Genistein mitigates nitroglycerine-induced migraine: modulation of nitric oxide-mediated vasodilation and oxidative stress.

Migraine is a widespread brain condition described by frequent, recurrent episodes of incapacitating, moderate-to-severe headaches with throbbing pain that are usually one-sided. It is the 2nd most debilitating state lived with disability in terms of years, with a prevalence rate of 15-20%. Significant drops in estrogen levels have been associated with triggering acute migraine attacks in certain cases. Phytoestrogens are plant-derived compounds that resemble estrogen in structure, enabling them to imitate estrogen's functions in the body by attaching to estrogen receptors. Thus, the study was aimed to explore the protective effect of genistein against migraine. Moreover, the role of nitric oxide was also studied in the observed effect of genistein. Nitric oxide (NO) is implicated in migraine pathophysiology due to its role in promoting cerebral vasodilation and modulation of pain perception. Exploring L-NAME, a nitric oxide synthase inhibitor in migraine research helps scientists better understand the role of NO in migraine. Nitroglycerine treatment significantly increased the facial-unilateral head pain and spontaneous pain, as evidenced by the increased number of head scratching and groomings. Nitroglycerine treatment also induced anxiogenic behavior in mice. A significant reduction in the number of entries in the light phase and open arm, respectively. Biochemical analysis indicated a significant increase in inflammatory and oxidative stress in the nitroglycerin group. A significant increase and decrease in brain TBARS and GSH were observed with nitroglycerine treatment, respectively. Moreover, nitroglycerine treatment has uplifted the serum TNF-α level. Genistein (20 mg/kg) significantly mitigated the facial-unilateral head pain, spontaneous pain, photophobia, and anxiety-like behavior induced by nitroglycerine. Biochemical analysis showed that genistein (20 mg/kg) significantly abrogated the nitroglycerine-induced lipid peroxidation and increased serum TNF-α level. Genistein treatment also upregulated the brain GSH level and downregulated the serum TNF-α level. The L-NAME-mediated alleviation of the protective effect of genistein might be attributed to the vasodilatory effect of L-NAME. Conclusively, it can be suggested that genistein might provide relief from migraine pain by inhibiting nitric oxide-mediated vasodilation and oxidative stress.

Comparative effect of deliberate hypotensive anesthesia using nitroglycerine vs. phentolamine on event related potentials and cognitive functions in patients undergoing septoplasty: a randomized controlled trial.

BACKGROUND: Postoperative cognitive dysfunction is a noteworthy complication of deliberate hypotensive anesthesia. The aim of this work was to compare the effect of deliberate hypotensive anesthesia using nitroglycerine versus phentolamine on event-related potentials and cognitive function in patients undergoing septoplasty surgery. METHODS: This prospective randomized controlled trial was conducted on 80 patients indicated for septoplasty under general anesthesia; 40 patients received intra-operative Nitroglycerine and 40 patients received intra-operative Phentolamine. Cognitive assessment (using Paired Associate Learning test (PALT) and Benton Visual Retention test (BVRT)) and P300 recording were done for all included patients pre-operatively and one week postoperatively. RESULTS: The scores of PALT and Benton BVRT significantly declined one week following surgery in both Nitroglycerine and Phentolamine groups. There was no statistically significant difference between Nitroglycerine and Phentolamine groups in the postoperative decline in either PALT or BVRT (P-value = 0.342, 0.662 respectively). The values of P300 latency showed a significant delay one week following surgery in both Nitroglycerine and Phentolamine groups (P-value ≤ 0.001, 0.001), but in Nitroglycerine group, the delay is significantly higher than in Phentolamine group (P-value = 0.003). The values of P300 amplitude significantly decreased one week following surgery in both Nitroglycerine and Phentolamine groups (P-value ≤ 0.001, 0.001), but there was no statistically significant difference between Nitroglycerine and Phentolamine groups (P-value = 0.099). CONCLUSION: Phentolamine is preferred over nitroglycerin in deliberate hypotensive anesthesia because it has less harmful effect on cognitive function than nitroglycerin.

Evaluation of nitric acid donor, transdermal glycerol trinitrate patches for facilitating cervical ripening: a randomised controlled trial.

PURPOSE: To evaluate the efficacy and safety of transdermal glycerol trinitrate skin patches as an additive and effective agent for facilitating cervical ripening for labour induction. METHODS: This was a double-blinded prospective randomised clinical trial carried out in a major obstetric unit in India. Women who planned for labour induction were randomly allocated for induction either by combined application of glycerol trinitrate skin patches [GTN patch] and intracervical dinoprostone gel or by the gel only. Sample randomisation was done using a stratified block randomisation technique with a sealed envelope. The numbers designating the group allocation sequence were concealed from doctors, research staff, and investigators. Six hourly improvements were assessed in the modified Bishop's score, induction-delivery time interval, the need for oxytocin, maternal side effects and foetal outcomes. Data were analysed using SPSS software. RESULTS AND DISCUSSION: Recruitment Bishop scores, parity and gestational age were matched in both cases and the control group. The modified Bishop's score was statistically improved in study groups, as evidenced compositely and irrespective of parity. The two groups appeared to have no significant differences regarding other outcomes. The additional application of the GTN patch seems helpful to accelerate the progress of labour but could not yield any favourable labour outcome. The GTN patch does not impose additional feto-maternal adverse effects apart from increased incidences of headaches.

Long-term vascular dysfunction in Kawasaki disease: systematic review and meta-analyses.

BACKGROUND: Long-term physiological dysfunction in coronary/systemic vasculature may persist in individuals with Kawasaki disease even in the absence of coronary artery abnormalities. We perform a systematic review and meta-analyses of studies assessing long-term vascular function in Kawasaki disease. METHODS: PubMed, Embase, and Web of Science databases were searched for relevant literature published till May 2021. Patients with Kawasaki disease were included as cases and healthy age/sex-matched individuals as controls. Newcastle Ottawa Scale was used to assess the study quality. Outcome measures were differences in markers of vascular function 1 year after diagnosis of Kawasaki disease. Data were analysed using Review Manager software. Comprehensive meta-analysis software was used for meta-regression. To assess the certainty of evidence, GRADE Profiler software was utilised. RESULTS: Of 2280 citations, 49 case-control studies (comprising 2714 cases and 2118 controls) were included for data synthesis. Decreased flow-mediated dilatation [3.83, 95%CI 0.94-6.72] and increased pulse-wave velocity [39.34 cm/sec, 95%CI 20.86-57.83], arterial stiffness [0.35, 95%CI 0.11-0.59], and common carotid artery intima-media thickness were noted in patients with Kawasaki disease. No significant difference was observed for nitroglycerine-mediated dilatation and endothelial peripheral artery tonometry (endo-PAT). Significant inter-study heterogeneity was observed for flow-mediated dilatation, arterial stiffness, carotid artery intima-media thickness, and endo-PAT. The GRADE evidence was of 'very low quality' for all outcome measures except 'moderate quality' for pulse-wave velocity. CONCLUSIONS: Evidence suggests the presence of long-term endothelial dysfunction in patients with Kawasaki disease even in the absence of coronary artery abnormalities. Avoidance of development of other cardiovascular risk factors seems prudent in patients with Kawasaki disease.

Effects of Nitric Oxide on the Activity of P2X and TRPV1 Receptors in Rat Meningeal Afferents of the Trigeminal Nerve.

Nitric oxide is one of the endogenous molecules that play a key role in migraine. However, the interaction between NO and the main players in the nociceptive activity of the meningeal trigeminal afferents-TRPV1 and P2X3 receptors-remains unstudied. In the current project, the effects of acute and chronic NO administration on the activity of TRPV1 and P2X3 receptors in the peripheral afferents were studied using electrophysiological recording of action potentials of the trigeminal nerve in the rat hemiskull preparations. The data obtained indicate that exogenous and endogenous NO increased the activity of the trigeminal nerve independent on the inhibition of the TRPV1 and P2X3 receptors. The activity of the trigeminal nerve triggered by ATP changed neither in acute incubation in the NO donor-sodium nitroprusside (SNP) nor in the chronic nitroglycerine (NG)-induced migraine model. Moreover, the chronic NG administration did not increase in the number of degranulated mast cells in the rat meninges. At the same time, the capsaicin-induced activity of the trigeminal nerve was higher with chronic NO administration or after acute NO application, and these effects were prevented by N-ethylmaleimide. In conclusion, we suggested that NO positively modulates the activity of TRPV1 receptors by S-nitrosylation, which may contribute to the pro-nociceptive action of NO and underlie the sensitization of meningeal afferents in chronic migraine.

Effects of smoking on controlled hypotension with nitroglycerin during ear-nose-throat surgery.

Background and Aim: In this study, the aim was to research the effects of smoking habits on controlled hypotension administered with nitroglycerin during ear-nose-throat surgery. Materials and Methods: This study administered controlled hypotension with nitroglycerin and total intravenous anesthesia to a total of 80 patients undergoing septoplasty operations. The patients were divided into two groups of 40 non-smokers (Group 1) and 40 smokers (Group 2). Intravenous propofol infusion was used for anesthesia maintenance. Nitroglycerin with 0.25-1 µg/kg/min dose was titrated to provide controlled hypotension. During this process, the hemodynamic parameters of patients, total propofol and nitroglycerin amounts used, operation duration, and duration of controlled hypotension were recorded at the end of the operation. At the end of the operation, the surgeon assessed the lack of blood in the surgical field with Fromme Scale. Results: Fromme scale values were significantly higher in Group 2 compared to Group 1. The MAP values at 10, 20, 30 min, and end of operation were lower, while 10- and 20-min heart rate values were higher in Group 2 compared to Group 1. Conclusion: Nitroglycerin, chosen for controlled hypotension to reduce hemorrhage in the surgical field during nasal surgery, was shown to cause more pronounced hypotension and reflex tachycardia due to endothelial dysfunction linked to nicotine in patients who smoke. Despite lower pressure values in the smoking group, the negative effects of nicotine on platelet functions combined with similar effects of nitroglycerin to increase bleeding amounts.

Intracoronary injection of nitroglycerine can prevent unnecessary percutaneous coronary intervention.

BACKGROUND: Despite the recommendation of the current guidelines, intracoronary administration of nitroglycerine during coronary angiography is often neglected. We investigated the effect of intra-coronary nitroglycerin on the relief of coronary artery stenosis in the candidates for percutaneous coronary intervention (PCI). METHODS: We included patients with angina pectoris or myocardial infarction who were candidates for PCI. In the coronary angiography, the culprit vessel involved was evaluated, and bolus nitroglycerin at a dose of 25-200 mcg was injected into the affected coronary artery. A significant change in the percentage of coronary artery stenosis was considered a positive response, and these patients were then compared with patients who did not have a substantial change in the percentage of stenosis at the same time. Univariate analysis and then multivariate logistic regression analysis was performed to determine the predictors of response to intracoronary nitroglycerin. RESULTS: Among 360 patients, 27 (7.5%) responded to nitroglycerine, and 333 (92.5%) were non-responsive. The mean age of patients was 60.2 ± 11.6 years, ranging from 23 to 93 years, and 265 (73.6%) were men. The study groups were not significantly different in the baseline demographic characteristics. The presence of multivessel disease (Odds ratio (OR) = 16.26, 95% confidence interval (CI):2.07-127.6; P = 0.008) and stenosis in the left circumflex artery (OR = 3.62, 95% CI: 1.03-12.70; P = 0.044) were the independent predictors for nonresponse to nitroglycerine, leading to PCI. CONCLUSION: In some cases, especially those without multivessel diseases, intracoronary nitroglycerine administration can efficiently relieve coronary stenosis and prevent unnecessary PCI.

Neonatal ischemic limb lesions: From etiology to topical nitroglycerine. A case series analysis.

Although rare, ischemic lesions in neonates may occur in Neonatal Intensive Care Units (NICUs) secondary to routine procedures and/or medicaments. We present double-center case series, reporting three preterm neonates with ischemic lesions following cardiac arrest and radial blood sampling. The overall outcome after treatment with 2% nitroglycerine (NTG) ointment showed optimal results with no adverse events. The most frequent causes responsible for the onset of such lesions are peripheral arterial catheterization procedures and dopamine extravasation. Our series describe the cardiac arrest as an underestimated cause of onset. Despite the optimal results emerging from the treatment of such lesions with NTG ointment, both in our experience and in the scientific literature, a defined protocol for its use in NICUs is not currently available, hence the need for further studies.

Modulation of Glia Activation by TRPA1 Antagonism in Preclinical Models of Migraine.

Preclinical data point to the contribution of transient receptor potential ankyrin 1 (TRPA1) channels to the complex mechanisms underlying migraine pain. TRPA1 channels are expressed in primary sensory neurons, as well as in glial cells, and they can be activated/sensitized by inflammatory mediators. The aim of this study was to investigate the relationship between TRPA1 channels and glial activation in the modulation of trigeminal hyperalgesia in preclinical models of migraine based on acute and chronic nitroglycerin challenges. Rats were treated with ADM_12 (TRPA1 antagonist) and then underwent an orofacial formalin test to assess trigeminal hyperalgesia. mRNA levels of pro- and anti-inflammatory cytokines, calcitonin gene-related peptide (CGRP) and glia cell activation were evaluated in the Medulla oblongata and in the trigeminal ganglia. In the nitroglycerin-treated rats, ADM_12 showed an antihyperalgesic effect in both acute and chronic models, and it counteracted the changes in CGRP and cytokine gene expression. In the acute nitroglycerin model, ADM_12 reduced nitroglycerin-induced increase in microglial and astroglial activation in trigeminal nucleus caudalis area. In the chronic model, we detected a nitroglycerin-induced activation of satellite glial cells in the trigeminal ganglia that was inhibited by ADM_12. These findings show that TRPA1 antagonism reverts experimentally induced hyperalgesia in acute and chronic models of migraine and prevents multiple changes in inflammatory pathways by modulating glial activation.

Topical nitroglycerin in newborns with ischemic injuries: A systematic review.

BACKGROUND: Arterial catheterization is frequently performed in neonatal intensive care units with an inherent risk of peripheral ischemic injury, especially in preterm infants. The treatment options following vascular damage involve invasive and non-invasive modalities. The primary objective of this systematic review was to evaluate the evidence of the use of topical nitroglycerine (TNG) either alone or as adjunctive therapy. The secondary aim was to develop an approach to the treatment of catheter induced ischemia in infants based on the available evidence. METHODS: A comprehensive search was conducted of available databases for relevant articles that involved the treatment of peripheral tissue ischemia in neonates with the use of TNG. Citations were restricted to human subjects. RESULTS: Six hundred and eighty-nine articles were identified, and twenty-seven case reports and case series were compatible with the inclusion and exclusion criteria. Sixty-eight infants out of the 76 published cases (89%) experienced a favorable outcome and 79% (n = 60) demonstrated complete recovery with the topical application of TNG to the ischemic site. CONCLUSION: The available evidence demonstrates that TNG is effective for the treatment of peripheral ischemia in neonates after standard conservative measures have failed. However, due to the absence of robust evidence for this therapeutic modality, there are no uniform guidelines regarding the frequency, duration, and safety of TNG use. Planning the management of peripheral ischemia in neonates with TNG should be a multidisciplinary decision that includes close surveillance of blood pressure, methemoglobin levels, and follow up cranial ultrasound.

Management of Heart Failure in the Emergency Department Setting: An Evidence-Based Review of the Literature.

BACKGROUND: Acute heart failure (AHF) is a common presentation to the emergency department (ED), with the potential to cause significant morbidity and mortality. It is important to tailor treatments to the appropriate type of heart failure. OBJECTIVES: This review provides an evidence-based summary of the current ED management of acute heart failure. DISCUSSION: Heart failure can present along a spectrum, especially in acute exacerbation. Treatment should focus on the underlying disease process, with guidelines focusing primarily on blood pressure and hemodynamic status. Treatment of patients with mild AHF exacerbations often focuses on intravenous diuretics. Patients with AHF with flash pulmonary edema should receive nitroglycerin and noninvasive positive pressure ventilation, with consideration of an angiotensin-converting enzyme inhibitor, while monitoring for hypotension. Patients with hypotensive AHF should receive emergent specialty consultation and an initial fluid bolus of 250-500 mL, followed by initiation of inotropic agents with or without vasopressors. Dobutamine is the inotrope of choice in these patients, with norepinephrine recommended if blood pressure support is needed. If noninvasive positive pressure ventilation is required, providers should monitor closely for acute decompensation. Mechanical circulatory support devices may be considered as a bridge to further therapeutic intervention. High-output heart failure can be managed acutely with vasoconstricting agents, with focus on treating the underlying etiology. Disposition is not always straightforward, and several risk scores may assist in this decision. CONCLUSION: AHF is a condition that requires rapid assessment and management. Understanding the appropriate management strategy can allow for more targeted treatment and improved outcomes.

Association of Vitamin D Metabolites With Arterial Function in the Hemodialysis Fistula Maturation Study.

BACKGROUND: Disturbances in vitamin D metabolism are common in patients with end-stage renal disease and may contribute to vascular dysfunction. STUDY DESIGN: Cross-sectional. SETTING & PARTICIPANTS: We evaluated 558 of 602 participants at baseline of the Hemodialysis Fistula Maturation (HFM) Study, a 7-center prospective cohort study of a cohort of patients with chronic kidney disease awaiting arteriovenous fistula (AVF) creation surgery. FACTOR: 4 vitamin D metabolites measured with liquid chromatography-tandem mass spectroscopy from samples obtained within 4 weeks prior to AVF surgery. OUTCOMES: Vasodilator functions and measurements of arterial stiffness. MEASUREMENTS: Trained HFM Study personnel measured brachial artery flow-mediated dilation, nitroglycerin-mediated dilation, and carotid-femoral and carotid-radial pulse wave velocities (PWVs) prior to AVF creation. We evaluated associations after basic adjustment for sex, age, and clinical site and more fully adjusted additionally for baseline education, smoking, body mass index, diabetes, dialysis status, and medication use. RESULTS: Mean participant age was 55±13 (SD) years and 65% were receiving maintenance dialysis. None of the vitamin D metabolites were significantly associated with flow-mediated dilation, carotid-femoral PWV, or carotid-radial PWV in basic or fully adjusted analyses. Higher serum concentrations of bioavailable vitamin D and 1,25-dihydroxyvitamin D were associated with 0.62% and 0.58% greater nitroglycerin-mediated dilation values, respectively, in basic models; however, these associations were no longer statistically significant with full adjustment. There were no significant associations of vitamin D metabolites with carotid-femoral or carotid-radial PWV in fully adjusted analyses. LIMITATIONS: Cross-sectional ascertainment of vitamin D metabolites and vascular functions late during the course of kidney disease. CONCLUSIONS: Serum concentrations of vitamin D metabolites are not associated with vasodilator functions or vascular stiffness at baseline in a cohort study of patients with chronic kidney disease awaiting AVF creation surgery. Laboratory measurements of vitamin D metabolites are unlikely to provide useful information regarding vascular functions in this setting.

Effect of Nitroglycerin on the Performance of MR Coronary Angiography.

PURPOSE: To systematically investigate the effect of sublingual glyceryl trinitrate (nitroglycerin=nitro=glyceryl trinitrate=GTN=C3 H5 N3 O9 [NTG]) on the diagnostic performance of MR coronary artery imaging (MRCA) to detect relevant coronary artery disease (CAD). MATERIALS AND METHODS: Thirty-five healthy volunteers and 25 patients with suspected or proven CAD (all in sinus rhythm) underwent MRCA before and after NTG using a contrast-agent free, three-dimensional, navigator-based, steady state free precession acquisition (voxel size 1.0 × 0.7 × 0.7 mm3 ) at 1.5 Tesla. Target parameters were stenosis detection (>50%), visible vessel length (straightened planar reconstruction) and vessel diameter (curved planar reconstruction, measured proximal/medial/distal). In patients, invasive coronary angiography served as reference. RESULTS: NTG led to increase of the coronary diameter both in healthy volunteers (right coronary artery [RCA]: 3.2 to 3.7 mm, P < 0.001; left anterior descending coronary artery [LAD]: 2.9 to 3.4 mm, P = 0.009; left circumflex coronary artery [LCx]: 2.8 to 3.3 mm, P < 0.001) and patients (RCA 3.5 to 4.0 mm, P = 0.01; LAD 3.3 to 3.7 mm, P = 0.008; LCx: 2.9 to 3.3 mm, P = 0.03). Visible vessel length increased after NTG for the LAD (volunteers: 72 to 84 mm, P = 0.03; patients: 56 to 78 mm, P = 0.01) and for LCx (volunteers: 48 to 60 mm, P = 0.02). Sensitivity to detect > 50% stenosis improved after NTG from 88.0 to 96%, specificity from 46.5 to 69.8%, diagnostic accuracy from 61.8 to 79.4% and positive/negative predictive value from 48.9 to 64.9% and 87.0 to 96.8%, respectively. CONCLUSION: Sublingual administration of NTG significantly enhanced the visibility of the coronary arteries and improved the detection of coronary artery stenosis. LEVEL OF EVIDENCE: 2 J. MAGN. RESON. IMAGING 2017;45:1419-1428.

Hemicrania Continua-Like Headache Related to Transdermal Nitroglycerine Therapy.

Several cases of symptomatic hemicrania continua (HC) have been reported. A 66-year-old man, suffering from migraine without aura, presented with a four month history of a new headache fulfilling the ICHD 3beta clinical criteria for HC. HC onset was strictly related to the use of transdermal nitroglycerine patch (TNP). In agreement with the cardiologist, TNP was discontinued and the headache promptly disappeared; symptoms reappeared within 6-12 hours after nitroglycerine reintroduction. After permanent discontinuation of TNP, headache disappeared at one year follow-up. To the best of our knowledge, this is the first report of the occurrence of an HC-like headache related to TNP.

Comparison of Efficacy, Pattern of Response, Occurrence of Arrhythmias, and the Tolerability of Nitroglycerine and Isoprenaline as Provocative Drugs During Head-Up Tilt Test.

BACKGROUND: Various protocols exist for performing head-up tilt test (HUTT). Serious ventricular arrhythmias have been reported during HUTT using Isoprenaline (ISO) provocation and their incidence with sublingual Nitroglycerine provocation is unknown. This study aims to assess the efficacy, pattern of response, tolerability, and frequency of arrhythmias during head-up tilt test with sublingual Nitroglycerine (NTG) provocation compared to ISO) provocation. METHODS: This is a retrospective observational study. RESULT: From 2007 to 2015, a total of 816 patients (68% men, median age 49 IQR 25.75-65 years) underwent head-up tilt testing using sublingual NTG provocation whereas ISO was used in 189 patients (66.1% men, median age 48 IQR 36-60 years). A positive response was more frequently observed in the NTG group than the ISO group (48.4% vs 35.9%, p=0.002), with more frequent type II b (cardio-inhibition with >3sec asystole) and type III (vasodepressor) responses ([15. 9% vs 4.1%, p=0.001] and 0% vs 29.4%, p=0.004) respectively. Bradyarrhythmias occurring always as a part of a positive HUTT response were the commonest arrhythmias (29% in NTG group vs 25.4% in ISO group, p=0.31). Tachyarrhythmias (or premature beats) were more frequent in the ISO group (12.7% vs 7.9%, p=<0.005). The use of NTG was significantly associated with a positive response (OR 1.775, 95% CI 1.269-2.483, p=0.001), whereas the use of ISO predicted the occurrence of premature beats/tachyarrhythmias (OR 3.06, 95% CI 2.195-4.267, p<0.005). Intolerance needing termination of the test was significantly more frequent in the ISO group than NTG group (1.6% vs 0.12%, p= 0.02). CONCLUSION: Head-up tilt test with NTG provocation has a higher yield of a positive response, lower incidence of unwanted arrhythmias and better tolerability compared to ISO. The occurrence of VASIS type II b and type III response was more with Nitroglycerine than Isoprenaline.

Early morphologic and functional changes of atherosclerosis in systemic sclerosis-a systematic review and meta-analysis.

OBJECTIVE: Cardiopulmonary manifestations have an important impact on the life expectancy of SSc patients. Functional and morphological macrovascular changes may appear early before the development of ischaemic symptoms. Several non-invasive methods are used in cardiovascular risk assessment. Heterogeneous data are available regarding these in SSc. We aimed to perform a systematic review and meta-analysis to characterize the importance of atherosclerosis in SSc. METHODS: A systematic literature search was performed to identify controlled studies on carotid intima-media thickness, flow- or nitrate-induced vasodilatation (flow-mediated dilatation, nitroglycerine-mediated dilatation), pulse wave velocity, augmentation index and ankle-brachial pressure index. Outcomes were pooled with the random-effects model. RESULTS: Thirty-five studies comprising a total of 1292 SSc patients qualified. Intima-media thickness, pulse wave velocity and ankle-augmentation index were higher and flow-mediated dilatation lower in SSc patients [standardized mean difference (SMD) 0.65 (95% CI: 0.29, 1.01), 0.62 (95% CI: 0.35, 0.88), 0.96 (95% CI: 0.45, 1.47) and -0.68 (95% CI: -1.39, -0.34), respectively, P < 0.01 for each]. Nitroglycerine-mediated dilatation and ankle-brachial pressure index were lower, but not significantly [SMD: -0.16 (95% CI: -0.50, 0.18) and -0.39 (95% CI: -0.91, 0.13), respectively]. Data showed high to moderate inconsistency and significant heterogeneity. Meta-regression analysis of the SMD and the disease duration found a regression coefficient of 0.086, P = 0.014, confirming that parameters of the included SSc population may have contributed to the heterogeneity. CONCLUSION: Meta-analysis of the published observational studies confirms that abnormalities attributable to macrovascular involvement are significantly more prevalent in SSc patients compared with controls. Considering the increasing importance of cardiovascular disease in SSc, a more widespread use of cardiovascular risk assessment is warranted.

sec-Butylpropylacetamide (SPD) has antimigraine properties.

BACKGROUND: Though migraine is disabling and affects 12%-15% of the population, there are few drugs that have been developed specifically for migraine prevention. Valproic acid (VPA) is a broad-spectrum antiepileptic drug (AED) that is also used for migraine prophylaxis, but its clinical use is limited by its side effect profile. sec-Butylpropylacetamide (SPD) is a novel VPA derivative, designed to be more potent and tolerable than VPA, that has shown efficacy in animal seizure and pain models. METHODS: We evaluated SPD's antimigraine potential in the cortical spreading depression (CSD) and nitroglycerin (NTG) models of migraine. To evaluate SPD's mechanism of action, we performed whole-cell recordings on cultured cortical neurons and neuroblastoma cells. RESULTS: In the CSD model, the SPD-treated group showed a significantly lower median number of CSDs compared to controls. In the NTG-induced mechanical allodynia model, SPD dose-dependently reduced mechanical sensitivity compared to controls. SPD showed both a significant potentiation of GABA-mediated currents and a smaller but significant decrease in NMDA currents in cultured cortical neurons. Kainic acid-evoked currents and voltage-dependent sodium channel currents were not changed by SPD. CONCLUSIONS: These results demonstrate SPD's potential as a promising novel antimigraine compound, and suggest a GABAergic mechanism of action.

Effects of nitroglycerine on coronary flow velocity before and during adenosine provocation.

BACKGROUND: Transthoracic echocardiography-assessed coronary flow velocity reserve (CFVR) evaluates coronary microvascular arterial function. Coronary flow velocity measurements at baseline and during hyperemia are used to calculate CFVR. Adenosine infusion induces hyperemia but it is not known if it causes a maximal response. We hypothesized that pre-treatment with nitroglycerine before adenosine provocation enhances hyperemia. METHODS: Twenty-three healthy study subjects (mean age 27.5 ± 5.5, 35% women) underwent CFVR measurements before and after pretreatment with sublingual nitroglycerine (0.5 mg). Hyperemia was induced by adenosine infusion (140 µg/kg/min). In addition, the effect of nitroglycerin on left main coronary artery diameter was assessed. RESULTS: Pretreatment with nitroglycerine increased median CFVR from 3.6 (range 2.8-4.3) to 5.0 (4.1-6.0), p = 0.002. The increase was caused by a marked reduction in baseline coronary flow velocity 17 (15-24) vs 27 (19-31) cm/s, p < 0.0001) while hyperemic velocity remained unchanged (90 (68-116) vs 93 (75-105) cm/s, p = 0.48). Nitroglycerin significantly dilated the left main coronary artery (from median 3.1 (2.7-3.6) mm to 3.8 (3.1-4.3) mm, p = 0.018). CONCLUSION: Pretreatment with nitroglycerine dilates coronary arteries and increases coronary flow velocity reserve indicating that adenosine alone causes a submaximal hyperemia.

Nitroglycerine, esmolol and dexmedetomidine for induced hypotension during functional endoscopic sinus surgery: A comparative evaluation.

BACKGROUND AND AIM: Induced hypotension limits intra-operative blood loss to provide better visibility of the surgical field and diminishes the incidence of major complications during functional endoscopic sinus surgery (FESS). We aimed at comparing nitroglycerine, esmolol and dexmedetomidine for inducing controlled hypotension in patients undergoing FESS. MATERIAL AND METHODS: One hundred and fifty American Society of Anesthesiologists physical status I or II adult patients undergoing FESS under general anesthesia were randomly allocated to three groups of 50 patients each. Group E received esmolol in a loading and maintenance dose of 1 mg/kg over 1 min and 0.5-1.0 mg/kg/h, respectively. Group D received a loading dose of dexmedetomidine 1 µg/kg over 10 min followed by an infusion 0.5-1.0 µg/kg/h, and group N received nitroglycerine infusion at a dose of 0.5-2 µg/kg/min so as to maintain mean arterial pressure (MAP) between 60 and 70 mmHg in all the groups. The visibility of the surgical field was assessed by surgeon using Fromme and Boezaart scoring system. Hemodynamic variables, total intra-operative fentanyl consumption, emergence time and time to first analgesic request were recorded. Any side-effects were noted. The postoperative sedation was assessed using Ramsay Sedation Score. RESULT: The desired MAP (60-70 mmHg) could be achieved in all the three study groups albeit with titration of study drugs during intra-operative period. No significant intergroup difference was observed in Fromme's score during the intra-operative period. The mean total dose of fentanyl (µg/kg) used was found to be significantly lower in group D compared to groups E and N (1.2 ± 0.75 vs. 3.6 ± 1.3 and 2.9 ± 1.1 respectively). The mean heart rate was significantly lower in group D compared to groups E and N at all times of measurement (P < 0.05). The MAP was found to be significantly lower in group D compared to groups E and N after infusion of study drugs, after induction, just after intubation and 5 min after intubation (P < 0.05). The Ramsay Sedation Scores were significantly higher in group D (score 3 in 46%) when compared to group E (score 2 in 50%) and group N (score 2 in 54%) (P < 0.001). The emergence time was significantly lower in group E and group N compared to group D. Time to first analgesic request was significantly longer in group D. CONCLUSION: Dexmedetomidine and esmolol provided better hemodynamic stability and operative field visibility compared to nitroglycerin during FESS. Dexmedetomidine provides an additional benefit of reducing the analgesic requirements and providing postoperative sedation.

Tilt-table testing of patients with pacemaker and recurrent syncope.

The diagnosis of recurrent syncope in patients with pacemakers (PM) is quite challenging and the etiology of syncope is often multifactorial. To portray the mechanism of syncope in PM patients, we report the results of head-up tilt table testing (HUT) in a series of patients with PM, originally implanted for reasons other than neurally mediated syncope, referred due to syncope or pre-syncope (aborted syncope, vertigo, suspected orthostatic hypotension). Forty-one patients with PM undergoing a HUT in our syncope unit between January 1st, 2007 and December 31st 2011 were included. A standard HUT protocol with nitroglycerine provocation was used and the test results were classified according to current guidelines. Baseline data were retrieved from the medical records. Overall, 54% of patients had a positive response to HUT. Vasodepressor or orthostatic hypotensive response were the most prevalent responses accounting for 72% of patients with a positive test. There were no differences between groups with positive or negative test result regarding age, gender, resting blood pressure and heart rate, daily fluid intake, pacing mode, pacing indication or pacing rhythm at rest. HUT in patients with pacemakers has a high diagnostic yield. Although, the majority of patients had a vasodepressor or orthostatic hypotensive response, cardioinhibitory response leading to syncope was also seen.