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Nitric Oxide, Sepsis and the Heart
Published in Malcolm J. Lewis, Ajay M. Shah, Endothelial Modulation of Cardiac Function, 2020
Louis H. Alarcon, Timothy R. Billiar, Richard L. Simmons
Literature is beginning to accumulate that contradicts a cardiac depressive role of NO. Using a simple model of isolated rat and cat papillary muscles, no negative inotropic effect was seen at physiologic concentrations of exogenous NO (1 nmol/L-100 μmol/L) using NO donors (such as S-nitroso-N-acetylpenicillamine [SNAP]). However, NO did exert a negative inotropic effect only in the presence of high levels of norepinephrine (5 μmol/L), and resulted in a decreased contractile force of only 6% (Weyrich et al., 1994). In this model, NO could not explain the degree of cardiac depression seen in sepsis.
Hindbrain Neuroactive Substances Controlling Gastrointestinal Function
Published in T. S. Gaginella, Regulatory Mechanisms — in — Gastrointestinal Function, 2017
Zbigniew K. Krowicki, Pamela J. Hornby
Microinjection of NO-related compounds into the DVC alters gastric motor function, which supports a role of NO in control of gastric relaxation in the DVC.44 A possible site where this effect is mediated is within the subnucleus gelatinosus, a region where NADPH-diaphorase staining is present in processes and fibers and where DMV dendrites synapse with primary efferents. Within the DMV itself, nitric oxide-generating drugs (L-arginine and S-nitroso-N- acetylpenicillamine) were shown to increase the spontaneous firing rate of the motor neurons in a concentration-dependent manner.192 Thus, NO is involved not only as a vagal preganglionic messenger but may also be an important mediator of reflexes involving gastrointestinal relaxation in the DVC.
Integrated physiology of the lower urinary tract
Published in Jacques Corcos, David Ginsberg, Gilles Karsenty, Textbook of the Neurogenic Bladder, 2015
Naoki Yoshimura, Jeong Yun Jeong, Dae Kyung Kim, Michael B. Chancellor
It has been reported that myelinated afferents innervating the urethra could contribute to bladder emptying during the voiding phase. Barrington97,98 reported that urine flow or mechanical stimulation of the urethra with a catheter could excite afferent nerves that, in turn, facilitated reflex bladder contractions in the anesthetized cat (Figure 3.4). He proposed that this facilitatory urethra-to-bladder reflex could promote complete bladder emptying. A study in the anesthetized rat has provided additional support for Barrington’s findings.62 Measurements of reflex bladder contractions under isovolumetric conditions during continuous urethral perfusion (0.075 mL/min) revealed that the frequency of micturition reflexes was significantly reduced when urethral perfusion was stopped or following infusion of 1% lidocaine into the urethra. Intraurethral infusion of NO donors (S-nitroso-N-acetylpenicillamine [SNAP] or nitroprusside, 1–2 mmol) markedly decreased urethral perfusion pressure (≈30%) and decreased the frequency of reflex bladder contractions (45%–75%), but did not change the amplitude of bladder contractions. It was thus concluded that activation of urethral afferents during urethral perfusion could modulate the micturition reflex.
Angiotensin converting enzyme inhibitor potentiates the hypoglycaemic effect of NG-nitro-L-arginine methyl ester (L-NAME) in rats
Published in Archives of Physiology and Biochemistry, 2022
Esther Oluwasola Aluko, Victor Udo Nna, Adesoji Adedipe Fasanmade
The pancreatic functions have been documented to be influenced by NO. Specifically, NO has been documented to be involved in the release of insulin; however, its role in insulin release is controversial. Some studies have reported that it has a stimulatory effect (Schmidt et al. 1992, Spinas et al. 1998, Spinas 1999), others have shown that its effect is inhibitory (Takamura et al. 1998, Broniowska et al. 2014), yet, some studies have suggested non-involvement of NO in the pancreatic insulin release (Jones et al. 1992, Weigert et al.1992). Ozden et al. (2009) reported that NG-nitro-L-arginine methyl ester (L-NAME) co-administered with insulin, reduced blood glucose level in diabetic rats. Similarly, another study reported that NO donor, S-nitroso N-acetylpenicillamine, increased blood glucose level, which was effectively reduced by the administration of L-NAME (Bryan et al. 2011).
The role of platelets, neutrophils and endothelium in COVID-19 infection
Published in Expert Review of Hematology, 2022
E. Falcinelli, E. Petito, P. Gresele
The use of inhaled nitric oxide (NO), due also to its antiviral, anti-inflammatory endothelium-protective and antiplatelet properties [204], is another promising strategy under consideration [205,206]. NO levels and bioavailability are decreased in patients with COVID-19, suggesting that exogenous supplementation with NO might be of benefit, a hypothesis also supported by in vitro data showing that the NO-donor S-nitroso-N-acetylpenicillamine dose dependently inhibited SARS-CoV-2 replication [207]. However, the results of published randomized trials and clinical observations are highly controversial. Small cohort studies have not demonstrated a significant improvement in oxygenation and clinical outcomes with inhaled NO (iNO) therapy [208]. On the other hand, the use of iNO in case series of severe COVID-19 patients treated with invasive mechanical ventilation suggested efficacy in preventing hypoxic respiratory failure [209]. Several large clinical trials registered in clinicaltrials.gov testing NO in COVID-19 infection are underway [210].
Topical drug therapeutics for neuropathic pain
Published in Expert Opinion on Pharmacotherapy, 2018
While the above approach in section 7.2 involves a multimodal targeting of various excitatory and inhibitory targets, recent studies have also shown that synergistic analgesic effects can be produced in animal models of CRPS and NP using combinations of agents that target more specific pathophysiological mechanisms associated with these conditions. Deep tissue and/or endoneurial microvascular dysfunction contributes to the pathophysiology of CRPS and NP [90]. It has recently been shown that alleviating microvascular dysfunction by using topical combinations of nitric oxide donors or α2-adrenergic agonists (which increase thermoregulatory blood flow) with type IV phosphodiesterase (PDE) inhibitors (which increase nutritive blood flow) produces synergistic analgesic effects in animal models of CRPS and NP [91,92]. Thus, topical combinations of α2-adrenergic agonists (clonidine and apraclonidine) or NO donors (linsidomine, S-nitroso-N-acetylpenicillamine) with PDE inhibitors (pentoxifylline and lisofylline) produce analgesic effects that are much greater than the analgesic effects of the individual agents given on their own. Given that the anti-allodynic effects of these treatments are paralleled by their anti-ischemic effects, it suggests their synergistic analgesic effects may depend partly on disease-modifying actions. It has also been recently shown that one such combination clonidine + pentoxifylline produces significantly greater analgesic effects than either of the single agents in a surrogate of NP (postcapsaicin ischemia-induced pain) in healthy human volunteers [93].