title: Vascular endothelium is critically involved in the hypotensive and hypovolemic actions of atrial natriuretic peptide.
abstract: 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 of this 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 endothelium-restricted deletion of the GC-A gene (EC GC-A KO) exhibited significant arterial hypertension and cardiac hypertrophy. Echocardiographic and Doppler flow evaluations together with 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 increases in hematocrit in control but not in EC GC-A KO mice, which indicated that ablation of endothelial GC-A completely prevented the acute contraction of intravascular volume produced by ANP. Furthermore, intravenous ANP acutely enhanced the rate of clearance of radio-iodinated albumin from the circulatory system in control but not in EC GC-A KO mice. We conclude that GC-A-mediated increases in endothelial permeability are critically involved in the hypovolemic, hypotensive actions of ANP.
authors.affiliation: Institute of Pharmacology and Toxicology, University of Münster, Münster, Germany.
authors.forename: Karim
authors.initials: K
authors.lastname: Sabrane
authors.forename: Markus N
authors.initials: MN
authors.lastname: Kruse
authors.forename: Larissa
authors.initials: L
authors.lastname: Fabritz
authors.forename: Bernd
authors.initials: B
authors.lastname: Zetsche
authors.forename: Danuta
authors.initials: D
authors.lastname: Mitko
authors.forename: Boris V
authors.initials: BV
authors.lastname: Skryabin
authors.forename: Melanie
authors.initials: M
authors.lastname: Zwiener
authors.forename: Hideo A
authors.initials: HA
authors.lastname: Baba
authors.forename: Masashi
authors.initials: M
authors.lastname: Yanagisawa
authors.forename: Michaela
authors.initials: M
authors.lastname: Kuhn
mesh_terms: D000818:Animals; D001158:Arteries / Q000378:metabolism / Q000473:pathology; D009320:Atrial Natriuretic Factor / Q000378:metabolism*; D002199:Capillary Permeability / Q000235:genetics; D006332:Cardiomegaly / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D004730:Endothelium, Vascular / Q000378:metabolism* / Q000473:pathology; D006162:Guanylate Cyclase / Q000235:genetics / Q000378:metabolism*; D006400:Hematocrit; D006801:Humans; D007022:Hypotension / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D020896:Hypovolemia / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D019426:Integrases / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000473:pathology; D017461:Receptors, Atrial Natriuretic Factor / Q000235:genetics / Q000378:metabolism*; D014664:Vasodilation / Q000235:genetics; D014764:Viral Proteins / Q000235:genetics
chemical_list: D014764:Viral Proteins; D009320:Atrial Natriuretic Factor; C045073:Cre recombinase; D019426:Integrases; D006162:Guanylate Cyclase; D017461:Receptors, Atrial Natriuretic Factor; C091715:atrial natriuretic factor receptor A