Characterization of the functional antagonism and antihypertensive activity displayed by a monoclonal antibody to angiotensin II.
In the present study, we have characterized the specificity and potency of KAA8, a monoclonal antibody displaying a high affinity for angiotensin II (AII), as a functional antagonist of AII in vitro and in vivo. In addition, we have studied its antihypertensive effect in the awake renal artery-ligated rat, whose elevated levels of plasma renin activity and sensitivity to captopril and saralasin define it as a renin-angiotensin system-dependent hypertensive model. Our results utilizing isolated rabbit aorta strips and pithed rats suggest that KAA8 is a specific AII functional antagonist because it selectively inhibited the AII response in these models without altering the effects of norepinephrine and vasopressin. In renal artery-ligated rats, KAA8, at 15 mg/kg i.v., decreased mean blood pressure from 148 +/- 3 to 119 +/- 4 mm Hg at 10 min postinjection (n = 9) and greatly inhibited the pressor response to AII but not to vasopressin. In contrast, a control immunoglobulin G1 molecule did not change mean blood pressure or influence the pressor effect of AII in this model. Pretreatment with captopril or saralasin, but not prazosin or hydralazine, blocked the antihypertensive effect of KAA8 in these renal hypertensive rats. These results suggest that the antibody KAA8 displays specific functional AII antagonism and, as such, may represent a specific probe for studying the physiologic roles of AII.
Reilly
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Medical Products Department, E. I. Du Pont de Nemours & Company, Inc.,Wilmington, Delaware.
Wong
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Price
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Timmermans
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D000804:Angiotensin II / Q000037:antagonists & inhibitors / Q000276:immunology*; D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D003655:Decerebrate State; D006973:Hypertension / Q000628:therapy*; D007167:Immunotherapy; D008026:Ligation; D008297:Male; D009638:Norepinephrine / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D012077:Renal Artery; D012083:Renin / Q000097:blood
D000911:Antibodies, Monoclonal; D000804:Angiotensin II; D012083:Renin; D009638:Norepinephrine