Contribution of Ras farnesyl transferase, MAP kinase and cytochrome P-450 metabolites to endothelin-1 induced hypertension

Farid Ljuca; Gorazd Drevenšek; Enver Zerem

doi:10.17305/bjbms.2011.2586

Authors

Farid Ljuca Department of Physiology, University of Tuzla, Faculty of Medicine
Gorazd Drevenšek Department of Pharmacology and experimental toxicology, University of Ljubljana, Faculty of Medicine
Enver Zerem University Clinical Center Tuzla

DOI:

https://doi.org/10.17305/bjbms.2011.2586

Keywords:

endothelin-1, hypertension, cytochrome P-450, Ras farnesyl transferase, mitogen activated protein kinase

Abstract

Endothelin 1 (ET-1) is vasoactive peptide that acts via ET-A receptors coupling inducing vascular smooth muscle cell proliferation and contraction. ET-1 is involved in the development and maintenance of hypertension.

Aim of this study was to determine the contribution of Ras farnesyl transferase, mitogen activated protein kinase (MAP kinase) and cytochrome P¬450 (CYP450) metabolites to ET-1 induced hypertension.

ET-1 (5 pmol/kg per minute) was chronically infused into to the jugular vein by use of mini-osmotic pump for 9 days in male Sprague-Dawley rats. Mean arterial blood pressure (MABP) in ET-1-treated rats was 154±2 mm Hg (hypertensive rats) compared with 98±3 mm Hg in control (normotensive) rats. Infusion of Ras farnesyl transferase inhibitor FPTIII (138 ng/min), MAP kinase inhibitor PD-98059 (694 ng/min) and CYP450 inhibitor 17-ODYA (189 ng/min) significantly attenuated MABP to 115±2.5 mm Hg, 109±3 mm Hg and 118±1.5 mm Hg, respectively. These results suggest that CYP-450 metabolites and Ras/MAP kinase pathway contribute to the development of ET-1 induced hypertension. Further investigation has to be done to confirm whether activation of RAS/MAP kinase pathway by arachidonic acid metabolites plays an important role in the development of ET-1 induced hypertension.