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Vascular effects of COX inhibition and AT1 receptor blockade in transgenic rats harboring mouse renin-2 gene

100%

Cheng Z. J., Tikkanen I., Vapaatalo H., Mervaala E. M. A.

Journal of Physiology and Pharmacology

2002

tom 53

nr 4,1

Ang II-induced endothelial dysfunction is associated with perivascular inflammation and increased superoxide production in the vascular wall. The present study examined the role of cyclo-oxygenase (COX)-synthetized eicosanoids in the pathogenesis of Ang II-induced endothelial dysfunction in transgenic rats harboring mouse renin-2 gene (mREN2 rats). Five-to-six-week-old, heterozygous mREN2 rats received the following drug regimens for 8 weeks: 1) vehicle, 2) cyclo-oxygenase-2 (COX-2) inhibitor (MF-tricyclic [3-(3,4-difluorophenyl)-4-(4-(methylsulfonyl) phenyl)-2(5H)-furanone], 14 mg/kg p.o.), 3) COX-l/COX-2 inhibitor (sulindac, 14 mg/kg p.o.), 4) angiotensin II receptor antagonist (losartan 40 mg/kg p.o.). Normotensive Sprague Dawley (SD) rats served as controls. In vitro vascular responses of the descending aorta and renal artery were studied using organ bath system. mREN2 rats developed pronounced hypertension which was associated with impaired endothelium-dependent and endothelium-independent vascular relaxations in the aorta. In contrast, the relaxation responses of the renal arteries remained largely unchanged in mREN2 rats. Urinary NOx excretion, a marker of total body NO generation, was also decreased in mREN2 rats. Neither non-selective COX inhibitor sulindac nor COX-2 selective MF-tricyclic were capable of preventing Ang II- induced hypertension or endothelial dysfunction in mREN2 rats, whereas ATi receptor antagonist losartan completely normalized blood pressure, vascular relaxation responses as well as urinary NOx excretion. Our findings indicate that NO synthesis and/or bioavailability as well as the sensitivity of arterial smooth muscle cells to NO are decreased in mREN2 rats. The present study also demonstrated that COX does not play a central role in the pathogenesis of Ang II-induced endothelial dysfunction in mREN2 rats.

Effects of calcium sensitizer OR-1896 on cardiovascular mortality and myocardial remodelling in hypertensive Dahl/Rapp rats

64%

Louhelainen M., Merasto S., Finckenberg P., Vahtola E., Kaheinen P., Leskinen H., Levijoki J., Pollesello P., Haikala H., Mervaala E. M. A.

Journal of Physiology and Pharmacology

2009

tom 60

nr 3

41-47

Calcium-sensitizing agents have been shown to improve cardiac function in patients suffering from acute decompensated heart failure, however, their long-term effects on cardiac remodeling and cardiovascular mortality are still largely unknown. In the present study we tested the hypothesis whether OR-1896, an active and long-lasting metabolite of calcium sensitizer levosimendan, prevents cardiovascular mortality and hypertension-induced myocardial remodelling in salt-sensitive Dahl/Rapp rats. OR-1896 was given orally to Dahl/Rapp SS rats on high-salt diet (NaCl 7% w/w) for 7 weeks at two different doses (0.5 and 0.05 mg/kg). OR-1896 prevented salt-induced cardiovascular mortality (survival rate 75 % in OR-1896 treated groups vs 38 % in untreated controls, p<0.01), ameliorated cardiac hypertrophy and improved systolic functions of the heart without major influence on systemic blood pressure. OR-1896 also ameliorated salt-induced increase in cardiac ANP mRNA expression and plasma BNP level. Salt-induced cardiac remodelling was associated with 4-fold increase in cardiac p16INK4a mRNA expression, a marker of cellular senescence. OR-1896 dose-dependently ameliorated cardiomyocyte senescence. Our findings suggest a therapeutic role for OR-1896 in the prevention of cardiac remodelling in salt-sensitive forms of hypertension. The present study also underscores the importance of cellular senescence in the pathogenesis of salt-induced hypertensive heart disease.

Ograniczanie wyników

2 Journal of Physiology and Pharmacology

2 Mervaala E. M. A.

1 Cheng Z. J.

1 Finckenberg P.

1 Haikala H.

1 Kaheinen P.

1 Leskinen H.

1 Levijoki J.

1 Louhelainen M.

1 Merasto S.

1 Pollesello P.

1 Tikkanen I.

1 Vahtola E.

1 Vapaatalo H.

1 2009

1 2002

Wyniki wyszukiwania

Vascular effects of COX inhibition and AT1 receptor blockade in transgenic rats harboring mouse renin-2 gene

Effects of calcium sensitizer OR-1896 on cardiovascular mortality and myocardial remodelling in hypertensive Dahl/Rapp rats