Therapeutic effects of angiotensin (AT1) receptor antagonists: potential contribution of mechanisms other than AT1 receptor blockade.
Blockade of the renin-angiotensin system improves morbidity and mortality of patients with cardiovascular diseases, e.g. arterial hypertension, renal failure, following myocardial infarction and in congestive heart failure. The angiotensin II type 1 (AT(1)) receptor antagonists (angiotensin receptor blockers; ARBs), i.e. losartan, eprosartan, irbesartan and valsartan were developed by computer-based molecule design. Early observations already indicate that the ARBs elicit pleiotropic effects developing anti-aggregatory, anti-inflammatory and anti-mitogenic effects independent from their actions at the AT(1) receptor. Losartan metabolism indicates a number of known active intermediates and pointed to further interactions of these derivatives with other receptors and cellular signaling systems. Here we discuss a compilation of detailed pharmacokinetic and pharmacodynamic data of active metabolites of ARBs indicating their mode of action and suggest novel therapeutic implications. The clinical observations that ARBs elicit potencies in patients with cardiovascular diseases via the regulation of inflammatory, growth and homeostatic factors lead us to focus on specific, reactive metabolites, which hold potential for future indications and possible drug interactions in cardiovascular diseases.
Schmidt
Boris
B
Institute for Organic Chemistry, Technische Universität Darmstadt, Darmstadt, Germany.
Drexler
Helmut
H
Schieffer
Bernhard
B
D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors; D047228:Angiotensin II Type 1 Receptor Blockers / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D002318:Cardiovascular Diseases / Q000188:drug therapy / Q000503:physiopathology; D002986:Clinical Trials as Topic; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D019382:Human Growth Hormone / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D011994:Recombinant Proteins / Q000494:pharmacology / Q000627:therapeutic use; D012084:Renin-Angiotensin System / Q000187:drug effects / Q000502:physiology
D047228:Angiotensin II Type 1 Receptor Blockers; D016861:Cyclooxygenase Inhibitors; D011994:Recombinant Proteins; D019382:Human Growth Hormone; D015105:3',5'-Cyclic-AMP Phosphodiesterases