Angiotensin II and endothelin-1 receptor antagonists have cumulative hypotensive effects in canine Page hypertension.
OBJECTIVE
To evaluate whether the cumulative hypotensive effect of the endothelin-1 receptor antagonist bosentan, previously demonstrated in the presence of an angiotensin converting enzyme inhibitor, persists under angiotensin II receptor blockade with losartan.


METHODS
The model of hypertension was canine renovascular hypertension (Page hypertension).


METHODS
Ten conscious dogs, studied on two occasions, were administered losartan (a 0.1 mg/kg bolus plus 90 min infusion at 0.1 mg/kg per min) and then bosentan vehicle (experiment I) or losartan and then two cumulative doses of bosentan (a 0.3 mg/kg bolus plus 30 min infusion at 0.7 mg/kg per min; and a 3 mg/kg bolus plus 30 min infusion at 7 mg/kg per min; experiment II).


RESULTS
At the end of the study, mean aortic pressure in dogs had decreased by 14% in experiment I (from 139 +/- 4.7 to 119 +/- 4.7 mmHg, P<0.05), whereas a 28% reduction occurred in experiment II (from 145 +/- 8.9 to 104 +/- 5.0 mmHg, P<0.005), corresponding to an additional 14% decrease after administration of bosentan (P<0.005 between groups). This cumulative effect of bosentan was related to a decrease in systemic vascular resistance (from 1220 +/- 119 to 847 +/- 189 mmHg/ml per min per kg x 10(3), P<0.05). Plasma angiotensin II level increased similarly in both experiments (in experiment I from 133 +/- 43 to 622 +/- 145 pg/ml, P=0.01; in experiment II from 198 +/- 63 to 771 +/- 134 pg/ml, P<0.005) whereas plasma endothelin-1 level increased only in experiment II (from 3.8 +/- 0.4 to 32.7 +/- 3.2 pg/ml, P<0.001).


CONCLUSIONS
The cumulative hypotensive effect of bosentan suggests that, besides angiotensin II, endothelin-1 is independently involved in the pathophysiology of hypertension, which presents new therapeutic perspectives.
Massart
P E
PE
Department of Physiology, University of Louvain, Brussels, Belgium.
Hodeige
D G
DG
Van Mechelen
H
H
Charlier
A A
AA
Ketelslegers
J M
JM
Heyndrickx
G R
GR
Donckier
J E
JE
D000804:Angiotensin II / Q000502:physiology; D057911:Angiotensin Receptor Antagonists; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects*; D000077300:Bosentan; D004195:Disease Models, Animal; D004285:Dogs; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000502:physiology; D006978:Hypertension, Renovascular / Q000097:blood / Q000503:physiopathology*; D007262:Infusions, Intravenous; D019808:Losartan / Q000008:administration & dosage*; D011863:Radioimmunoassay; D044022:Receptor, Endothelin A; D013449:Sulfonamides / Q000008:administration & dosage*; D014655:Vascular Resistance / Q000187:drug effects
D057911:Angiotensin Receptor Antagonists; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D044022:Receptor, Endothelin A; D013449:Sulfonamides; D000804:Angiotensin II; D019808:Losartan; D000077300:Bosentan