[Pathophysiological function of angiotensin II AT1 and AT2 receptors and clinical application of AT1 antagonists].
Angiotensin II (Ang II) receptors are classified into two subtypes, type 1 (ATF-R) and type 2 (AT2-R) by development of non-peptidic antagonists. Classical Ang II function including vasopressor effect, cardiotropic action and aldosterone production is mainly mediated through AT1-R that present in cardiovascular system, adrenal glands and kidneys. AT1-R is abundantly expressed in whole bodies of fetus and its expression is abruptly decreased after birth, and in the adult AT2-R is expressed in brain nuclei, uterus, adrenal medullary glands and ovary. AT1-R and AT2-R are both G-protein coupled receptors and have 46% similarity in amino acid levels with seventh transmembrane conformation. Signal transduction pathway of AT1-R is mainly CA2+ and activation of protein kinase C, while that of AT2-R is still unknown. Clinical application of AT1-R antagonist started and this causes elevation of plasma Ang II levels, which selectively stimulates AT2-R. Thus, one should realize AT2-R-mediated effect in treatment with AT1-R antagonist. We have shown that AT2-R has anti-AT1-R action, such as inhibitory action against AT1-R-mediated positive chronotropic effect or AT1-R-induced proliferative effect, resulting in the protective effects on Ang II-induced cardiovasucular and renal action. Thus, elucidation of AT2-R function will be important in clinical treatment with AT1-R antagonists.
Matsubara
H
H
Mori
Y
Y
Masaki
H
H
Inada
M
M
D000804:Angiotensin II / Q000097:blood; D057911:Angiotensin Receptor Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002216:Captopril / Q000494:pharmacology / Q000627:therapeutic use; D002319:Cardiovascular System / Q000378:metabolism; D002986:Clinical Trials as Topic; D006333:Heart Failure / Q000188:drug therapy; D006801:Humans; D007668:Kidney / Q000378:metabolism; D019808:Losartan / Q000494:pharmacology / Q000627:therapeutic use; D011493:Protein Kinase C / Q000378:metabolism; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D011945:Receptors, Angiotensin / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction
D057911:Angiotensin Receptor Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D011945:Receptors, Angiotensin; D000804:Angiotensin II; D002216:Captopril; D011493:Protein Kinase C; D019808:Losartan; D002118:Calcium