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.

Regulation of plasma vasopressin and renin activity in conscious hindlimb-unloaded rats

“…Vasopressin levels in saline-treated animals were very similar to baseline vasopressin levels reported previously (46,50,56). Figure 2 illustrates the effects of two levels of hypotension due to diazoxide (15 or 25 mg/kg) or control conditions (saline injection) on plasma vasopressin levels in HU or control rats.…”

Peripheral and Central Effects of Melatonin on Blood Pressure Regulation

“…The precise site of this action, however, is still not unequivocally elucidated. Previously, several possible sites for the modulation of central nervous system output by melatonin were suggested [38]: The activity of the SCN might be modulated by melatonin activity [69,88], reducing thusly the sympathetic tone and providing a protective mechanism against excessive sympathetic excitation.In neurons projecting from the SCN to the PVN [70] or in neurons projecting from the caudal ventrolateral medulla (CVLM) to the rostral ventrolateral medulla (RVLM) [89], the GABA-ergic signaling might be potentiated by melatonin [90], either directly or via enhancement of the NO bioavailability [91]. …”

Nitric oxide modulation of ETB receptor-induced vasopressin release by rat and mouse hypothalamo-neurohypophyseal explants

“…Results from in vivo studies are more variable depending upon the use and type of anesthetic, the hydration state of the animal, or whether the nitric oxide donor or NOS inhibitor was injected intravenously or into the cerebral ventricles (11). Notably, pharmacological inhibition of NOS is frequently associated with a concurrent increase in arterial pressure that may suppress AVP release via baroreflex mechanisms, thereby masking an effect by nitric oxide (27,29). Although the mechanism of interaction of ET, AVP, and nitric oxide has been studied in several other tissues (10,19,44), the direct effect of nitric oxide on ET B receptor-induced AVP secretion has not been studied.…”

“…Recent studies indicate that nitric oxide generated by neural-astroglial sources modifies ET signaling within the central nervous system (19,27,42). Immunohistochemical and in situ hybridization studies have demonstrated nitric oxide synthase (NOS), citrulline, and NADPH-diaphorase activity within the hypothalamo-neurohypophyseal system (HNS; 11,39,42).…”

“…All components of the ET system, including both ET-1 and ET-3 isoforms, their respective mRNAs, ET-converting enzyme activity and both ET A and ET B receptor subtypes, exist within nonvascular brain tissues, and specifically in loci involved in vasopressin (AVP) secretion (13,15,17,38,45). Moreover, several studies have implicated ET peptides in the regulation of AVP secretion in vivo (24,27,29,30) and in vitro (23-26, 28, 31, 34).The actions of ET on the vasopressinergic system are complex and depend on the specific ET isoform, as well as the site of action and the receptor subtype involved (26, 41). ET A receptors are located on magnocellular neurons within the supraoptic and paraventricular nucleus and also nonvasopressinergic neurons within the hypothalamus (13, 43).…”