Angiotensin II stimulates the release of phospholipid-derived second messengers through multiple receptor subtypes in heart cells.
The octapeptide angiotensin II (Ang-II) induces both acute functional changes and longer lasting molecular changes in cultured mammalian heart myocytes, yet the underlying molecular mechanisms are poorly understood. In this study, Ang-II was found to stimulate a sustained release (> 30 min) of arachidonic acid (ARA) from cultured neonatal rat cardiac myocytes, with a half-maximal response observed at 0.1 nM. Mass spectroscopy analysis showed that Ang-II stimulated a specific release equivalent to 104 fmol of ARA/micrograms of protein in 10 min. Only Ang-II type 1 (AT1) receptor-specific antagonists were potent inhibitors of hormone-evoked [3H]inositol phosphate accumulation (DuP 753 IC50 approximately 7 nM compared to CGP 42112A IC50 > 1 microM). In contrast, only AT2 receptor-specific antagonists were potent inhibitors of [3H]ARA release (CGP 42112A IC50 approximately 7 nM, EXP 3880 IC50 approximately 2 nM, and PD 123177 IC50 approximately 10 nM). Further studies with phospholipase inhibitors (p-amylcinnamoylanthranilic acid and U73122) revealed that the production of [3H]-inositol phosphates and [3H]ARA occurs through parallel and independent pathways involving phospholipase C and phospholipase A2, respectively. Ang-II also increased the level of lysophosphatidylcholine by 49%, direct evidence that this peptide activated phospholipase A2. Thus, Ang-II stimulates distinct phospholipases in parallel through AT1 and AT2 receptors. These results reveal coordinate signaling roles for multiple Ang-II receptor subtypes in heart.
Lokuta
A J
AJ
Department of Biological Chemistry, University of Maryland School of Medicine, Baltimore 21201.
Cooper
C
C
Gaa
S T
ST
Wang
H E
HE
Rogers
T B
TB
D000804:Angiotensin II / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D057911:Angiotensin Receptor Antagonists; D000818:Animals; D000831:Animals, Newborn; D001713:Biphenyl Compounds / Q000494:pharmacology; D002478:Cells, Cultured; D002934:Cinnamates / Q000494:pharmacology; D015777:Eicosanoids / Q000378:metabolism*; D006321:Heart / Q000187:drug effects*; D006352:Heart Ventricles; D007093:Imidazoles / Q000494:pharmacology; D007295:Inositol Phosphates / Q000378:metabolism*; D007700:Kinetics; D008244:Lysophosphatidylcholines / Q000378:metabolism*; D009206:Myocardium / Q000378:metabolism*; D009842:Oligopeptides / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011945:Receptors, Angiotensin / Q000502:physiology; D015290:Second Messenger Systems / Q000187:drug effects*; D013777:Tetrazoles / Q000494:pharmacology; D062367:ortho-Aminobenzoates / Q000494:pharmacology
D057911:Angiotensin Receptor Antagonists; D001713:Biphenyl Compounds; D002934:Cinnamates; D015777:Eicosanoids; D007093:Imidazoles; D007295:Inositol Phosphates; D008244:Lysophosphatidylcholines; D009842:Oligopeptides; D011945:Receptors, Angiotensin; D013777:Tetrazoles; D062367:ortho-Aminobenzoates; C085901:4-amylcinnamoylanthranilic acid; D000804:Angiotensin II; C060894:CGP 42112A; C073721:EXP3880