Arterial blood pressure is regulated by the (inter)actions of two hormones: atrial natriuretic peptide (ANP) and angiotensin II (Ang II). ANP, via its cGMP-forming GC-A-receptor, exerts well characterized hypotensive effects, such as vasorelaxation, diuresis, endothelial hyperpermeability, and inhibition of the sympathetic tone. These actions are counter-regulated by Ang II. Arterioles within the microcirculation represent the main peripheral resistance within the circulation. Because nothing is known about the interaction of both hormones at this level, here we performed intravital microscopy studies of the mouse cremaster microcirculation.

Arteriolar diameters were measured before (Ø~15 mm) and during local superfusion of Ang II (10 pM-1 nM), or ANP (1 nM-1 mM). Ang II induced concentration-dependent stable constrictions. Of note, ANP did not affect diameters of unstimulated arterioles, however it completely reversed Ang II - induced vasoconstrictions. Moreover, in Ang II - preconstricted arterioles, ANP provoked a prominent dilatation. Ang II activates smooth muscle contraction through the Gaq-coupled AT₁-receptor. The regulator of G protein signalling RGS2 is a negative regulator of Gaq. Because RGS2 is known to be stimulated by cGMP-dependent protein kinase (cGKI), we hypothesized that ANP counteracts the vasoconstrictory actions of Ang II by activation of RGS2. Indeed, in overexpressing HEK293 cells ANP/cGKI stimulated the expression and membrane translocation of RGS2. Moreover, in RGS2-deleted (RGS2^-/-) mice, ANP failed to reverse the vasoconstrictory actions of Ang II.

We conclude that the RGS2-mediated interplay between ANP and Ang II is critically involved in the regulation of peripheral resistance and blood pressure.Supported by SFB 688.