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Nitric oxide synthase inhibition restores orthostatic tolerance in young vasovagal syncope patients.

ABSTRACT: OBJECTIVE:Syncope is sudden transient loss of consciousness and postural tone with spontaneous recovery; the most common form is vasovagal syncope (VVS). We previously demonstrated impaired post-synaptic adrenergic responsiveness in young VVS patients was reversed by blocking nitric oxide synthase (NOS). We hypothesised that nitric oxide may account for reduced orthostatic tolerance in young recurrent VVS patients. METHODS:We recorded haemodynamics in supine VVS and healthy volunteers (aged 15-27 years), challenged with graded lower body negative pressure (LBNP) (-15, -30, -45?mm Hg each for 5?min, then -60?mm Hg for a maximum of 50?min) with and without NOS inhibitor NG-monomethyl-L-arginine acetate (L-NMMA). Saline plus phenylephrine (Saline+PE) was used as volume and pressor control for L-NMMA. RESULTS:Controls endured 25.9±4.0?min of LBNP during Saline+PE compared with 11.6±1.4?min for fainters (p<0.001). After L-NMMA, control subjects endured 24.8±3.2?min compared with 22.6±1.6?min for fainters. Mean arterial pressure decreased more in VVS patients during LBNP with Saline+PE (p<0.001) which was reversed by L-NMMA; cardiac output decreased similarly in controls and VVS patients and was unaffected by L-NMMA. Total peripheral resistance increased for controls but decreased for VVS during Saline+PE (p<0.001) but was similar following L-NMMA. Splanchnic vascular resistance increased during LBNP in controls, but decreased in VVS patients following Saline+PE which L-NMMA restored. CONCLUSIONS:We conclude that arterial vasoconstriction is impaired in young VVS patients, which is corrected by NOS inhibition. The data suggest that both pre- and post-synaptic arterial vasoconstriction may be affected by nitric oxide.

SUBMITTER: Stewart JM

PROVIDER: S-EPMC5819615 | biostudies-literature | 2017 Nov

REPOSITORIES: biostudies-literature

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Nitric oxide synthase inhibition restores orthostatic tolerance in young vasovagal syncope patients.

Stewart Julian M JM Sutton Richard R Kothari Mira L ML Goetz Amanda M AM Visintainer Paul P Medow Marvin Scott MS

Heart (British Cardiac Society) 20170513 21

<h4>Objective</h4>Syncope is sudden transient loss of consciousness and postural tone with spontaneous recovery; the most common form is vasovagal syncope (VVS). We previously demonstrated impaired post-synaptic adrenergic responsiveness in young VVS patients was reversed by blocking nitric oxide synthase (NOS). We hypothesised that nitric oxide may account for reduced orthostatic tolerance in young recurrent VVS patients.<h4>Methods</h4>We recorded haemodynamics in supine VVS and healthy volunt ...[more]

PMID: 28501796

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Project description:Aim: The aim of this study was to assess the effect of home orthostatic training (HOT) on autonomic reflexes in elderly patients with vasovagal syncope (VVS). Methods: Design and Setting: A single-blind randomised control trial was conducted at Eastbourne District General Hospital, East Sussex NHS Trust. Patients: Individuals with recurrent syncope underwent tilt-table testing between August 2007 and October 2009.Those with at least two syncopal episodes and tilt-test proven VVS were recruited. Participants were divided into those aged >65 years (O65) and those aged <65 years (U65). Interventions: Patients in the O65 group were randomised 1:1 to receive active HOT (O65+) or sham HOT (O65-). The U65 group received active HOT. Participants performed HOT/sham HOT and recorded their training and symptoms. Patients had a repeat tilt test at 3 months. Outcome Measures: Time to syncope at repeat tilt-table testing, low-frequency heart rate variability (LF-HRV), high-frequency heart rate variability (HF-HRV), mean upslope baroreflex sensitivity (BRS) and mean downslope BRS were assessed. Results: A total of 106 patients with recurrent syncope underwent tilt-table testing. Of these, 45 consecutive patients (30 in the O65 group and 15 in the U65 group) were recruited. Two, one and three patients withdrew or were lost-to-follow-up in the O65+, O65-, and U65 groups, respectively. Symptomatic benefit occurred in four (31 %) of the O65+, four (29 %) of the O65-, and six (50 %) of the U65. None of the autonomic measures changed significantly in any group. No difference was seen with HF-HRV, LF-HRV mean upslope BRS and mean downslope BRS. Fifty per-cent of the O65+ group stopped training because of back pain. Time constraint (25 %) was the most common reason for cessation in the U65 group. Conclusions: Despite good tilt training compliance, no improvement in autonomic measures in any group was shown. The most common reason for cessation of training was back pain in the elderly groups. This study does not support the use of HOT in elderly patients.

Project description:Nitric oxide synthase (NOS) converts l-arginine into l-citrulline and releases the important signaling molecule nitric oxide (NO). In the cardiovascular system, NO produced by endothelial NOS (eNOS) relaxes smooth muscle which controls vascular tone and blood pressure. Neuronal NOS (nNOS) produces NO in the brain, where it influences a variety of neural functions such as neural transmitter release. NO can also support the immune system, serving as a cytotoxic agent during infections. Even with all of these important functions, NO is a free radical and, when overproduced, it can cause tissue damage. This mechanism can operate in many neurodegenerative diseases, and as a result the development of drugs targeting nNOS is a desirable therapeutic goal. However, the active sites of all three human isoforms are very similar, and designing inhibitors specific for nNOS is a challenging problem. It is critically important, for example, not to inhibit eNOS owing to its central role in controlling blood pressure. In this Account, we summarize our efforts in collaboration with Rick Silverman at Northwestern University to develop drug candidates that specifically target NOS using crystallography, computational chemistry, and organic synthesis. As a result, we have developed aminopyridine compounds that are 3800-fold more selective for nNOS than eNOS, some of which show excellent neuroprotective effects in animal models. Our group has solved approximately 130 NOS-inhibitor crystal structures which have provided the structural basis for our design efforts. Initial crystal structures of nNOS and eNOS bound to selective dipeptide inhibitors showed that a single amino acid difference (Asp in nNOS and Asn in eNOS) results in much tighter binding to nNOS. The NOS active site is open and rigid, which produces few large structural changes when inhibitors bind. However, we have found that relatively small changes in the active site and inhibitor chirality can account for large differences in isoform-selectivity. For example, we expected that the aminopyridine group on our inhibitors would form a hydrogen bond with a conserved Glu inside the NOS active site. Instead, in one group of inhibitors, the aminopyridine group extends outside of the active site where it interacts with a heme propionate. For this orientation to occur, a conserved Tyr side chain must swing out of the way. This unanticipated observation taught us about the importance of inhibitor chirality and active site dynamics. We also successfully used computational methods to gain insights into the contribution of the state of protonation of the inhibitors to their selectivity. Employing the lessons learned from the aminopyridine inhibitors, the Silverman lab designed and synthesized symmetric double-headed inhibitors with an aminopyridine at each end, taking advantage of their ability to make contacts both inside and outside of the active site. Crystal structures provided yet another unexpected surprise. Two of the double-headed inhibitor molecules bound to each enzyme subunit, and one molecule participated in the generation of a novel Zn(2+) site that required some side chains to adopt alternate conformations. Therefore, in addition to achieving our specific goal, the development of nNOS selective compounds, we have learned how subtle differences in dynamics and structure can control protein-ligand interactions and often in unexpected ways.

Project description:BackgroundVasovagal syncope (VVS) significantly reduces quality of life, yet lacks effective medical therapies. Pharmacological norepinephrine transporter (NET) inhibition increases synaptic norepinephrine reuptake, which may be able to prevent hypotension, bradycardia, and syncope.ObjectiveThe objective of this systematic review was to evaluate the ability of 3 NET inhibitors-reboxetine, sibutramine, and atomoxetine-to prevent head-up tilt-induced vasovagal outcomes in healthy participants and patients with VVS.MethodsRelevant studies were identified from Medical Literature Analysis and Retrieval System Online, Excerpta Medica Database, Cochrane Central Register of Controlled Trials, and Cumulative Index to Nursing and Allied Health Literature without language restriction from database inception to August 2019. All randomized controlled trials comparing the benefit of a NET inhibitor vs placebo in adult populations were selected for review and meta-analysis.ResultsFour studies (101 participants) met inclusion criteria. The mean study size was 25 (range 11-56) participants. NET inhibition reduced the likelihood of vasovagal reactions marked by hypotension and bradycardia in healthy participants during head-up tilt testing (relative risk 0.15; 95% confidence interval 0.04-0.52; P = .003). This relative risk reduction also occurred in patients with VVS during head-up tilt when given atomoxetine (relative risk 0.49; 95% confidence interval 0.28-0.86; P = .01). This was achieved through heart rate compensation with NET inhibition toward the end of tilt testing (106 ± 32 beats/min vs 60 ± 22 beats/min; P < .001), which in turn preserved cardiac output and mean arterial pressure (71 ± 20 mm Hg vs 43 ± 13 mm Hg; P < .001) in the absence of significantly increased systemic vascular resistance.ConclusionNET inhibition prevents severe vasovagal reactions and syncope induced by head-up tilt testing in both healthy participants and patients with VVS. Pharmacological NET inhibition is a promising potential treatment of recurrent syncope.

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Nitric oxide synthase inhibition restores orthostatic tolerance in young vasovagal syncope patients.

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Nitric oxide synthase inhibition restores orthostatic tolerance in young vasovagal syncope patients.

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