title: Vascular natriuretic peptide receptor-linked particulate guanylate cyclases are modulated by nitric oxide-cyclic GMP signalling.
abstract: (1) The sensitivity of the particulate guanylate cyclase-cyclic guanosine-3',5'-monophosphate (cGMP) system to atrial (ANP) and C-type (CNP) natriuretic peptides was investigated in aortae and mesenteric small arteries from wild-type (WT) and endothelial nitric oxide synthase (eNOS) knockout (KO) mice. (2) ANP and CNP produced concentration-dependent relaxations of mouse aorta that were significantly attenuated by the natriuretic peptide receptor (NPR)-A/B antagonist HS-142-1 (10(-5) M). Both ANP and CNP were more potent in aortae from eNOS KO mice compared to WT. (3) The potency of ANP and CNP in aortae from WT animals was increased in the presence of the NOS inhibitor, N(G)-nitro-L-arginine (3 x 10(-4) M) and the soluble guanylate cyclase inhibitor 1H-[1,2,4]oxadiazolol[4,3,a]quinoxalin-1-one (5 x 10(-6) M). (4) In contrast, the potency of ANP and CNP in aortae from eNOS KO animals was reduced following pretreatment of tissues with supramaximal concentrations of the NO-donor, glyceryl trinitrate (3 x 10(-5) M, 30 min) or ANP (10(-7) M, 30 min). (5) Responses to acetylcholine in aortae from WT mice (dependent on the release of endothelium-derived NO) were significantly reduced following pretreatment of tissues with GTN (3 x 10(-5) M, 30 min) and ANP (10(-7) M, 30 min). (6) CNP and the NO-donor, spermine-NONOate caused concentration-dependent relaxations of mesenteric small arteries from WT animals that were significantly increased in eNOS KO mice compared to WT. ANP was unable to significantly relax mesenteric arteries from WT or eNOS KO animals. (7) In conclusion, both NPR-A- and NPR-B-linked pGC pathways are modulated by NO-cGMP in murine aorta and mesenteric small arteries and crossdesensitisation occurs between NPR subtypes. The biological activity of endothelium-derived NO is also influenced by the ambient concentration of NO and natriuretic peptides. Such an autoregulatory pathway may represent an important physiological homeostatic mechanism and link the paracrine activity of NO and CNP with the endocrine functions of ANP and BNP in the regulation of vascular tone and blood pressure.
authors.affiliation: Wolfson Institute for Biomedical Research, University College London, Cruciform Building, Gower Street, London WC1E 6AE.
authors.forename: Melanie
authors.initials: M
authors.lastname: Madhani
authors.forename: Ramona S
authors.initials: RS
authors.lastname: Scotland
authors.forename: Raymond J
authors.initials: RJ
authors.lastname: MacAllister
authors.forename: Adrian J
authors.initials: AJ
authors.lastname: Hobbs
mesh_terms: D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid / Q000037:antagonists & inhibitors / Q000494:pharmacology; D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects / Q000502:physiology; D009320:Atrial Natriuretic Factor / Q000037:antagonists & inhibitors / Q000494:pharmacology; D006152:Cyclic GMP / Q000378:metabolism / Q000502:physiology*; D004305:Dose-Response Relationship, Drug; D004336:Drug Antagonism; D004357:Drug Synergism; D006162:Guanylate Cyclase / Q000037:antagonists & inhibitors / Q000502:physiology*; D008297:Male; D008638:Mesenteric Arteries / Q000187:drug effects / Q000502:physiology; D051379:Mice; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D009126:Muscle Relaxation / Q000187:drug effects; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D020098:Natriuretic Peptide, C-Type / Q000037:antagonists & inhibitors / Q000494:pharmacology; D009569:Nitric Oxide / Q000502:physiology*; D019001:Nitric Oxide Synthase / Q000502:physiology; D009589:Nitrogen Oxides; D005996:Nitroglycerin / Q000494:pharmacology; D010069:Oxadiazoles / Q000037:antagonists & inhibitors / Q000494:pharmacology; D010656:Phenylephrine / Q000037:antagonists & inhibitors / Q000494:pharmacology; D011134:Polysaccharides / Q000494:pharmacology; D011810:Quinoxalines / Q000037:antagonists & inhibitors / Q000494:pharmacology; D017461:Receptors, Atrial Natriuretic Factor / Q000187:drug effects / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology; D013096:Spermine / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: C095284:1H-(1,2,4)oxadiazolo(4,3-a)quinoxalin-1-one; C072551:HS 142-1; D009589:Nitrogen Oxides; D010069:Oxadiazoles; D011134:Polysaccharides; D011810:Quinoxalines; D020098:Natriuretic Peptide, C-Type; C091861:spermine nitric oxide complex; D010656:Phenylephrine; D013096:Spermine; D009569:Nitric Oxide; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D009320:Atrial Natriuretic Factor; D019001:Nitric Oxide Synthase; D006162:Guanylate Cyclase; D017461:Receptors, Atrial Natriuretic Factor; D005996:Nitroglycerin; D006152:Cyclic GMP; D000109:Acetylcholine; D019331:NG-Nitroarginine Methyl Ester