Overexpression of eNOS in the RVLM Causes Hypotension and Bradycardia Via GABA Release

Abstract

In this study, we examine the role of NO located in the rostral ventrolateral medulla (RVLM) in the control of blood pressure and the activity of the sympathetic nervous system. To determine the effect of an increase in NO production in the RVLM on blood pressure in conscious rats, adenovirus vectors encoding either endothelial NO synthase (AdeNOS) or β-galactosidase (Adβgal) were transfected into the bilateral RVLM. The local expression of endothelial NO synthase (eNOS) protein in the RVLM was confirmed by immunohistochemical staining for the eNOS protein and by Western blot analysis. Mean arterial blood pressure (MAP) and heart rate, which were monitored using a radio-telemetry system, were significantly decreased in the AdeNOS-treated group from day 5 to day 10 after the gene transfer. Urinary norepinephrine excretion was decreased on day 7 after the gene transfer in the AdeNOS-treated group. Microinjection of either N G -monomethyl- l -arginine (L-NMMA) or bicuculine, a γ-amino butyric acid (GABA) receptor antagonist, into the RVLM at day 7 after the gene transfer increased MAP to significantly greater levels in the AdeNOS-treated group. However, microinjection of kynurenic acid into the RVLM on day 7 after the gene transfer did not alter MAP levels in either group. GABA and glutamate levels in the RVLM, when measured by in vivo microdialysis, were significantly increased in the AdeNOS-treated group. These results suggest that the increase in NO production caused by the overexpression of eNOS in the bilateral RVLM decreases blood pressure, heart rate, and sympathetic nerve activity in conscious rats. Furthermore, these responses may be mediated by an increased release of GABA in the RVLM.

Changes in Neurons of Medulla Oblongata Nuclei under Conditions of Chronic NO-Synthase Inhibition

“…Similar changes in metric values were noted for the distribution of NO-neurons in rats with elevated blood pressure [1]. The changes observed in the medulla oblongata of experimental rats seem to be determined by the hypertensive effect of L-NAME [12]. It is well known that suppression of nitroxidergic mechanisms activates the sympathetic nervous system and increases blood pressure, while activation of nitroxidergic processes produces an opposite effect [10,12,13].…”

“…The changes observed in the medulla oblongata of experimental rats seem to be determined by the hypertensive effect of L-NAME [12]. It is well known that suppression of nitroxidergic mechanisms activates the sympathetic nervous system and increases blood pressure, while activation of nitroxidergic processes produces an opposite effect [10,12,13]. With increasing the time from the last L-NAME injection, blood pressure gradually returned to normal (over 3-4 weeks) and the differences between the control and experimental groups in most studied metric parameters decreased in all nuclei (Fig.…”

Cardiovascular effects of angiotensin II in the rostral ventrolateral medulla: The push-pull hypothesis

“…In the NTS, the Ang II-induced facilitation of GABA release appears to be mediated by nitric oxide produced via endothelial nitric oxide synthase [39], and so this mechanism could also operate within the RVLM. Indeed, it has been demonstrated that overproduction of endothelial nitric oxide synthase in the RVLM causes a decrease in SNA, via increased release of GABA [40]. As shown in Figure 1, the AT1 receptors that trigger the release of nitric oxide may be located on the endothelial cells of blood vessels.…”

Statins and the autonomic nervous system

“…In animal models of hypertension icv infusion of an NADPH oxidase inhibitor or tempol, a SOD (superoxide dismutase) mimetic given to reduce central ROS production, decreases both RSNA (renal sympathetic nerve activity) and BP (blood pressure) [24,34,46]. Reductions in RSNA with icv tempol involve NO-mediated release of GABA within the RVLM [34,47]. Conversely, reducing NO by icv NOS inhibition using L-NMMA (N G -monomethyl-Larginine) increases sympathetic outflow [34].…”