Central nervous system nitric oxide synthase activity regulates insulin secretion and insulin action.

Shankar, R. Ravi; Zhu, Jin-Su; Ladd, Byron; Henry, David P.; Shen, Hua-Qiong; Baron, Alain

doi:10.1172/jci3030

Cited by 74 publications

(57 citation statements)

References 56 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Intracerebroventricular injection of L-NMMA, at doses that have no effect when given systemically, has been shown to increase sympathetic activity and BP (19,24). The hypotensive effect of the central sympatholytic dexmedetomidine is absent in endothelial nitric oxide synthase (eNOS) knockout mice, indicating that an intact eNOS system within the central nervous system is required for autonomic BP regulation.…”

Section: Discussionmentioning

confidence: 99%

Sympathetic activation and nitric oxide function in early hypertension

Gamboa

Okamoto²,

Diedrich³

et al. 2012

American Journal of Physiology-Heart and Circulatory Physiology

View full text Add to dashboard Cite

The purpose of this study was to determine if tonic restrain of blood pressure by nitric oxide (NO) is impaired early in the development of hypertension. Impaired NO function is thought to contribute to hypertension, but it is not clear if this is explained by direct effects of NO on vascular tone or indirect modulation of sympathetic activity. We determined the blood pressure effect of NO synthase inhibition with N -monomethyl-L-arginine (L-NMMA) during autonomic blockade with trimethaphan to eliminate baroreflex buffering and NO modulation of autonomic tone. In this setting, impaired NO modulation of vascular tone would be reflected as a blunted pressor response to L-NMMA. We enrolled a total of 66 subjects (39 Ϯ 1.3 yr old, 30 females), 20 normotensives, 20 prehypertensives (blood pressure between 120/80 and 140/90 mmHg), 17 hypertensives, and 9 smokers (included as "positive" controls of impaired NO function). Trimethaphan normalized blood pressure in hypertensives, suggesting increased sympathetic tone contributing to hypertension. In contrast, L-NMMA produced similar increases in systolic blood pressure in normal, prehypertensive, and hypertensive subjects (31 Ϯ 2, 32 Ϯ 2, and 30 Ϯ 3 mmHg, respectively), whereas the response of smokers was blunted (16 Ϯ 5 mmHg, P ϭ 0.012). Our results suggest that sympathetic activity plays a role in hypertension. NO tonically restrains blood pressure by ϳ30 mmHg, but we found no evidence of impaired modulation by NO of vascular tone contributing to the early development of hypertension. If NO deficiency contributes to hypertension, it is likely to be through its modulation of the autonomic nervous system, which was excluded in this study.hypertension; nitric oxide; nervous system; autonomic; nervous system; sympathetic; nitric oxide synthase NITRIC OXIDE (NO) is arguably the most important metabolic modulator of blood pressure (BP); our previous studies suggest that NO tonically restrains BP by at least 30 mmHg in healthy young adults (6). Not surprisingly, there has been great interest in determining if impaired NO function plays a role in hypertension. Reduced NO production (5) or bioavailability (1), or impaired NO-mediated vasodilation (17), have been implicated in the development or maintenance of hypertension (2). There is, indeed, significant evidence that NO function is impaired in hypertension, but the precise mechanism underlying this problem is less clear. There are at least two mechanisms by which NO can lower BP. NO, derived from endothelial cells or from nitrergic nerves, tonically produces vasodilatation. NO also interacts with the sympathetic nervous system at multiple levels and, through this interaction, can modulate BP. In particular, several lines of evidence suggest that NO tonically suppresses sympathetic tone (22,31), and impaired NO function could contribute to the sympathetic activation observed in hypertension. Conversely, sympathetic activation can impair NO function (9). It is possible, therefore, that these interactions between NO and the symp...

show abstract

Section: Discussionmentioning

confidence: 99%

Sympathetic activation and nitric oxide function in early hypertension

Gamboa

Okamoto²,

Diedrich³

et al. 2012

American Journal of Physiology-Heart and Circulatory Physiology

View full text Add to dashboard Cite

show abstract

“…In rats, insulin-mediated increase in limb blood flow is blocked by systemically administered NO synthase inhibitors [27,28], as is insulin-mediated capillary recruitment [27,28] and glucose uptake [27,28], although the latter is controversial in humans [24,29,30]. However, since a centrally injected NO synthase inhibitor can mimic the insulin resistance and hypertension seen with systemic NO synthase inhibitors [31], a local mechanism involving endothelial insulin receptors, endothelial NO synthase and NO-dependent vasodilatation is far from clear. In addition, the vascular endothelial insulin receptor knock-out mouse is not insulin resistant [32], unless subjected to low-salt diet.…”

Section: Discussionmentioning

confidence: 99%

Vascular and metabolic effects of methacholine in relation to insulin action in muscle

et al. 2006

View full text Add to dashboard Cite

Aims/hypothesis: Methacholine (MC) is a nitric oxide vasodilator, but unlike other vasodilators, it potentiates insulin-mediated glucose uptake by muscle. The present study aimed to resolve whether this action was the result of a vascular effect of MC leading to increased muscle perfusion or a direct effect of MC on the myocytes. We hypothesise that vascular-mediated insulin-stimulated glucose uptake responses to MC occur at lower doses than direct myocyte MC-mediated increases in glucose uptake. Methods: The vascular and metabolic effects of this vasodilator were examined in rats in vivo using a novel local infusion technique, and in the pump-perfused rat hindlimb under conditions of constant flow. Results: Local infusion of low-dose MC (0.3 μmol/l) into the epigastric artery of one leg (test) in vivo markedly increased femoral blood flow and decreased vascular resistance, without effects in the contra-lateral leg. Capillary recruitment, but not glucose uptake, was increased in the test leg. All increases caused by MC were confined to the test leg and blocked by local infusion into the test leg of N ω -nitro-L-arginine methyl ester (L-NAME), but not by infusion of N ω -nitro-D-arginine methyl ester (D-NAME). In the constant-flow pumpperfused rat hindlimb, infusion of 0.6 μmol/l MC vasodilated the pre-constriction effected by 70 nmol/l noradrenaline or 300 nmol/l serotonin, and this was blocked by 10 μmol/l L-NAME. 2-Deoxyglucose in muscle was increased by 30 μmol/l MC (p<0.05), but was unaffected by 3 μmol/l MC. All increases in 2-deoxyglucose uptake by 30 μmol/l MC were blocked by 10 μmol/l L-NAME. Conclusions/interpretation: MC has dose-dependent effects both on the vasculature and on muscle metabolism. At low dose (0.3-3 μmol/l), MC is a potent vasodilator in muscle, both in vivo and in vitro, without metabolic effects; at higher doses (≥30 μmol/l) MC has a direct metabolic effect leading to increased glucose uptake. Both the vascular and metabolic effects are sensitive to L-NAME. The lowdose enhancement of insulin action in vivo by MC, which has been reported previously, thus seems to be attributable to vascular effects.

show abstract

“…In addition, the overall insulin secretion could be regulated by nerve blockers [76,131] and neurotransmitters such as galanine [134], epinephrine [135,136], GABA [137] dopamine [138], as well as nitric oxide [139], and because overall insulin release is pulsatile, the impact of these agents is probably involved in the regulation of pulses, although they have not been studied. In addition, sensory nerve blocking markedly increases insulin release [140], suggesting an inhibitory role of sensory nerves, and this could explain the loss of auto-feedback inhibition of insulin on insulin release in humans with pancreas transplant [141].…”

Section: Contribution Of Pulsatile Insulin Release To the Overall Insmentioning

confidence: 99%

The in vivo regulation of pulsatile insulin secretion

2002

View full text Add to dashboard Cite

In 1922, Karen Hansen [1] measured two series of blood glucose concentrations and reported oscillations in the peripheral concentrations of this substrate, results which were validated by simultaneous sampling from two sites to exclude the possibility that assay variability was a cause of the observed variations. Furthermore she studied the glucose concentrations in diabetic patients, and described both rapid and slower oscillations [1]. Half a century later the observation of rapid oscillations was shown to correlate with oscillations in the peripheral insulin concentrations [2±6], with glucose concentration increases slightly out of phase with insulin secretion pulses [7]. The pulsatile secretion of insulin was shown to coincide with islet pulsatile release of glucagon [4,6,8,9], and somatostatin [9±11]. A number of studies have reported importance of this release pattern for optimal insulin action [10, 12±21, 21±25], for overall insulin secretion [26±35], and for possible development of disease [36±43]. Studies on pulsatile insulin secretion could therefore be important for appreciating how insulin release is regulated overall and how Diabetologia (2002) 45: 3±20 ReviewsThe in vivo regulation of pulsatile insulin secretion

show abstract

Central nervous system nitric oxide synthase activity regulates insulin secretion and insulin action.

Cited by 74 publications

References 56 publications

Sympathetic activation and nitric oxide function in early hypertension

Sympathetic activation and nitric oxide function in early hypertension

Vascular and metabolic effects of methacholine in relation to insulin action in muscle

The in vivo regulation of pulsatile insulin secretion

Contact Info

Product

Resources

About