Endothelin-1 receptor blockade induces upregulation of renin-angiotensin-aldosterone system expression in terms of blood pressure regulation.
OBJECTIVE
To compare the level of expression of the renin-angiotensin-aldosterone system (RAAS) in mice with or without the endothelin-1 receptor antagonist bosentan and to examine the potential value in blood pressure regulation.


METHODS
Bosentan (10 mg/kg/d) and placebo were given to two groups of male C57BL/6 mice (n=5) from ages 6 to 12 weeks. The mRNAs of liver, kidney and lung were isolated for Northern blot analysis. A further 15 male C57BL/6 mice were divided into three groups (n=5): mice in group A were given the angiotensin II type 1 receptor blocker valsartan (10 mg/kg/d); mice in group B were given bosentan (10 mg/kg/d); and mice in group C were given both valsartan and bosentan (10 mg/ kg/d for each drug). All mice were administered the drugs from 6 to 12 weeks of age and had their systolic blood pressure (SBP) measured at the end of the drug treatments.


RESULTS
Northern blot analysis demonstrated that the expression levels of angiotensinogen in liver (p=0.0126), renin in kidney (p=0.002), and angiotensin-converting enzyme in lung (p=0.0041) were upregulated in mice treated with bosentan. No difference in SBP was found among the groups before drug administration. Six weeks after monotherapy with valsartan, SBP was slightly lowered (126+/-2 vs. 122+/-3 mmHg, p=0.0381). Monotherapy with bosentan also had a small effect on SBP (126+/-2 vs. 122+/-3 mmHg, p=0.0381), whereas dual blockade with valsartan and bosentan significantly lowered SBP (127+/-3 vs. 103+/-3 mmHg, p<0.001).


CONCLUSIONS
We conclude that RAAS components are upregulated under endothelin blockade. Dual blockade of the RAAS and endothelin system is beneficial for blood pressure control.
Bo Yang
Department of Cardiology, Chinese PLA (People's Liberation Army) General Hospital, No. 28, Fu-xing Road, Beijing 100853, China. dryangb@yahoo.com.cn
Chen
Yun-Dai
YD
Li
Tian-De
TD
Feng
Quan-Zhou
QZ
D000808:Angiotensinogen / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects / Q000235:genetics*; D015152:Blotting, Northern; D065130:Endothelin A Receptor Antagonists; D007668:Kidney / Q000187:drug effects / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008168:Lung / Q000187:drug effects / Q000201:enzymology; D051379:Mice; D008810:Mice, Inbred C57BL; D007703:Peptidyl-Dipeptidase A / Q000235:genetics / Q000378:metabolism; D044022:Receptor, Endothelin A / Q000378:metabolism; D012083:Renin / Q000235:genetics / Q000378:metabolism; D012084:Renin-Angiotensin System / Q000187:drug effects / Q000235:genetics*; D013599:Systole / Q000187:drug effects; D013777:Tetrazoles / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics*; D014633:Valine / Q000031:analogs & derivatives / Q000494:pharmacology; D000068756:Valsartan
D000959:Antihypertensive Agents; D065130:Endothelin A Receptor Antagonists; D044022:Receptor, Endothelin A; D013777:Tetrazoles; D000808:Angiotensinogen; D000068756:Valsartan; D007703:Peptidyl-Dipeptidase A; D012083:Renin; D014633:Valine