The AT4 receptor agonist [Nle1]-angiotensin IV reduces mechanically induced immediate-early gene expression in the isolated rabbit heart.
Angiotensin II (ANG II), acting principally at the AT1 receptor, modulates mechanically-induced cardiac growth. The ANG II metabolite Angiotensin IV (ANG IV) has been shown to inhibit ANG II-induced mRNA and protein synthesis in chick cardiomyocytes. This effect did not involve the AT1 receptor, but was likely an action at the AT4 receptor. To determine if ANG IV also modulates a mechanically-induced cardiac growth response, we studied the effects of two AT4 receptor ligands, [Nle1]-ANG IV and [divalinal]-ANG IV, on mechanically-induced immediate-early gene expression (c-fos, egr-1, and c-jun) in the buffer perfused (30 degrees C), ejecting, isolated rabbit heart. Mechanical load alone (high systolic pressure and high end-diastolic volume) induced approximately 23-, 49- and 5-fold increases in c-fos, egr-1 and c-jun mRNA (in comparison to control hearts). Perfusion with [Nle1]-ANG IV (10[-10] mol/l) reduced the mechanically-induced expression of c-/fos and egr-1 by 42% and 48%, respectively (P < 0.05). Mechanically-induced c-jun expression was not significantly reduced. Perfusion with [divalinal]-ANG IV (10[-8] mol/l) had no effect on mechanically-induced immediate-early gene expression. We conclude that AT4 receptor agonism influences mechanical immediate-early gene expression, and propose the hypothesis that AT1 and AT4 receptors initiate opposing effects on mechanically-induced immediate-early gene expression in the isolated rabbit left ventricle.
Yang
Q
Q
Department of Veterinary and Comparative Anatomy, Pharmacology and Physiology, Washington State University, Pullman 99164-6520, USA.
Hanesworth
J M
JM
Harding
J W
JW
Slinker
B K
BK
D000804:Angiotensin II / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D057911:Angiotensin Receptor Antagonists; D000818:Animals; D004268:DNA-Binding Proteins / Q000187:drug effects / Q000235:genetics; D015870:Gene Expression / Q000187:drug effects; D017781:Genes, Immediate-Early / Q000187:drug effects*; D016762:Genes, fos / Q000187:drug effects; D016758:Genes, jun / Q000187:drug effects; D006321:Heart / Q000187:drug effects* / Q000502:physiology; D066298:In Vitro Techniques; D008297:Male; D009206:Myocardium / Q000378:metabolism; D011817:Rabbits; D011945:Receptors, Angiotensin / Q000819:agonists; D014157:Transcription Factors / Q000187:drug effects / Q000235:genetics
C090830:AT4 receptor; D057911:Angiotensin Receptor Antagonists; D004268:DNA-Binding Proteins; D011945:Receptors, Angiotensin; D014157:Transcription Factors; C104765:divalinal-angiotensin IV; D000804:Angiotensin II; C012877:angiotensin II, des-Asp(1)-des-Arg(2)-Ile(5)-