Endothelin blockade in angiotensin II hypertension: prevention and treatment studies in the rat.
1. The participation of endothelin (ET) in the development and maintenance of hypertension induced by angiotensin (Ang) II was assessed using the non-specific ET receptor antagonist bosentan (30 mg/kg per day). 2. In the prevention study, bosentan was given 24 h prior to and during the 17 day period of AngII infusion (200 ng/kg per min, s.c., osmotic pump), whereas in the treatment study, bosentan was administered from day 10 to day 17. Tail-cuff pressure (TCP) was measured before and on days 10 and 17 of AngII infusion. At the end of studies, heart weight index was calculated as the ratio of heart to bodyweight (HWI) and the wall thickness of the carotid artery (perfusion/fixation at 120 mmHg) was measured. Tail-cuff pressure increased from 129 +/- 3 to 179 +/- 7 and 189 +/- 9 mmHg on days 10 and 17 of AngII infusion, respectively. 3. Final TCP was markedly lowered in rats pretreated with bosentan, whereas TCP remained comparable with untreated hypertensive rats when bosentan was given from day 10 of AngII infusion (177 +/- 9 mmHg). 4. The increase in cardiac mass associated with AngII hypertension was similarly attenuated in the two groups receiving bosentan. 5. The HWI was 3.49 +/- 0.12 mg/g in untreated hypertensive rats and 3.18 +/- 0.08 and 3.11 +/- 0.09 mg/g in rats pretreated with bosentan and those receiving the antagonist from day 10. 6. The increase in carotid wall thickness induced by AngII was prevented, but not reversed, by bosentan. 7. These results support the hypothesis that endogenous ET participates only in the initial phase of AngII hypertension. In addition, the beneficial effect of bosentan of cardiac mass but not on arterial wall thickness is in favour of a role of ET as a local mediator of the cardiac hypertrophic effect of AngII, independently of the level of blood pressure and duration of hypertension.
Ficai
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S
Groupe Rein et Hypertension, Faculté de Médecine, University Montpellier I, Montpellier, France.
Herizi
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A
Mimran
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A
Jover
B
B
D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology / Q000627:therapeutic use; D001794:Blood Pressure / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D000077300:Bosentan; D002339:Carotid Arteries / Q000187:drug effects / Q000473:pathology; D065128:Endothelin Receptor Antagonists; D006973:Hypertension / Q000139:chemically induced* / Q000188:drug therapy* / Q000517:prevention & control; D008297:Male; D009206:Myocardium / Q000473:pathology; D009929:Organ Size / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D017466:Receptors, Endothelin / Q000378:metabolism; D013449:Sulfonamides / Q000494:pharmacology* / Q000627:therapeutic use*
D000959:Antihypertensive Agents; D065128:Endothelin Receptor Antagonists; D017466:Receptors, Endothelin; D013449:Sulfonamides; D000804:Angiotensin II; D000077300:Bosentan