0,05). W grupie zwierząt z hipercholesterolemią ocena wartości rytmu serca po łącznym podaniu różnych dawek simwastatyny (1 i 20 mg × kg–1 m.c.) łącznie z metoprololem wykazywała podobną zależność statystyczną. Łączne podanie różnych dawek simwastatyny łącznie z metoprololem nie wpłynęło istotnie statystycznie na wartości ciśnienia tętniczego.
Wnioski. Nie zaobserwowano wpływu przewlekłego podawania simwastatyny w różnych dawkach na zwolnienie rytmu serca u szczurów z prawidłowym i podwyższonym stężeniem cholesterolu otrzymujących metoprolol.

Key words

rats, simvastatin, metoprolol, heart rate

Słowa kluczowe

szczury, simwastatyna, metoprolol, rytm serca

References (25)

  1. Tanaka N, Katayama Y, Katsumata T, Otori T, Nishiyama Y: Effects of long-term administration of HMG-CoA reductase inhibitor, atorvastatin, on stroke events and local cerebral blood flow in stroke-prone spontaneously hypertensive rats. Brain Res 2007, 1169, 125–132.
  2. Sacks FM, Pfeffer MA, Moye LA, Rouleau JL, Rutherford JD, Cole TG, Brown L, Warnica JW, Arnold JMO, Wun CC, Davis BR, Braunwald E: The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. N Engl J Med 1996, 335, 1001–1009.
  3. Jasińska M, Owczarek J, Orszulak-Michalak D: Statins: a new insight into their mechanisms of action and consequent pleiotropic effects. Pharmacol Rep 2007, 59, 483–499.
  4. Wierzbicki AS, Chowienczyk PJ, Cockcroft JR, Brett SE, Watts GF, Jenkins BS et al.: Endothelial dysfunction is strictly connected with hypertension development and LDL-C levels. Cardiovascular risk factors and endothelial dysfunction. Clin Sci 2004, 107, 609–615.
  5. Fox K, Borer JS, Camm AJ, Danhin N, Ferrari R, Lopez Sendon JL, Steg PG, Tardif J-C, Tavazzi L, Tendera M: Resting heart rate in cardiovascular disease. J Am Coll Cardiol 2007, 50, 823–830.
  6. Tverdal A, Hjellvik V, Selmer R: Heart rate and mortality from cardiovascular causes: a 12 year follow-up study of 379 843 men and women aged 40–45 years. Eur Heart J 2008, 29, 2772–2781.
  7. Chen ZM, Pan HC, Chen YP, Peto R, Collins R, Jiang LX, Xie JX, Liu LS: COMMIT Collaborative group. Early intravenous then oral metoprolol in 45,852 patients with acute myocardial infarction: randomized placebocontrolled trial. Lancet 2005, 366, 1622–1632.
  8. Freemantle N, Cleland J, Young P, Mason J, Harrison J: Beta blockade after myocardial infarction: systematic review and meta regression analysis. BMJ 1999, 318, 1730–1737.
  9. Mühlhäuser U, Zolk O, Rau T, Münzel F, Wieland T, Eschenhagen T: Atorvastatin desensitizes β-adrenergic signaling in cardiac myocytes via reduced isoprenylation of G-protein γ-subunits. The FASEB Journal Express Article 2006, doi:10.1096/fj.05-5067fje.
  10. Owczarek J, Jasińska M, Orszulak-Michalak D: Dose-dependent influence of two-week administration of simvastatin and metoprolol injection on blood pressure in normocholesterolemic rats. Acta Pol Pharm – Drug Res 2008, 65, 147–151.
  11. Owczarek J, Jasińska M, Orszulak-Michalak D: Interaction between different doses of simvastatin after two-week administration and metoprolol injection on the heart rate in normocholesterolemic rats. Acta Pol Pharm – Drug Res 2008, 65, 141–145.
  12. Muntz K, Sternweis PC, Gilman AG, Mumby SM: Influence of gamma subunit prenylation and association of guanine nucleotide-binding regulatory proteins with membranes. Mol Biol Cell 1992, 3, 49–61.
  13. Myung CS, Yasuda H, Liu WW, Harden TK, Garrison JC: Role of isoprenoid lipids on the heterotrimeric G protein gamma subunit in determining effector activation. J Biol Chem 1999, 274, 16595–16603.
  14. Takida S, Wedegaertner PB: Heterotrimer Formation, Together with Isoprenylation, Is Required for Plasma Membrane Targeting of Gβγ. J Biol Chem 2003, 278, 17284–17290.
  15. Golomb BA, Ritchie JB, Criqui MH, Dimsdale JE: Statins lower blood pressure: results from the UCSD Statin Study. Circulation 2004, 110, III–402.
  16. Poulter N, Sever PS: Do statins lower blood pressure? Evidence from the Anglo-Scandinavian Cardiac Outcomes Trial-Lipid-Lowering Arm (ASCOT-LLA). Circulation 2004, 110, III–402.
  17. Morikawa S, Takabe W, Mataki C, Kanke T, Itoh T, Wada Y, Izumi A, Saito Y, Hamakubo T, Kodama T: The effect of statins on mRNA levels of genes related to inflammation, coagulation and vascular constriction in HUVEC. Human umbilical vein endothelial cells. J Atheroscler Thromb 2002, 9, 177–183.
  18. De Jongh S, Lilien MR, op’t Roodt J, Stroes ES, Bakker HD, Kastelein JJ: Early statin therapy restores endothelial function in children with familial hypercholesterolemia. J Am Coll Cardiol 2002, 40, 2117–2121.
  19. Omori H, Nagashima H, Tsurumi Y, Takagi A, Ishizuka N, Hagiwara N, Kawana M, Kasanuki H: Direct in vivo evidence of a vascular statin: a single dose cerivastatin increases vascular endothelial responsiveness in healthy normocholesterolemic patients. Br J Pharmacol 2002, 54, 395–399.
  20. Kalinowski L, Dobrucki LW, Brovkovych V, Malinski T: Increased nitric oxide bioavailability in endothelial cells contributes to the pleiotropic effect of cerivastatin. Circulation 2002, 105, 933–938.
  21. Laufs U, Gertz K, Dirnagl U, Bohm M, Nickenig G, Endres M: Rosuvastatin a new-CoA reductase inhibitor, upregulates endothelial nitric oxide synthase and protects from ischaemic stroke in mice. Brain Res 2002, 942, 23–30.
  22. Strazzullo P, D’Elia L, Versiero M: Response to Upregulation of Nitric Oxide, Inhibition of Oxidative Stress, and Antihypertensive Effects of Statins. Hypertension 2007, 49, 792–798.
  23. Hernandez-Perera O, Perez-Sala D, Navarro-Antolin J, Sanchez-Pascuala R, Hernandez G, Diaz C, Lamas S: Effects of the 3-hydroxy-3-methylglutaryl-CoA reductase inhibitors, atorvastatin and simvastatin on the expression of endothelin-1 and endothelial nitric oxide synthase in vascular endothelial cells. J Clin Invest 1998, 101, 2711–2719.
  24. Nickenig G, Baumer AT, Temur Y, Kebben D, Jockenhovel F, Bohm M: Statin-sensitive dysregulated AT1 receptor function and density in hypercholesterolemic men. Circulation 1999, 100, 2131–2134.
  25. Ferrier KE, Muhlmann MH, Baguet JP, Cameron JD, Jennings GL, Dart AM, Kingwell BA: Intensive cholesterol reduction lowers blood pressure and large artery stiffness in isolated systolic hypertension. J Am Coll Cardiol 2002, 39, 1020–1025.
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