Reversal of low dose angiotension hypertension by angiotensin receptor antagonists.
During acute angiotension II (Ang II) infusion (200 ng/kg/min i.v.) into anesthetized rats, mean arterial pressure rose from 124 +/- 1 to 154 +/- 2 mm Hg. The peptidic Ang II antagonist saralasin lowered arterial pressure in a dose-dependent manner. The maximal decrease in pressure was similar to that observed after the Ang II infusion was discontinued. The nonpeptide Ang II antagonist, 4'-[( 2-butyl-4-chloro-5-(hydroxymethyl)-1H-imidazole-1-yl] methyl) [1,1'-biphenyl] -2-carboxylic acid (SC-48742), lowered acutely elevated arterial pressure to a level similar to that on discontinuation of the angiotensin infusion. Chronic (8 days) infusion of Ang II (20 ng/kg/min i.v.) increased mean arterial pressure from 116 +/- 3 to 164 +/- 7 mm Hg, which then decreased to 121 +/- 6 mm Hg on termination of the infusion. Saralasin (10 micrograms/kg/min, a maximally effective dose during acute angiotensin infusion) decreased mean arterial pressure from 168 +/- 7 to 141 +/- 3 mm Hg, a pressure significantly higher (p less than 0.05) than the pressure observed after the angiotensin infusion was discontinued. SC-48742 decreased mean arterial pressure from 167 +/- 7 to 127 +/- 3 mm Hg, a pressure not statistically different from the minimum pressure observed after the angiotensin infusion was terminated. The mechanism of blood pressure elevation during acute high dose or chronic low dose Ang II infusion is different, the latter having a significant neural component as measured by the response to trimethaphan. The peptidic antagonist saralasin was fully effective in lowering acute angiotensin hypertension but only partially effective during chronic hypertension.(ABSTRACT TRUNCATED AT 250 WORDS)
Smits
G J
GJ
Cardiovascular Diseases Research, Searle Research and Development, St. Louis, Mo 63167.
Koepke
J P
JP
Blaine
E H
EH
D000704:Analysis of Variance; D000804:Angiotensin II; D057911:Angiotensin Receptor Antagonists; D000818:Animals; D001713:Biphenyl Compounds / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D006973:Hypertension / Q000139:chemically induced* / Q000517:prevention & control; D007093:Imidazoles / Q000494:pharmacology*; D007262:Infusions, Intravenous; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains; D012504:Saralasin / Q000494:pharmacology*
D057911:Angiotensin Receptor Antagonists; D001713:Biphenyl Compounds; D007093:Imidazoles; D000804:Angiotensin II; C064482:EXP7711; D012504:Saralasin