Arterial blood pressure and intravascular volume are regulated by the (inter)actions of two humoral systems: cardiac atrial natriuretic peptide (ANP) and the renin-angiotensin (Ang II)-aldosterone system (RAAS). ANP, via its guanylyl cyclase-A (GC-A) receptor, exerts hypotensive/hypovolemic effects, such as vasorelaxation, diuresis, endothelial hyperpermeability, and inhibition of the sympathetic tone. These effects are counter-regulated by the RAAS. In addition, ANP acts as local antihypertrophic and antifibrotic factor. Conversely, many studies showed that Ang II and aldosterone both contribute to pathological cardiac remodeling and endothelial dysfunction. To characterize the role of the cross-talk between the NP/GC-A and RAA systems in hypertensive cardiac remodeling and endothelial dysfunction, here we compared the effects of blockade of the Ang II-AT₁ receptor (by losartan) or the mineralcorticoid receptor (by eplerenone) in mice with either global (GC-A^-/-) or endothelial-restricted deletion of GC-A (EC GC-A KO). Consistent with our previous observations (Sabrane et al., J Clin Invest 2005) GC-A^-/- and (less) EC GC-A KO mice exhibited significant arterial hypertension (tail cuff measurements), hypervolemia (evan's blue dilution method) and cardiac hypertrophy. Eplerenone (100 mg/kg body weight/day during 4 weeks, 8 mice per group) had no effect on hypervolemic hypertension and cardiac enlargement of GC-A^-/- and EC GC-A KO mice. In contrast, losartan (30 mg/kg/day), almost completely reversed systemic arterial hypertension and left ventricular hypertrophy of GC-A^-/- mice. We conclude that Angiotensin II plays a more important role than aldosterone in the pathogenesis of hypervolemic hypertension and cardiac hypertrophy in GC-A gene disrupted mice.

(Supported by SFB 688)