Blockade of the pre- and postjunctional effects of angiotensin in vivo with a non-peptide angiotensin receptor antagonist.
Recent reports indicate that some imidazole-5-acetic acid derivatives are competitive antagonists of angiotensin II receptors. However, to our knowledge, there is no published information regarding: 1) what constant infusion rate of these non-peptide angiotensin receptor blockers is necessary to effectively antagonize angiotensin receptors in vivo, 2) whether imidazole-5-acetic acid derivatives antagonize both prejunctional and postjunctional angiotensin receptors, and 3) whether effective levels of these compounds exert non-specific actions and/or partial agonist activity. To address these issues, either vehicle, 2-butyl-4-chloro-1-(2-nitrobenzyl) imidazole-5-acetic acid (CV-2961; 30 and 100 micrograms/min) or a standard angiotensin receptor blocker, 1Sar8Ile-angiotensin II (100 ng/min), was infused intravenously into captopril-treated rats that were prepared for in situ perfusion of their mesenteric vascular beds. Infusion of CV-2961 for two and one-half hours did not alter arterial blood pressure, mesenteric perfusion pressure, plasma aldosterone level, or mesenteric vascular responses to sympathetic nerve stimulation or exogenous norepinephrine. The higher dose of CV-2961 (100 micrograms/min) completely blocked angiotensin II-induced enhancement of vascular responses to sympathetic nerve stimulation and shifted the angiotensin dose-response curve 10-fold to the right with respect to angiotensin II-induced increases in mesenteric perfusion pressure. The effects of the lower dose of CV-2961 (30 micrograms/min) on these actions of angiotensin II were not statistically significant. 1Sar8Ile-angiotensin II abolished both the prejunctional and postjunctional effects of angiotensin II. We conclude that in intact rats CV-2961, infused at 100 micrograms/min, antagonizes both prejunctional and postjunctional angiotensin II receptors, yet has a somewhat greater effect on the prejunctional actions of angiotensin II. CV-2961 is devoid of partial agonist activity, and no non-specific actions of CV-2961 are evident. Imidazole-5-acetic acid derivatives may find considerable utility as pharmacological probes and as therapeutic agents.
Jackson
E K
EK
Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, Tennessee.
Inagami
T
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D000450:Aldosterone / Q000097:blood; D000804:Angiotensin II / Q000037:antagonists & inhibitors*; D057911:Angiotensin Receptor Antagonists; D000818:Animals; D000959:Antihypertensive Agents / Q000008:administration & dosage / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004558:Electric Stimulation; D007093:Imidazoles / Q000008:administration & dosage / Q000494:pharmacology*; D007262:Infusions, Intravenous; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains; D013152:Splanchnic Circulation / Q000187:drug effects; D014661:Vasoconstriction / Q000187:drug effects
D057911:Angiotensin Receptor Antagonists; D000959:Antihypertensive Agents; D007093:Imidazoles; D000804:Angiotensin II; C058909:S 8308; D000450:Aldosterone