Neuronal nitric oxide synthase activity in the paraventricular nucleus buffers central endothelin-1-induced pressor response and vasopressin secretion

Noreen F. Rossi, Stephen M. Black, Sabine Telemaque-Potts, Haiping Chen

Research output: Contribution to journalArticle

18 Citations (Scopus)

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 γ-amino-butyric acidergic inputs in the paraventricular nucleus (PVN). It has been suggested that nitric oxide enhances these γ-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 β-galactosidase, Ad.CMV.β-gal (6.25 × 104 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 μg Nω-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 contracts prevents the rise in plasma AVP in baroreflex-intact rats.

Original languageEnglish (US)
JournalJournal of Cardiovascular Pharmacology
Volume44
Issue numberSUPPL. 1
DOIs
StatePublished - Nov 1 2004

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Nitric Oxide Synthase Type I
Paraventricular Hypothalamic Nucleus
Endothelin-1
Vasopressins
Buffers
Arterial Pressure
Cerebral Ventricles
Lateral Ventricles
Nitric Oxide
Injections
Galactosidases
Long Evans Rats
Baroreflex
Contracts
Heme
Nitric Oxide Synthase
Reaction Time
Protein Isoforms
Plasmids
Control Groups

Keywords

  • Arterial baroreflex
  • Endothelin
  • Long Evans rats
  • Nitric oxide
  • Paraventricular nucleus
  • Vasopressin

ASJC Scopus subject areas

  • Pharmacology
  • Cardiology and Cardiovascular Medicine

Cite this

Neuronal nitric oxide synthase activity in the paraventricular nucleus buffers central endothelin-1-induced pressor response and vasopressin secretion. / Rossi, Noreen F.; Black, Stephen M.; Telemaque-Potts, Sabine; Chen, Haiping.

In: Journal of Cardiovascular Pharmacology, Vol. 44, No. SUPPL. 1, 01.11.2004.

Research output: Contribution to journalArticle

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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 γ-amino-butyric acidergic inputs in the paraventricular nucleus (PVN). It has been suggested that nitric oxide enhances these γ-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 β-galactosidase, Ad.CMV.β-gal (6.25 × 104 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 μg Nω-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 contracts prevents the rise in plasma AVP in baroreflex-intact rats.",
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T1 - Neuronal nitric oxide synthase activity in the paraventricular nucleus buffers central endothelin-1-induced pressor response and vasopressin secretion

AU - Rossi, Noreen F.

AU - Black, Stephen M.

AU - Telemaque-Potts, Sabine

AU - Chen, Haiping

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N2 - 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 γ-amino-butyric acidergic inputs in the paraventricular nucleus (PVN). It has been suggested that nitric oxide enhances these γ-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 β-galactosidase, Ad.CMV.β-gal (6.25 × 104 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 μg Nω-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 contracts prevents the rise in plasma AVP in baroreflex-intact rats.

AB - 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 γ-amino-butyric acidergic inputs in the paraventricular nucleus (PVN). It has been suggested that nitric oxide enhances these γ-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 β-galactosidase, Ad.CMV.β-gal (6.25 × 104 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 μg Nω-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 contracts prevents the rise in plasma AVP in baroreflex-intact rats.

KW - Arterial baroreflex

KW - Endothelin

KW - Long Evans rats

KW - Nitric oxide

KW - Paraventricular nucleus

KW - Vasopressin

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