The AT4 receptor agonist [Nle1]-angiotensin IV reduces mechanically induced immediate-early gene expression in the isolated rabbit heart

Abstract Angiotensin II (ANG II), acting principally at the AT 1 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 AT 1 receptor, but was likely an action at the AT 4 receptor. To determine if ANG IV also modulates a mechanically-induced cardiac growth response, we studied the effects of two AT 4 receptor ligands, [Nle 1 ]-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°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 [Nle 1 ]-ANG IV (10 −10 mol/l) reduced the mechanically-induced expression of c- fos and egr -1 by 42% and 48%, respectively ( P 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 AT 4 receptor agonism influences mechanical immediate-early gene expression, and propose the hypothesis that AT 1 and AT 4 receptors initiate opposing effects on mechanically-induced immediate-early gene expression in the isolated rabbit left ventricle.