Angiotensin II-stimulated nitric oxide release from porcine pulmonary endothelium is mediated by angiotensin IV

In this study, a nitric oxide (NO) sensor was used to examine the ability o f angiotensin II (AngII), AngIV, and bradykinin (Bk) to stimulate NO releas e from porcine pulmonary artery (PPAE) and porcine aortic endothelial (PAE) cells and to explore the mechanism of the AngII-stimulated NO release. Phy siologic concentrations of AngII, but not Bk, caused release of NO from PPA E cells. In contrast, Bk, but not AngII, stimulated NO release from PAE cel ls. AngII-stimulated NO release from PPAE cells required extracellular L-ar ginine and was inhibited by L-nitro-arginine methyl ester. AT(1) and AT(2) receptor inhibition had no affect on AngII-mediated NO release or activatio n of NO synthase (NOS). AngIV, an AngII metabolite with binding sites that are pharmacologically distinct from the classic AngII receptors, stimulated considerably greater NO release and greater endothelial-type constitutive NOS activity than the same amount of AngII. The AngIV receptor antagonist, divalinal AngIV, blocked both AngII- and AngIV-mediated NO release as well as NOS activation. The results demonstrate that AngIV and the AngIV recepto r are responsible, at least in part, for AngII-stimulated NO release and th e associated endothelium-dependent vasorelaxation. Furthermore, these resul ts suggest that differences exist in both AngII- and Bk-mediated NO release between PPAE and PAE cells, which may reflect important differences in res ponse to these hormones between vascular beds.