Administration Of Sodium Nitroprusside Research Articles

Effects of Sodium Nitroprusside on Lipopolysaccharide-Induced Inflammation and Disruption of Blood–Brain Barrier

In various neurodegenerative conditions, inflammation plays a significant role in disrupting the blood–brain barrier (BBB), contributing to disease progression. Nitric oxide (NO) emerges as a central regulator of vascular function, with a dual role in inflammation, acting as both a pro- and anti-inflammatory molecule. This study investigates the effects of the NO donor sodium nitroprusside (SNP) in protecting the BBB from lipopolysaccharide (LPS)-induced inflammation, using bEnd.3 endothelial cells as a model system. Additionally, Raw 264.7 macrophages were employed to assess the effects of LPS and SNP on their adhesion to a bEnd.3 cell monolayer. Our results show that LPS treatment induces oxidative stress, activates the JAK2/STAT3 pathway, and increases pro-inflammatory markers. SNP administration effectively mitigates ROS production and IL-6 expression, suggesting a potential anti-inflammatory role. However, SNP did not significantly alter the adhesion of Raw 264.7 cells to bEnd.3 cells induced by LPS, probably because it did not have any effect on ICAM-1 expression, although it reduced VCAM expression. Moreover, SNP did not prevent BBB disruption. This research provides new insights into the role of NO in BBB disruption induced by inflammation.

Sodium nitroprusside enhances stepping test performance and increases medium spiny neurons responsiveness to cortical inputs in a rat model of Levodopa-induced dyskinesias.

Levodopa (L-DOPA) is the classical gold standard treatment for Parkinson's disease. However, its chronic administration can lead to the development of L-DOPA-induced dyskinesias (LIDs). Dysregulation of the nitric oxide-cyclic guanosine monophosphate pathway in striatal networks has been linked to deficits in corticostriatal transmission in LIDs. This study investigated the effects of the nitric oxide (NO) donor sodium nitroprusside (SNP) on behavioural and electrophysiological outcomes in sham-operated and 6-hydroxydopamine-lesioned rats chronically treated with vehicle or L-DOPA, respectively. In sham-operated animals, systemic administration of SNP increased the spike probability of putative striatal medium spiny neurons (MSNs) in response to electrical stimulation of the primary motor cortex. In 6-hydroxydopamine-lesioned animals, SNP improved the stepping test performance without exacerbating abnormal involuntary movements. Additionally, SNP significantly increased the responsiveness of putative striatal MSNs in the dyskinetic striatum. These findings highlight the critical role of the NO signalling pathway in facilitating the responsiveness of striatal MSNs in both the intact and dyskinetic striata. The study suggests that SNP has the potential to enhance L-DOPA's effects in the stepping test without exacerbating abnormal involuntary movements, thereby offering new possibilities for optimizing Parkinson's disease therapy. In conclusion, this study highlights the involvement of the NO signalling pathway in the pathophysiology of LIDs.

Assessment of the Effects of Sodium Nitroprusside Administered Via Intracranial Subdural Catheters on the Cerebral Blood Flow and Lactate Using Dynamic Susceptibility Contrast Magnetic Resonance Imaging and Proton Magnetic Resonance Spectroscopy in a Pig Cardiac Arrest Model.

Background Cerebral blood flow (CBF) is impaired in the early phase after return of spontaneous circulation. Sodium nitroprusside (SNP) administration via intracranial subdural catheters improves cerebral cortical microcirculation. We determined whether the SNP treatment improves CBF in the subcortical tissue and evaluated the effects of this treatment on cerebral lactate. Methods and Results Sixty minutes after return of spontaneous circulation following 14 minutes of untreated cardiac arrest, 14 minipigs randomly received 4 mg SNP or saline via intracranial subdural catheters. CBF was measured in regions of interest within the cerebrum and thalamus using dynamic susceptibility contrast-magnetic resonance imaging. After return of spontaneous circulation, CBF was expressed as a percentage of the baseline value. In the saline group, the %CBF in the regions of interest within the cerebrum remained at approximately 50% until 3.5 hours after return of spontaneous circulation, whereas %CBF in the thalamic regions of interest recovered to approximately 73% at this time point. The percentages of the baseline values in the cortical gray matter and subcortical white matter were higher in the SNP group (group effect P=0.026 and 0.025, respectively) but not in the thalamus. The cerebral lactate/creatine ratio measured using magnetic resonance spectroscopy increased over time in the saline group but not in the SNP group (group-time interaction P=0.035). The thalamic lactate/creatine ratio was similar in the 2 groups. Conclusions SNP administered via intracranial subdural catheters improved CBF not only in the cortical gray matter but also in the subcortical white matter. The CBF improvement by SNP was accompanied by a decrease in cerebral lactate.

Impact of vericiguat on baroreflex-mediated sympathetic circulatory regulation: An open-loop analysis.

To quantify in vivo the effects of the soluble guanylate cyclase (sGC) stimulator, vericiguat, on autonomic cardiovascular regulation in comparison with the nitric oxide (NO) donor, sodium nitroprusside. In anesthetized Wistar-Kyoto rats, baroreflex-mediated changes in sympathetic nerve activity (SNA), arterial pressure (AP), central venous pressure (CVP), and aortic flow (AoF) were examined before and during the intravenous continuous administration (10 μg·kg-1·min-1) of vericiguat or sodium nitroprusside (n = 8 each). Systemic vascular resistance (SVR) was calculated as SVR = (AP-CVP) / AoF. Neither vericiguat nor sodium nitroprusside affected fitted parameters of the baroreflex-mediated SNA response. Both vericiguat and sodium nitroprusside decreased the AP mainly through their peripheral effects. Vericiguat halved the slope of the SNA-SVR relationship from 0.012 ± 0.002 to 0.006 ± 0.002 mmHg·min·mL-1·%-1 (P = 0.008), whereas sodium nitroprusside caused a near parallel downward shift in the SNA-SVR relationship with a reduction of the SVR intercept from 1.235 ± 0.187 to 0.851 ± 0.123 mmHg·min/mL (P = 0.008). Neither vericiguat nor sodium nitroprusside significantly affected the baroreflex-mediated SNA response. The vasodilative effect of vericiguat became greater toward high levels of SNA and AP, possibly reflecting the increased sGC sensitivity to endogenous NO. By contrast, the effect of sodium nitroprusside was more uniform over the range of SNA. These results help better understand cardiovascular effects of vericiguat.

Intranasal administration of sodium nitroprusside augments antigen-specific mucosal and systemic antibody production in mice

The coronavirus disease 2019, i.e., the COVID-19 pandemic, caused by a highly virulent and transmissible pathogen, has profoundly impacted global society. One approach to combat infectious diseases caused by pathogenic microbes is using mucosal vaccines, which can induce antigen-specific immune responses at both the mucosal and systemic sites. Despite its potential, the clinical implementation of mucosal vaccination is hampered by the lack of safe and effective mucosal adjuvants. Therefore, developing safe and effective mucosal adjuvants is essential for the fight against infectious diseases and the widespread clinical use of mucosal vaccines. In this study, we demonstrated the potent mucosal adjuvant effects of intranasal administration of sodium nitroprusside (SNP), a known nitric oxide (NO) donor, in mice. The results showed that intranasal administration of ovalbumin (OVA) in combination with SNP induced the production of OVA-specific immunoglobulin A in the mucosa and increased serum immunoglobulin G1 levels, indicating a T helper-2 (Th2)-type immune response. However, an analog of SNP, sodium ferrocyanide, which does not generate NO, failed to show any adjuvant effects, suggesting the critical role of NO generation in activating an immune response. In addition, SNPs facilitated the delivery of antigens to the lamina propria, where antigen-presenting cells are located, when co-administered with antigens, and also transiently elicited the expression of interleukin-6, interleukin-1β, granulocyte colony-stimulating factor, C-X-C motif chemokine ligand 1, and C-X-C motif chemokine ligand 2 in nasal tissue. These result suggest that SNP is a dual-functional formulation with antigen delivery capabilities to the lamina propria and the capacity to activate innate immunity. In summary, these results demonstrate the ability of SNP to induce immune responses via an antigen-specific Th2-type response, making it a promising candidate for further development as a mucosal vaccine formulation against infectious diseases.

Alleviation of Hg-, Cr-, Cu-, and Zn-Induced Heavy Metals Stress by Exogenous Sodium Nitroprusside in Rice Plants.

The cultivation of rice is widespread worldwide, but its growth and productivity are hampered by heavy metals stress. However, sodium nitroprusside (SNP), a nitric oxide donor, has been found to be effective for imparting heavy metals stress tolerance to plants. Therefore, the current study evaluated the role of exogenously applied SNP in improving plant growth and development under Hg, Cr, Cu, and Zn stress. For this purpose, heavy metals stress was induced via the application of 1 mM mercury (Hg), chromium (Cr), copper (Cu), and zinc (Zn). To reverse the toxic effects of heavy metals stress, 0.1 mM SNP was administrated via the root zone. The results revealed that the said heavy metals significantly reduced the chlorophyll contents (SPAD), chlorophyll a and b, and protein contents. However, SNP treatment significantly reduced the toxic effects of the said heavy metals on chlorophyll (SPAD), chlorophyll a and b, and protein contents. In addition, the results also revealed that heavy metals significantly increased the production of superoxide anion (SOA), hydrogen peroxide (H2O2), malondialdehyde (MDA), and electrolyte leakage (EL). However, SNP administration significantly reduced the production of SOA, H2O2, MDA, and EL in response to the said heavy metals. Furthermore, to cope with the said heavy metals stress, SNP administration significantly enhanced the activities of superoxide dismutase (SOD), catalase (CAT), peroxidase (POD), and polyphenol peroxidase (PPO). Furthermore, in response to the said heavy metals, SNP application also upregulated the transcript accumulation of OsPCS1, OsPCS2, OsMTP1, OsMTP5, OsMT-I-1a, and OsMT-I-1b. Therefore, SNP can be used as a regulator to improve the heavy metals tolerance of rice in heavy-metals-affected areas.

Effects of low doses of different nitric oxide (NO) donors in rat models of obsessive-compulsive disorder (OCD) and posttraumatic stress disorder (PTSD)

Several lines of evidence suggest that the intra- and inter-cellular messenger nitric oxide (NO) is critically involved in anxiety. Contrasting findings are reported, however, regarding the effects of NO donors in preclinical models of anxiety. Previous research has shown that challenge with a low dose range of the NO donors sodium nitroprusside (SNP) and molsidomine induce anti-anxiety-like effects in rodents. There is poor information concerning the effects of these NO donors on preclinical models mimicking the obsessive-compulsive disorder (OCD) and the post-traumatic stress disorder (PTSD). The present research was designed to investigate this issue in the rat. To this end, the mCPP-induced excessive self-grooming and the contextual fear conditioning (CFC) test which are behavioural paradigms resembling OCD and PTSD respectively in rodents were used. Acute administration of SNP (1 mg/kg) and molsidomine (4 mg/kg) attenuated excessive self-grooming induced by the 5-HT2C receptor agonist mCPP (0.6 mg/kg). Further, at the same dosage, both these NO donors reduced freezing behaviour evidenced in the CFC test. The present results suggest that NO donors are efficacious in attenuating abnormal behaviours revealed in animal models of OCD and PTSD which are among the most severe pathologies of anxiety.

Endothelial dysfunction of the mesenteric arteries of rats in the early obesity induced by high-fat diet

Background: Disturbance of the morphological and functional properties of the vascular bed in obesity are a serious clinical problem. Basis to their development is endothelial dysfunction. The developed models of obesity in animals using various diets indicate a change in vascular reactivity, however, questions about the stage at which this occurs and what mechanisms are involved in this process remain open, while they are decisive for choosing the correct tactics for correcting dysfunctions.Aim: The aim of the present study is to determine the changes in acetylcholine (ACh)-induced vasodilation of isolated arteries from rats after six weeks of administration of a high-fat diet (HFD).Materials and methods: The experiments were performed on Sprague-Dawley males, which at the age of 8 weeks were divided into 2 experimental groups that were treated for the next 6 weeks in the following manner: 1 - control) with standard dry food; 2 - a group fed with a HFD, the total amount of fat in which was 50%. At finish of the diet, the degree of obesity, biochemical parameters in the blood, and blood pressure were measured. Intravital microscopy of the rat mesentery with video recording was used to study the reactivity of the vessels. The contractile and relaxant responses of the vessels were determined by changes in their diameter.Results: The rats after treatment with the HFD (n=15) had higher body weight and amount of visceral fat, significantly increased blood triglycerides, moderate increases in glucose level in blood and systolic pressure compared with the control (n=15). Relaxation responses of mesenteric arteries, having a diameter of 140 to 300 μm in PSS, were recorded after precontraction by phenylephrine. A decrease in ACh-induced vasorelaxation was obtained, which manifests itself before the development of significant changes in carbohydrate metabolism. Incubation of drugs with the inhibitor of endothelial NO synthase L-NAME led to a pronounced weakening of relaxation in animals on a standard diet, and had little effect on vasodilation in the arteries of rats with the HFD. Vasodilation induced by the administration of sodium nitroprusside (NO donor) did not differ significantly in control and experimental animals, which indicates that the sensitivity of vascular smooth muscle to NO remained practically unchanged. ACh-induced relaxation of arteries in dietary rats did not change when the cyclooxygenase pathway was blocked by diclofenac.Conclusion: Functional changes in the contractile activity of the mesenteric arteries, manifested in the form of a decrease in ACh-induced vasorelaxation, occur after treatment with the HFD when animals had an early stage of obesity development before the onset of pronounced disorders of carbohydrate metabolism. This decrease is mainly due to the disruption of the NO-dependent mechanism underlying ACh-induced relaxation in the norm.

TMEM16A blockers T16Ainh-A01 and benzbromarone do not modulate the regulation of sweating and cutaneous vasodilatation in humans in vivo.

What is the central question of this study? Do transmembrane member 16A (TMEM16A) blockers modulate the activation of heat loss responses of sweating and cutaneous vasodilatation? What are the main finding and its importance? Relative to the vehicle control site, TMEM16A blockers T16Ainh-A01 and benzbromarone had no effect on sweat rate or cutaneous vascular conductance during whole-body heating inducing a 1.1±0.1°C increase in core temperature above baseline resting levels. These results suggest that TMEM16A blockers T16Ainh-A01 and benzbromarone do not modulate the regulation of sweating and cutaneous vasodilatation during whole-body heat stress. Animal and in vitro studies suggest that transmembrane member 16A (TMEM16A), a Ca2+ -activated Cl- channel, contributes to regulating eccrine sweating. However, direct evidence supporting this possibility in humans is lacking. We assessed the hypothesis that TMEM16A blockers attenuate sweating during whole-body heating in humans. Additionally, we assessed the associated changes in the heat loss response of cutaneous vasodilatation to determine if a functional role of TMEM16A may exist. Twelve young (24±2years) adults (six females) underwent whole-body heating using a water-perfused suit to raise core temperature 1.1±0.1°C above baseline. Sweat rate and cutaneous vascular conductance (normalized to maximal conductance via administration of sodium nitroprusside) were evaluated continuously at four forearm skin sites treated continuously by intradermal microdialysis with (1) lactated Ringer's solution (control), (2) 5% dimethyl sulfoxide (DMSO) serving as a vehicle control, or (3) TMEM16A blockers 1mM T16Ainh-A01 or 2mM benzbromarone dissolved in 5% DMSO solution. All drugs were administered continuously via intradermal microdialysis. Whole-body heating increased core temperature progressively and this was paralleled by an increase in sweat rate and cutaneous vascular conductance at all skin sites. However, sweat rate (all P>0.318) and cutaneous vascular conductance (all P≥0.073) did not differ between the vehicle control site relative to the TMEM16A blocker-treated sites. Collectively, our findings indicate that TMEM16A blockers T16Ainh-A01 and benzbromarone do not modulate the regulation of sweating and cutaneous vasodilatation during whole-body heating in young adults in vivo.

Pregnancy restores altered sympathetic vasomotor modulation and parasympathetic cardiac modulation in hypertensive rats

Hypertension is associated to impaired baroreflex sensitivity (BRS). In spontaneously hypertensive rats (SHR), pregnancy reduces blood pressure, and this effect has been associated to increase nitric oxide (NO) bioavailability. Increased NO bioavailability has been linked to improve BRS in hypertensive animals. Therefore, we hypothesize that pregnancy improves the BRS in SHR. We performed experiments to evaluate the vasomotor and cardiac autonomic modulation, also to evaluate the BRS at baseline conditions (spontaneous) and after phenylephrine (PE) and sodium nitroprusside (SNP) administrations in non-pregnant (NP) and pregnant (P) Wistar rats and SHR. Beat-to-beat time series with systolic arterial pressure values were generated and processed by Fast Fourier Transform (spectral analysis). Next, spectra were integrated into low-frequency (LF) band and had their power taken as an index of sympathetic modulation on arterial pressure. Reduced mean arterial pressure was observed in P-groups when compared to NP matched rats, although we did not observe alterations in heart rate (HR). In SHR-NP, spectral analysis revealed altered cardiovascular autonomic modulation when compared to the other groups. However, in SHR-P the autonomic parameters were similar to those observed in Wistar-NP, suggesting that pregnancy changed autonomic modulation. BRS assessed by means of the sequence method was found similar in P-groups. Pregnancy reduced the BRS during hypotension in Wistar. BRS assessed with PE and SNP administration was found lower in SHR-NP as compared to Wistar-NP, and it was not altered by pregnancy. In conclusion, pregnancy did not improve the BRS in SHR, but normalized altered sympathetic vasomotor modulation in SHR.

Effects of Sodium Nitroprusside Administered Via a Subdural Intracranial Catheter on the Microcirculation, Oxygenation, and Electrocortical Activity of the Cerebral Cortex in a Pig Cardiac Arrest Model.

BackgroundPostischemic cerebral hypoperfusion has been indicated as an important contributing factor to secondary cerebral injury after cardiac arrest. We evaluated the effects of sodium nitroprusside administered via a subdural intracranial catheter on the microcirculation, oxygenation, and electrocortical activity of the cerebral cortex in the early postresuscitation period using a pig model of cardiac arrest.Methods and ResultsTwenty‐nine pigs were resuscitated with closed cardiopulmonary resuscitation after 14 minutes of untreated ventricular fibrillation. Thirty minutes after restoration of spontaneous circulation, 24 pigs randomly received either 4 mg of sodium nitroprusside (IT‐SNP group) or saline placebo (IT‐saline group) via subdural intracranial catheters and were observed for 5 hours. The same dose of sodium nitroprusside was administered intravenously in another 5 pigs. Compared with the IT‐saline group, the IT‐SNP group had larger areas under the curve for tissue oxygen tension and percent changes of arteriole diameter and number of perfused microvessels from baseline (all P<0.05) monitored on the cerebral cortex during the 5‐hour period, without severe hemodynamic instability. This group also showed faster recovery of electrocortical activity measured using amplitude‐integrated electroencephalography. Repeated‐measures analysis of variance revealed significant group–time interactions for these parameters. Intravenously administered sodium nitroprusside caused profound hypotension but did not appear to increase the cerebral parameters.ConclusionsSodium nitroprusside administered via a subdural intracranial catheter increased post–restoration of spontaneous circulation cerebral cortical microcirculation and oxygenation and hastened electrocortical activity recovery in a pig model of cardiac arrest. Further studies are required to determine its impact on the long‐term neurologic outcomes.

Calcium‐activated Chloride Channel TMEM16A/ANO1 Does Not Mediate the Regulation of Sweating and Cutaneous Vasodilation in Humans In Vivo

The regulation of human body temperature during a heat stress is dependent on the activation of the heat loss responses of cutaneous vasodilation and eccrine sweating. While significant advancements have been made in our understanding of the mechanisms governing their regulation, new potential modifiers such as transmembrane member 16A (TMEM16A), a Ca2+‐activated Cl‐ channel also known as anoctamin 1 (ANO1), continue to be identified. In vitro and animal studies suggest a role for TMEM16A in the regulation of sweat secretion and vascular tone. For example, Ca2+ induced Cl‐current was abolished in TMEM16A deficit, but not BEST2 deficit, NCL‐SG3 human eccrine sweat gland cell lines. Further, animal models showed the activation of TMEM16A on vascular smooth muscle cells blunts vasodilation. However, direct evidence supporting a role of TMEM16 in mediating cutaneous vasodilation as well as eccrine sweating in humans in vivo remains to be established. Therefore, we evaluated the hypothesis that TMEM16A mediates the regulation of sweating and cutaneous vasodilation during a whole‐body heat stress in young adults.Twelve young (24 ± 2 years) adults (6 females) underwent a whole‐body heat stress induced by a water‐perfused suit to raise core temperature 1.1±0.1ºC above baseline resting levels. Sweat rate (ventilated capsule) and cutaneous vascular conductance (assessed as skin blood flow/mean arterial pressure and normalised to maximal conductance achieved via simultaneous local skin heating to 44°C and administration of sodium nitroprusside) were assessed at four skin sites on the forearm treated with 1) lactated Ringers (control), 2) 5 % dimethyl sulfoxide serving as a vehicle control, 3) 1 mM T16Ainh‐A01 (a TMEM16A blocker) or 4) 2 mM benzbromarone (another TMEM16A blocker). All drugs were administered continuously via intradermal microdialysis.Sweat rate increased as heating continued at all skin sites (P &lt; 0.001 for a main effect of heating stage). Neither the main effect of treatment site nor the interaction between treatment site and heating stage was significant (both P ≥ 0.318). Cutaneous vascular conductance increased in parallel to elevations in core temperature (P &lt; 0.001 for a main effect of heating stage). Although no main effect of treatment site was observed (P = 0.109), a significant interaction between heating stage and treatment site was measured (P &lt; 0.001). Post‐hoc analysis revealed that cutaneous vascular conductance at the DMSO‐treated site was higher than the control site at baseline (P = 0.047). By contrast, cutaneous vascular conductance at moderate elevations in core temperature (i.e., ≥0.4‐0.8 °C) was greater at the control site relative to the DMSO‐treated site (all P ≤ 0.013). Importantly, no differences were measured in cutaneous vascular conductance between the DMSO‐treated site and TMEM16A blocker‐treated sites (all P ≥ 0.073).Taken together, our findings demonstrate for the first time that TMEM16A does not contribute to the regulation of sweating and cutaneous vasodilation during whole‐body heating in young adults in vivo.

Magnesium and dexmedetomidine combination reduces sodium nitroprusside requirement in laparoscopic pheochromocytoma.

Anesthesia management of pheochromocytoma excision surgery is associated with severe hemodynamic fluctuations. The objective of this study is to compare the number of hypertensive crisis requiring sodium nitroprusside (SNP) administration between the groups treated with magnesium (Mg)-dexmedetomidine (Dex) and conventional group in pheochromocytoma. This retrospective cohort study included patients who underwent pheochromocytoma surgery between 2011 and 2020. Patients were examined into two groups: 1-Conventional group (GC) included patients who were operated between 2011 and 2015 under standard anesthesia care and who did not receive perioperative additional medication. 2- Mg-Dex therapy group (GMD) comprised the patients who were operated between 2015 and 2020 and who had received 300 mg Mg per oral daily 1 week before the surgery and Mg-Dex infusion intraoperatively. Blood pressure, heart rate (HR), and SNP requirement were recorded throughout surgery as well as demographics and operative data. Hypertensive crisis was defined as systolic blood pressure (SBP) >180 mmHg, and tachycardia was defined as HR >110 bpm. A total of 78 patients' data were analyzed from 108 patients' documentary. (38 in GC, 40 in GMD) SNP requirement was significantly higher in GC (39.5%) comparing GMD (7.5%) (p=0.001). SBPs during tumor manipulation period were statistically higher in GC than in GMD at 10th, 15th, 20th, 25th, 30th, and 35th min. HR values were significantly higher in GC compared to GMD at 10th and 15th min of tumor manipulation period (p<0.05). Combination of Mg-Dex seems to be an alternative therapy for reducing vasodilator requirement in perioperative management of pheochromocytoma.

Sodium nitroprusside injection immediately before balloon inflation during percutaneous coronary intervention.

BACKGROUNDNo reflow or slow flow frequently occurs during percutaneous coronary inter-vention (PCI) and it is associated with adverse outcomes. Strategies should be undertaken to prevent its occurrence.AIMTo observe whether conventional target intracoronary administration of sodium nitroprusside immediately before balloon inflation can reduce the incidence of no reflow and slow flow, which are defined as thrombolysis in myocardial infarction flow grade ≤ II during PCI. METHODSA retrospective study was conducted in 740 patients with coronary artery disease admitted to Gansu Provincial Hospital of Traditional Chinese Medicine between January 2016 and October 2020. Among them, 360 patients receiving sodium nitroprusside immediately before balloon inflation during PCI were enrolled in an experimental group between January 2019 and October 2020 and 380 patients receiving sodium nitroprusside after incident no reflow and slow flow during PCI were enrolled in a control group between January 2016 and January 2019. The occurrence of no reflow and slow flow was compared between the two groups and left ventricular end-diastolic diameter (LVEDD) and left ventricular ejection fraction (LVEF) were detected 1 mo after the operation. RESULTSAfter treatment, the proportion of patients with thrombolysis in myocardial infarction flow grades 0 to II was lower in the experimental group than in the control group (P < 0.05). At 1 mo after treatment, LVEDD was lower and LVEF was higher in the experimental group than in the control group (P < 0.05). In terms of incidence of adverse cardiovascular events within 1 mo after treatment, in the experimental group, malignant arrhythmia occurred in three patients, intractable myocardial ischemia in three, congestive heart failure in four, and recurrent myocardial infarction in five; one patient died. In the control group, malignant arrhythmia occurred in eight patients, intractable myocardial ischemia in five, congestive heart failure in seven, and recurrent myocardial infarction in 14; two patients died. The incidence of adverse cardiovascular events was 4.4% in experimental group which was lower than that of the control group at 1 mo after operation (9.5%; P < 0.05). CONCLUSIONAdministration of sodium nitroprusside into target vessels immediately before balloon inflation can significantly reduce the incidence of no reflow and slow flow, improve LVEDD and LVEF, and reduce the incidence of adverse cardio-vascular events in patients treated by PCI. It is worthy of clinical promotion.

Solitary Nitric Oxide Signaling Mediates Mild Stress-Induced Anxiety and Norepinephrine Release in the Bed Nucleus of the Stria Terminalis during Protracted Ethanol Withdrawal.

Ethanol withdrawal (EtOHW) alters the pattern of neurohormonal and behavioral response toward internal and external stimuli, which mediates relapse to alcohol use even after a long period of abstinence. Increased noradrenergic signaling from the nucleus tractus solitarius (NTS) to the bed nucleus of the stria terminalis (BNST) during EtOHW underlies withdrawal-induced anxiety, while nitric oxide synthase (NOS) inhibitors injected into the periaqueductal area attenuate EtOHW-induced anxiety. Therefore, this study investigated the involvement of NOS within the NTS in anxiety and increased norepinephrine (NE) release in the BNST during protracted EtOHW in rats exposed to a mild stress. Rats were intraperitoneally administered 3 g/kg/day EtOH for 21 days followed by 28 days of withdrawal, and on the 28th day of withdrawal, the rats were subjected to restraint stress for 7 minutes. The elevated plus maze test was employed to evaluate anxiety-like behavior in rats, and in vivo microdialysis was used to measure the extracellular NE level in the BNST. In elevated plus maze tests, EtOHW rats but not EtOH-naive rats exhibited anxiety-like behavior when challenged with 7-minute mild restraint stress, which was, respectively, mitigated by prior intra-NTS infusion of the nitric oxide scavenger 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide (carboxy-PTIO), nonselective NOS inhibitor NG-nitro-L-arginine methyl ester (L-NAME), or selective neuronal NOS (nNOS) inhibitor 7-nitroindazole (7-NI). Each of these agents also decreased the plasma corticosterone levels in EtOHW rats. In in vivo microdialysis, prior intra-NTS infusion of carboxy-PTIO, L-NAME, or 7-NI attenuated the mild stress-induced NE release in the BNST of EtOHW rats. Additionally, EtOHW rats showed increased solitary nNOS gene and protein expression. Moreover, the anxiolytic effect of intra-NTS administration of 7-NI was abolished by subsequent intra-NTS administration of sodium nitroprusside. These results suggest that elevation of solitary nitric oxide signaling derived from nNOS mediates stress-precipitated anxiety and norepinephrine release in the BNST during protracted EtOHW.

Cyclic GMP-Dependent Regulation of Vascular Tone and Blood Pressure Involves Cysteine-Rich LIM-Only Protein 4 (CRP4).

The cysteine-rich LIM-only protein 4 (CRP4), a LIM-domain and zinc finger containing adapter protein, has been implicated as a downstream effector of the second messenger 3′,5′-cyclic guanosine monophosphate (cGMP) pathway in multiple cell types, including vascular smooth muscle cells (VSMCs). VSMCs and nitric oxide (NO)-induced cGMP signaling through cGMP-dependent protein kinase type I (cGKI) play fundamental roles in the physiological regulation of vascular tone and arterial blood pressure (BP). However, it remains unclear whether the vasorelaxant actions attributed to the NO/cGMP axis require CRP4. This study uses mice with a targeted deletion of the CRP4 gene (CRP4 KO) to elucidate whether cGMP-elevating agents, which are well known for their vasorelaxant properties, affect vessel tone, and thus, BP through CRP4. Cinaciguat, a NO- and heme-independent activator of the NO-sensitive (soluble) guanylyl cyclase (NO-GC) and NO-releasing agents, relaxed both CRP4-proficient and -deficient aortic ring segments pre-contracted with prostaglandin F2α. However, the magnitude of relaxation was slightly, but significantly, increased in vessels lacking CRP4. Accordingly, CRP4 KO mice presented with hypotonia at baseline, as well as a greater drop in systolic BP in response to the acute administration of cinaciguat, sodium nitroprusside, and carbachol. Mechanistically, loss of CRP4 in VSMCs reduced the Ca2+-sensitivity of the contractile apparatus, possibly involving regulatory proteins, such as myosin phosphatase targeting subunit 1 (MYPT1) and the regulatory light chain of myosin (RLC). In conclusion, the present findings confirm that the adapter protein CRP4 interacts with the NO-GC/cGMP/cGKI pathway in the vasculature. CRP4 seems to be part of a negative feedback loop that eventually fine-tunes the NO-GC/cGMP axis in VSMCs to increase myofilament Ca2+ desensitization and thereby the maximal vasorelaxant effects attained by (selected) cGMP-elevating agents.

NEUROPROTECTIVE EFFECT OF SODIUM NITROPRUSSIDE INTRANASAL ADMINISTRATION ON FUNCTIONAL ACTIVITY OF THE BRAIN AND ANXIETY OF RATS WITH ALCOHOL DEPENDENCE

Introduction. Disturbances of the molecular nitrosergic mechanisms of brain activity regulation underlie the reduction of brain protective functions under alcohol dependence. However, development of pathogenetically substantiated approaches to the correction of nitrogen oxide (NO) imbalance in the structures of the limbico-neocortical system of the brain (LNCSB) remains insufficient. Objective. To study the effect of intranasal sodium nitroprusside (SNP) administration on anxiety, electrical activity of the LNCSB and NO content in the hippocampus, hypothalamus and septum + nucleus аccumbens of rats with alcohol dependence. Materials and methods. The studies were carried out on 50 nonlinear white adult male rats in a chronic experiment in 3 groups: intact rats; rats with alcohol dependence; rats with alcohol dependence and intranasal SNP administration. The model of alcohol dependence was created by voluntary alcohol intake at a dose of 1.25 g/kg body weight of rat for 35 days. SNP was administered intranasal at a dose of 8 μg/kg body weight of the animal. The level of anxiety was determined by means of neuroethological tests: multi-parameter comprehensive assessment of anxiety, «open field» and «tail suspension test». The electrical activity of LNCSB was registered by the stereotactic introduction of electrodes. The concentration of NO was investigated in the hippocampus, hypothalamus, septum + nucleus аccumbens Results. Intranasal administration of SNP to rats with alcohol dependence led to suppression of convulsive and paroxysmal activity, caused by alcoholization and withdrawal of alcohol, on the electroencephalogram of the structures of the LNCSB and increased the absolute power of biopotentials of the delta and theta ranges on the spectrogram of the hippocampus. Reduction of anxiety was found in rats with a high baseline level of anxiety accompanied by recovery of NO level, which was depleted by chronic alcoholization, in the hypothalamus and hippocampus. Conclusions. Intranasal administration of SNP as a NO donor causes anxiolytic effects in the state of alcohol withdrawal depending on the baseline level of anxiety: in rats with the high baseline level of anxiety – reduces this level; in rats with the low baseline level – restrains it at the level of anxiety after alcohol intake. Intranasal administration of SNP to the rats with alcohol withdrawal causes positive changes in the electroencephalogram of the LNCSB, which are manifested in suppression of convulsive and paroxysmal activity and enhancement of brain biopotentials in alpha and delta ranges on spectrogram of hippocampus with sustaining this effect for whole day. Intranasal administration of SNP is a source of short-term supply of NO to brain cells, which leads to the restoration of NO levels in the hypothalamus, hippocampus, septum and nucleus accumbens – structures that are involved in the regulation of emotional motivational behavior. Key words. limbic-neocortical system of the brain, model of alcohol dependence, anxiety, nitric oxide, sodium nitroprusside

A case report on the management of severe vasospasm in subarachnoid hemorrhagic patients using intra-arterial nimodipine, intrathecal sodium nitroprusside and intra-arterial papaverine

Management and prevention of vasospasm in subarachnoid haemorrhage are one of the complex dictums so far. Aneurysmal subarachnoid haemorrhage (aSAH) is the condition in which bleeding occurs in subarachnoid space. Vasospasm is a complex immunologically active phenomenon which requires a multimodality approach in the treatment of established vasospasm. Various treatment strategies for vasospasm and related disabilities include vasodilators such as nimodipine, sodium nitroprusside and papaverine. Intra-arterial nimodipine shows drastic improvement in several patients by resolving and preventing vasospasm. Intra-arterial administration of nimodipine can cause hypotension which can be easily managed. Papaverine is also an efficient drug-producing vasodilatory action on cerebral arteries. Papaverine is considered as the first intraarterial agent to reduce angiographic cerebral vasospasm which has the side effect of elevated intracranial pressure. Besides, the intrathecal administration of sodium nitroprusside has also demonstrated the effect in ischemic vasospasm after subarachnoid haemorrhage. Intraarterial administration of this drug can induce arterial hypotension which is not a recommended method. Vomiting is the main side effect of sodium nitroprusside, which can be managed with antiemetics such as ondansetron. Here we present a case of management of cerebral vasospasm in subarachnoid patients using the combination of these three effective drugs which showed a remarkable improvement in the resolution of aneurysmal vasospasm.

Establishment of a Rapid Lesion-Controllable Retinal Degeneration Monkey Model for Preclinical Stem Cell Therapy.

Background: Retinal degenerative disorders (RDs) are the main cause of blindness without curable treatment. Our previous studies have demonstrated that human-induced pluripotent stem cells can differentiate into retinal organoids with all subtypes of retina, which provides huge promise for treating these diseases. Before these methods can be realized, RD animal models are required to evaluate the safety and efficacy of stem cell therapy and to develop the surgical tools and procedures for cell transplantation in patients. This study involved the development of a monkey model of RD with controllable lesion sites, which can be rapidly prepared for the study of preclinical stem cell therapy among other applications. Methods: Sodium nitroprusside (SNP) in three doses was delivered into the monkey eye by subretinal injection (SI), and normal saline was applied as control. Structural and functional changes of the retinas were evaluated via multimodal imaging techniques and multifocal electroretinography (mfERG) before and after the treatment. Histological examination was performed to identify the target layer of the affected retina. The health status of monkeys was monitored during the experiment. Results: Well-defined lesions with various degrees of retinal degeneration were induced at the posterior pole of retina as early as 7 days after SNP SI. The damage of SNP was dose dependent. In general, 0.05 mM SNP caused mild structural changes in the retina; 0.1 mM SNP led to the loss of outer retinal layers, including the outer plexiform layer (OPL), outer nuclear layer (ONL), and retinal pigment epithelium (RPE); while 0.2 mM SNP impacted the entire layer of the retina and choroid. MfERG showed reduced amplitude in the damaged region. The structural and functional damages were not recovered at 7-month follow-up. Conclusion: A rapidly induced lesion site-controllable retinal degeneration monkey model was established by the subretinal administration of SNP, of which the optimal dose is 0.1 mM. This monkey model mimics the histological changes of advanced RDs and provides a valuable platform for preclinical assessment of stem cell therapy for RDs.

Pulmonary Artery Wedge Pressure Respiratory Variation Increases With Sodium Nitroprusside Vasodilator Challenge

BackgroundThe physiologic factors leading to pulmonary arterial wedge pressure respiratory variation (PAWPvar) are underexplored. We hypothesized that PAWPvar is associated with baseline PAWP and would predict response to sodium nitroprusside (SNP). Methods and ResultsWe performed a retrospective study of right heart catheterization studies in 51 subjects with SNP challenge at our institution from 2012 to 2019. PAWPvar was defined as expiratory minus inspiratory PAWP. Baseline %PAWPvar was inversely correlated with baseline PAWP (R = –0.5). SNP administration led to increased %PAWPvar (+27%, P < .01). Subjects with low baseline PAWPvar (less than the median) had an increase in PAWPvar with SNP (3 ± 4 mm Hg), whereas those with a high baseline PAWPvar (greater than the median) did not (–0.6 ± 4 mm Hg, P = .003). Those who had a greater than the median PAWPvar increase with SNP had greater cardiac output augmentation compared with those who had less than a median increase in PAWPvar (1.7 ± 1.5 L/min vs 0.9 ± 0.7 L/min, P = .02). An increasing PAWPvar after SNP was associated with significant discrepancy in the number of subjects achieving transplant-acceptable pulmonary vascular resistance (<2.5 Wood units) when calculated by expiratory versus mean PAWP (37 vs 27 subjects, 20% discrepancy rate). Subjects with a higher PAWPvar after SNP were more likely to demonstrate discrepant transplant-acceptable pulmonary vascular resistance calculations comparing expiratory versus mean PAWP than those with lower PAWPvar post-SNP (47% vs 13%, odds ratio 5.5, P = .03). ConclusionsOur findings indicate that PAWPvar is a meaningful physiologic parameter that is influenced by the compliance of the left heart/pulmonary vascular system and its relative preload and afterload states.