Synergistic effects of combined converting enzyme inhibition and angiotensin II antagonism on blood pressure in conscious telemetered spontaneously hypertensive rats.
OBJECTIVE
To investigate the chronic effects of combined administration of an angiotensin II receptor antagonist (valsartan) and an angiotensin converting enzyme inhibitor (benazeprilat) on blood pressure and heart rate in conscious telemetered spontaneously hypertensive rats.


METHODS
Blood pressure and heart rate were monitored (by radiotelemetry) during 2-week infusions of 0.5-10 mg/kg valsartan per day and 0.5-10 mg/kg benazeprilat per day, alone or in combination, into conscious spontaneously hypertensive rats. Also, responses of blood pressure in conscious spontaneously hypertensive rats to exogenous angiotensin I and II were determined.


RESULTS
Synergistic antihypertensive effects were observed when valsartan and benazeprilat were coadministered at submaximal monotherapy doses in the range 0.5-1.5 mg/kg per day. For all combination groups, the area over the curve (mmHg x days) for lowering of blood pressure was significantly greater (synergy) than that predicted from the sum of the monotherapy responses. Combination therapy abrogated pressor responses to angiotensin I more effectively than did comparable doses of the monotherapies.


CONCLUSIONS
These results demonstrate that combination therapy aimed at interrupting operation of the renin-angiotensin system simultaneously at multiple sites can prevent the partial escape which occurs during chronic angiotensin converting enzyme inhibitor monotherapy. Furthermore, multiple-site intervention results in a more efficacious antihypertensive response than that achieved with high doses of the individual monotherapies.
Webb
R L
RL
Metabolic and Cardiovascular Diseases, Pharmaceuticals Division, Novartis Corp., Summit, New Jersey, USA.
Navarrete
A E
AE
Davis
S
S
de Gasparo
M
M
D057911:Angiotensin Receptor Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D001552:Benzazepines / Q000008:administration & dosage / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects; D004195:Disease Models, Animal; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D006339:Heart Rate; D006973:Hypertension / Q000097:blood / Q000188:drug therapy / Q000503:physiopathology*; D008297:Male; D007703:Peptidyl-Dipeptidase A / Q000187:drug effects*; D051381:Rats; D011918:Rats, Inbred SHR; D013686:Telemetry; D013777:Tetrazoles / Q000008:administration & dosage / Q000494:pharmacology*; D016896:Treatment Outcome; D014633:Valine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D000068756:Valsartan
D057911:Angiotensin Receptor Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors; D001552:Benzazepines; D013777:Tetrazoles; D000068756:Valsartan; D007703:Peptidyl-Dipeptidase A; D014633:Valine; C052133:benazeprilat