title: Angiotensin II-Induced Hypertension Is Attenuated by Reduction of Sympathetic Output in NO-Sensitive Guanylyl Cyclase 1 Knockout Mice.
abstract: In the regulation of vascular tone, the dilatory nitric oxide (NO)/cGMP pathway balances vasoconstriction induced by the renin-angiotensin and sympathetic nervous systems. NO-induced cGMP formation is catalyzed by two guanylyl cyclases (GC), NO-sensitive guanylyl cyclase 1 (NO-GC1) and NO-GC2, with indistinguishable enzymatic properties. In vascular smooth muscle cells, NO-GC1 is the major isoform and is responsible for more than 90% of cGMP formation. Despite reduced vasorelaxation, NO-GC1-deficient mice are not hypertensive. Here, the role of NO-GC1 in hypertension provoked by contractile agonists angiotensin II (Ang II) and norepinephrine (NE) was evaluated in NO-GC1-deficient mice. Hypertension induced by chronic Ang II treatment did not differ between wild-type (WT) and NO-GC1 knockout mice (KO). Also, attenuation of NO-dependent aortic relaxation induced by the Ang II treatment was similar in both genotypes and was most probably attributable to an increase of phosphodiesterase 1 expression. Analysis of plasma NE content-known to be influenced by Ang II-revealed lower NE in the NO-GC1 KO under Ang II-treated- and nontreated conditions. The finding indicates reduced sympathetic output and is underlined by the lower heart rate in the NO-GC1 KO. To find out whether the lack of higher blood pressure in the NO-GC1 KO is a result of reduced sympathetic activity counterbalancing the reduced vascular relaxation, mice were challenged with chronic NE application. As the resulting blood pressure was higher in the NO-GC1 KO than in WT, we conclude that the reduced sympathetic activity in the NO-GC1 KO prevents hypertension and postulate a possible sympatho-excitatory action of NO-GC1 counteracting NO-GC1's dilatory effect in the vasculature.
authors.affiliation: Institut für Pharmakologie, Ruhr-Universität Bochum, Bochum, Germany (K.B., M.R., D.K., E.M.) and Klinik für Nephrologie, Universitätsklinikum Düsseldorf, Heinrich-Heine-Universität Düsseldorf, Germany (J.S., S.A.P.).
authors.forename: Kathrin
authors.initials: K
authors.lastname: Broekmans
authors.affiliation: Institut für Pharmakologie, Ruhr-Universität Bochum, Bochum, Germany (K.B., M.R., D.K., E.M.) and Klinik für Nephrologie, Universitätsklinikum Düsseldorf, Heinrich-Heine-Universität Düsseldorf, Germany (J.S., S.A.P.).
authors.forename: Johannes
authors.initials: J
authors.lastname: Stegbauer
authors.affiliation: Institut für Pharmakologie, Ruhr-Universität Bochum, Bochum, Germany (K.B., M.R., D.K., E.M.) and Klinik für Nephrologie, Universitätsklinikum Düsseldorf, Heinrich-Heine-Universität Düsseldorf, Germany (J.S., S.A.P.).
authors.forename: Sebastian A
authors.initials: SA
authors.lastname: Potthoff
authors.affiliation: Institut für Pharmakologie, Ruhr-Universität Bochum, Bochum, Germany (K.B., M.R., D.K., E.M.) and Klinik für Nephrologie, Universitätsklinikum Düsseldorf, Heinrich-Heine-Universität Düsseldorf, Germany (J.S., S.A.P.).
authors.forename: Michael
authors.initials: M
authors.lastname: Russwurm
authors.affiliation: Institut für Pharmakologie, Ruhr-Universität Bochum, Bochum, Germany (K.B., M.R., D.K., E.M.) and Klinik für Nephrologie, Universitätsklinikum Düsseldorf, Heinrich-Heine-Universität Düsseldorf, Germany (J.S., S.A.P.).
authors.forename: Doris
authors.initials: D
authors.lastname: Koesling
authors.affiliation: Institut für Pharmakologie, Ruhr-Universität Bochum, Bochum, Germany (K.B., M.R., D.K., E.M.) and Klinik für Nephrologie, Universitätsklinikum Düsseldorf, Heinrich-Heine-Universität Düsseldorf, Germany (J.S., S.A.P.) mergia@evanthia.de.
authors.forename: Evanthia
authors.initials: E
authors.lastname: Mergia
mesh_terms: D000804:Angiotensin II; D000818:Animals; D001794:Blood Pressure / Q000235:genetics; D006152:Cyclic GMP / Q000378:metabolism; D006162:Guanylate Cyclase / Q000235:genetics / Q000502:physiology*; D006339:Heart Rate / Q000235:genetics; D006973:Hypertension / Q000139:chemically induced* / Q000188:drug therapy* / Q000235:genetics; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D009638:Norepinephrine / Q000494:pharmacology; D010727:Phosphoric Diester Hydrolases / Q000096:biosynthesis; D011956:Receptors, Cell Surface / Q000235:genetics / Q000502:physiology*; D013564:Sympathetic Nervous System / Q000503:physiopathology*; D014662:Vasoconstrictor Agents; D014664:Vasodilation / Q000187:drug effects
chemical_list: D011956:Receptors, Cell Surface; D014662:Vasoconstrictor Agents; C110715:guanylate cyclase 1; D000804:Angiotensin II; D010727:Phosphoric Diester Hydrolases; D006162:Guanylate Cyclase; D006152:Cyclic GMP; D009638:Norepinephrine