Genetic and pharmacological dissection of pathways involved in the angiotensin II-mediated depression of baroreflex function.
Heart failure and hypertension are associated with increases in angiotensin II (ANG II) activity. One brain area where ANG II effects may be particularly important in these situations is the nucleus of the solitary tract (NTS). Located in the dorsomedial medulla, the NTS is the termination site of baroreceptor afferents and is essential for mediating the baroreflex. In hypertensive animals the baroreflex is impaired; this may be reversed by antagonizing ANG II AT1 receptors in the NTS. Recently, we showed that the baroreflex depressant action of ANG II in the NTS is mediated by activation of endothelial nitric oxide synthase (eNOS) and enhanced release of GABA. Using conventional pharmacological tools and a range of adenoviral-mediated expression of dominant negative proteins, we have determined the intracellular pathway(s) in the NTS by which ANG II activates eNOS. Our data indicate that ANG II acting in the NTS depresses the baroreflex via a Gq protein-mediated activation of phospholipase C, which through 1,4,5-inositol triphosphate causes release of calcium from the IP3-sensitive intracellular stores and calcium-calmodulin formation. In contrast, multiple site disruption of a pathway leading to eNOS activation via the serine/threonine kinase Akt was ineffective
Wong
Liang-Fong
LF
University Research Centre for Neuroendocrinology, University of Bristol, Bristol Royal Infirmary, Bristol BS2 8HW, UK.
Polson
Jaimne W
JW
Murphy
David
D
Paton
Julian F R
JF
Kasparov
Sergey
S
D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D017704:Baroreflex / Q000187:drug effects* / Q000502:physiology; D001933:Brain Stem / Q000187:drug effects / Q000502:physiology; D002118:Calcium / Q000378:metabolism; D004963:Estrenes / Q000494:pharmacology; D043802:GTP-Binding Protein alpha Subunits, Gq-G11; D005822:Genetic Vectors / Q000235:genetics; D049452:Green Fluorescent Proteins; D006321:Heart / Q000187:drug effects / Q000294:innervation / Q000502:physiology; D020962:Heterotrimeric GTP-Binding Proteins / Q000235:genetics / Q000502:physiology; D066298:In Vitro Techniques; D008164:Luminescent Proteins / Q000235:genetics / Q000378:metabolism; D008297:Male; D008845:Microinjections; D009154:Mutation; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D010791:Phrenic Nerve / Q000502:physiology; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000502:physiology; D051057:Proto-Oncogene Proteins c-akt; D011760:Pyrrolidinones / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D017552:Solitary Nucleus / Q000378:metabolism; D010738:Type C Phospholipases / Q000037:antagonists & inhibitors; D014662:Vasoconstrictor Agents / Q000494:pharmacology*
D000804:Angiotensin II; D002118:Calcium; D004963:Estrenes; D043802:GTP-Binding Protein alpha Subunits, Gq-G11; D049452:Green Fluorescent Proteins; D020962:Heterotrimeric GTP-Binding Proteins; D008164:Luminescent Proteins; D019869:Phosphatidylinositol 3-Kinases; D010726:Phosphodiesterase Inhibitors; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D011760:Pyrrolidinones; D017382:Reactive Oxygen Species; D010738:Type C Phospholipases; D014662:Vasoconstrictor Agents; C060229:1-(6-((3-methoxyestra-1,3,5(10)-trien-17-yl)amino)hexyl)-1H-pyrrole-2,5-dione; C494920:Akt1 protein, rat