טכניון מכון טכנולוגי לישראל
הטכניון מכון טכנולוגי לישראל - בית הספר ללימודי מוסמכים  
M.Sc Thesis
M.Sc StudentFrancis Bahaa'
SubjectRegulation of Renal and Intrarenal Hemodynamics:
Involvement of the Endothelin System
DepartmentDepartment of Medicine
Supervisor Professor Zaid A. Abassi


Abstract

Endothelin-1(ET-1) is involved in the pathogenesis of cardiac and renal hemodynamic changes and impaired excretory function in congestive heart failure (CHF). We demonstrated that acute administration of ABT-627(ETA blocker) abolished the systemic and renal vasoconstriction induced by ET-1 administration to controls and CHF rats induced by surgically created aorto-caval fistula. In contrast, acute ETB blockade by A192621.1 exaggerated the ET-1-induced systemic and renal vasoconstriction. We also examined the renal and systemic effects of chronically administrated ABT-627 or A192621.1 through osmotic minipumps. Tail-cuff measurements revealed that ABT-627 significantly decreased mean arterial pressure (MAP), whereas A192621.1 significantly increased MAP in controls.  Despite the hypotensive effect of ABT-627, the daily sodium excretion(UNaV) dramatically increased, but to a lesser extent compared with A192621.1-treated controls. Chronic treatment of CHF animals with ABT-627 did not influence UNaV, whereas treatment with A192621.1 significantly improved UNaV. Interestingly, treatments with either ABT-627 or A192621.1 significantly decreased cardiac hypertrophy in CHF rats.

Endothelin system regulates renal regional blood flow. ET-1 induces renal-cortical vasoconstriction via ETA, whereas ETB mediates renal-medullary vasodilatation. The ETB-mediated medullary vasodilatation is much more significant and persistent in CHF rats.

Finally, we examined the immunostaining and localization of ETA and ETB in the renal cortex and medulla of CHF rats, which were further subdivided into rats with compensated(UNaV>1200µEq/day) and decompensated CHF(UNaV<200µEq/day). In both subgroups, we observed preferential upregulation of ETA in the cortex and ETB in the vasa-recta which contribute to the cortical vasoconstriction and preserved medullary perfusion, respectively, in CHF. Whereas, the downregulation of ETB receptors in collecting ducts of decompensated CHF rats represents possible explanation for the exaggerated sodium and water retention in this subgroup.