title: Significance of angiotensin type 1 receptor blockade: why are angiotensin II receptor blockers different?
abstract: The angiotensin II receptor blockers (ARBs) are safe and effective agents in the treatment of hypertension, and they have potential in treating other cardiovascular disorders such as heart failure. These drugs share a common mechanism of action: They selectively block the angiotensin type 1 (AT1) receptor. A new ARB, candesartan cilexetil is a prodrug that is converted completely into the active metabolite candesartan during gastrointestinal absorption, whereas losartan is converted partially by hepatic metabolism into the more active compound EXP 3174. Valsartan and irbesartan are active in their own right. These ARBs differ pharmacologically in terms of their affinity for the AT1 receptor, the mechanism by which they block the receptor, and the duration of their receptor-blocking activity. In radioligand-binding studies, candesartan had a slightly higher affinity for the AT1 receptor than the other ARBs. In the rabbit aorta, candesartan blocked angiotensin II-induced contractions in an insurmountable manner, whereas losartan blocked the contractions competitively, and EXP 3174, valsortan and irbesartan blocked the contractions in a manner intermediate between competitive and insurmountable antagonism. The insurmountable antagonism exhibited by candesartan likely reflects its long-lasting blockade of the AT1 receptor due to a slow dissociation rate. This suggests that candesartan will exhibit a longer duration of action than would be predicted simply from its pharmacokinetic elimination half-life. Comparative clinical trials with several ARBs are needed to define the clinical significance of these pharmacologic differences.
authors.affiliation: Department of Pharmacology, Institute for Pharmacology, University of Kiel, Germany.
authors.forename: T
authors.initials: T
authors.lastname: Unger
mesh_terms: D057911:Angiotensin Receptor Antagonists; D000959:Antihypertensive Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use; D001562:Benzimidazoles / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use; D001667:Binding, Competitive / Q000187:drug effects; D001713:Biphenyl Compounds / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D006973:Hypertension / Q000188:drug therapy; D011355:Prodrugs / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D011945:Receptors, Angiotensin / Q000187:drug effects* / Q000378:metabolism; D013777:Tetrazoles; D013997:Time Factors
chemical_list: D057911:Angiotensin Receptor Antagonists; D000959:Antihypertensive Agents; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D011355:Prodrugs; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D011945:Receptors, Angiotensin; D013777:Tetrazoles; C077793:candesartan cilexetil