Endothelium-mediated actions of the ANP/cGMP system

Atrial natriuretic peptide (ANP) via its vasodilating and diuretic effects has an important physiological role in the maintenance of arterial blood pressure and volume. Its guanylyl cyclase-A (GC-A) receptor is highly expressed in vascular endothelium, but the functional relevance is controversial. To dissect the endothelium – mediated actions of ANP in vivo, we inactivated the GC-A gene selectively in endothelial cells by homologous loxP/Tie2-Cre-mediated recombination. Notably, despite full preservation of the direct vasodilating effects of ANP, mice with endothelial-restricted GC-A deletion (EC GC-A KO mice) exhibited significant arterial hypertension and cardiac hypertrophy. Echocardiographic and Doppler flow evaluations demonstrated that cardiac output and stroke volume as well as the mean pressure gradient and maximal flow velocity across the aortic valve were increased in EC GC-A KO as compared to control mice with normal GC-A expression levels. Application of the Evan's Blue dilution technique showed that the total plasma volume of EC GC-A KO mice was increased by 11–13%, even under conditions of normal dietary salt intake. Infusion of ANP caused immediate raises in hematocrit in control but not in EC GC-A KO mice, indicating that ablation of endothelial GC-A completely prevented the acute contraction of intravascular volume by ANP. Furthermore, intravenous ANP acutely enhanced the rate of clearance of radio-iodinated albumin from the circulatory system in control mice but not in EC GC-A KO littermates. We conclude that GC-A – mediated increases in endothelial permeability are critically involved in the hypovolemic, hypotensive actions of ANP.