title: Neuronal nitric oxide synthase activity in the paraventricular nucleus buffers central endothelin-1- induced pressor response and vasopressin secretion.
abstract: Endothelin 1 (ET-1) injected into the lateral cerebral ventricle increases sympathetic output, arterial pressure and plasma vasopressin (AVP). These responses are mediated by glutamatergic inputs and inhibited by gamma-amino-butyric acidergic inputs in the paraventricular nucleus (PVN). It has been suggested that nitric oxide enhances these gamma-amino-butyric acidergic inhibitory inputs. The present studies were designed to test the hypothesis that decreasing neuronal nitric oxide synthase (nNOS) activity within the PVN will potentiate ET-1-induced increases in arterial pressure and alter plasma AVP secretion. Male Long Evans rats underwent adenoviral gene transfer of beta-galactosidase, Ad.CMV.beta-gal (6.25 x 10(4) pfu/PVN; control, n = 5) or injection with DNA plasmids encoding dominant-negative forms of nNOS (RSV hemedomain or RSV heme-RedF; mutant, n = 5) having < 8% normal catalytic activity into the PVN bilaterally. Five days post-injection, the baseline mean arterial pressure in conscious rats was similar in both groups: control, 130 +/- 5 mmHg versus mutant, 122 +/- 6 mmHg. The latency of the pressor response observed after lateral cerebral ventricle injection of 10 pmol ET-1 was 4.8 minutes in controls compared with < 1.5 minutes in rats injected with the mutant nNOS (P < 0.05). After ET-1 administration, the average rise in mean arterial pressure was significantly higher in the nNOS mutant group at 1-2 minutes (16.2 +/- 3.5 mmHg versus -0.6 +/- 4.1 mmHg; P < 0.05) as well as 7-10 minutes later (20.2 +/- 5.1 mmHg versus 8 +/- 2.5 mmHg; P < 0.05). Plasma AVP increased from 2.9 +/- 0.7 pg/mL to 11.5 +/- 1.9 pg/mL in controls (P < 0.004) versus 0.3 +/- 0.2 pg/mL to 1.5 +/- 0.9 pg/mL in the mutant group after ET-1. When the residual effect of nitric oxide generated by other nitric oxide synthase isoforms was assessed by injection of 200 microg Nomega-nitro-L-arginine methyl ester bilaterally into the PVN, the mean arterial pressure increased by 12.2 +/- 2.7 mmHg in controls but was almost unchanged in the mutant group (1.8 +/- 2.4 mmHg; P < 0.025 versus control). These results are consistent with the hypothesis that nitric oxide generated by nNOS within the PVN mediates the inhibition of the pressor response to lateral cerebral ventricle ET-1 and that the greater pressor response seen with the dominant-negative nNOS contructs prevents the rise in plasma AVP in baroreflex-intact rats.
authors.affiliation: Department of Medicine, Wayne State University School of Medicine and John D. Dingell VA Medical Center, Detroit, Michigan 48201, USA. nrossi@med.wayne.edu
authors.forename: Noreen F
authors.initials: NF
authors.lastname: Rossi
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Black
authors.forename: Sabine
authors.initials: S
authors.lastname: Telemaque-Potts
authors.forename: Haiping
authors.initials: H
authors.lastname: Chen
mesh_terms: D000818:Animals; D001127:Arginine Vasopressin / Q000097:blood*; D017704:Baroreflex / Q000187:drug effects; D001794:Blood Pressure / Q000187:drug effects; D019332:Endothelin-1 / Q000008:administration & dosage / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006339:Heart Rate; D007276:Injections, Intraventricular; D008297:Male; D009154:Mutation; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D052248:Nitric Oxide Synthase Type I; D010286:Paraventricular Hypothalamic Nucleus / Q000187:drug effects / Q000201:enzymology*; D051381:Rats; D020318:Rats, Long-Evans; D014161:Transduction, Genetic
chemical_list: D019332:Endothelin-1; D004791:Enzyme Inhibitors; D001127:Arginine Vasopressin; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D052248:Nitric Oxide Synthase Type I; C496322:Nos1 protein, rat; D019331:NG-Nitroarginine Methyl Ester