Administration Of Isosorbide Dinitrate Research Articles

Nitrate-Induced Headache Response in Patients with Coronary Artery Disease and Coronary Artery Ectasia: A Retrospective Case-Control Study

Abstract Background: Coronary artery ectasia (CAE), while being considered a variant of atherosclerosis, harbors distinct features that significantly differ from atherosclerosis in terms of pathophysiological mechanisms. On the other hand, headache appears to be the most common side effect of nitrates that have been used traditionally for decades. In this context, we aimed to compare the frequency and temporal characteristics of nitrate-induced headache (NIH) between subjects with sole coronary artery disease (CAD) and subjects with CAD and coexisting CAE. Materials and Methods: Two hundred and forty-four patients who had undergone coronary angiogram (CAG) and received a single dose of sublingual isosorbide dinitrate during the procedure comprised in this retrospective study population. CAG is performed in the indications due to guidelines. All patients who had undergone CAG were held under close supervision, at least, for 6 h following CAG (and administration of sublingual nitrate); duration and emergence time of NIH were recorded for all patients. Of these 244 patients, 225 patients having sole CAD were assigned to Group I, whereas 19 patients having both CAD and CAE were assigned to Group II. Results: NIH was observed in 19 out of 225 patients (8%) with sole CAD and in 9 out of 19 patients (56%) with CAD and CAE (P = 0.003). The mean interval between the administration of sublingual isosorbide dinitrate and NIH onset was significantly lower in Group II in comparison to Group I (44 ± 14 min vs. 87 ± 63 min, respectively, P = 0.018). However, the duration of NIH was comparable between the two groups (Group I: 203 ± 53 min vs. Group II: 173 ± 61 min, P = 0.24); logistic regression analysis revealed an independent association between NIH and CAE (odds ratio: 11.5, 95% confidential interval: 3.9–33.8, P < 0.001). Conclusion: We have demonstrated that sublingual nitrates might induce NIH more frequently in subjects with CAE and CAD in comparison to those with sole CAD. Furthermore, NIH has been demonstrated to be independently associated with CAE.

VARIOUS ASPECTS OF PERCUTANEOUS CORONARY INTERVENTIONS AS PREDICTORS OF DEATH IN MYOCARDIAL INFARCTION AND CORONARY MICROVASCULAR OBSTRUCTION (NO-REFLOW)

HighlightsThe review analyzed the role of various preoperative indicators as predictors of long-term mortality in patients with myocardial infarction and coronary microvascular obstruction (no-reflow) that developed during percutaneous coronary intervention. As a result of a multifactorial analysis, taking into account the confounders available for evaluation, we have found that predilation serves as an independent predictor of death within two years. AbstractAim. To evaluate the role of various aspects of percutaneous coronary interventions (PCI) as predictors of long-term death in myocardial infarction (MI) and coronary microvascular obstruction (CMVO, no-reflow).Methods. The unmatched case-control study included 232 patients with type 1 MI and CMVO developed during PCI. CMVO criteria were as follows: TIMI flow grade <3, Myocardial blush grade <2, ST segment resolution after PCI <70%. The “cases” group consisted of 54 (23.3%) patients who died within the next two years, the “controls” group consisted of 178 (76.7%) patients who survived. The analysis included the following indicators: predilation, high-pressure balloon post-dilation, vacuum assisted manual thromboaspiration, intra-aortic balloon pump, intracoronary administration of isosorbide dinitrate and verapamil hydrochloride, glycoprotein IIb/IIIa inhibitors and “potent” p2y12 inhibitors usage, bare-metal stents, stent implantation with exceeded rated burst pressure, 3 or more stents usage, PCI on more than one artery, the ratio of contrast agent volume to glomerular filtration rate (GFR) >3.0. A univariate comparative analysis of the groups regarding PCI aspects and potential confounders was performed (Mann-Whitney, Fisher). To control the confounders, a multivariate analysis was carried out (logistic regression).Results. Differences were obtained for the following indicators: “predilation” – in 51 (94%) patients in the “cases” group and in 139 (78%) in the “control” group, p-value = 0.005; “intra-aortic balloon pump” – in 9 (17%) and 7 (4%) patients respectively, p-value = 0.003; “the ratio of contrast agent volume to GFR >3.0” – in 26 (48%) and 48 (27%) patients, p-value = 0.005. Multivariate analysis revealed that only predilation was an independent predictor of death within two years – odds ratio 7.38 (95% confidence interval 1.70–49.04, p-value = 0.005).Conclusion. Predilation of the infarct-related coronary artery is an independent predictor of death within two years in MI patients who develop CMVO during PCI.

Efficacy of Intravaginal Administration of Isosorbide Dinitrate Together with Misoprostol versus Misoprostol Alone in Induction of Labor

Background Cervical ripening is a complex process involving extensive remodeling and dynamic anatomic and physiologic alternations governed by hormonal changes, inflammatory responses, vasodilatory changes, and other biological processes. Prostaglandins, produced both locally in the cervix and uterus as well as originating from the fetal membranes, play a critical role in cervical ripening and uterine contractility by increasing inflammatory mediators in the cervix and inducing cervical remodeling. Objective To assess the adjunctive Role of intravaginal administration of Isosorbide dinitrate in induction of labor. Patients and Methods This randomized controlled clinical trial was conducted at tertiary care hospital at Ain Shams University Maternity hospital (labor ward) and was randomly selected from full term patients attending the labor ward and scheduled for induction of labor. Results Our results revealed that the need to cesarean section was statistically significantly less frequent among Isosorbide dinitrate group. Our results revealed that the duration of induction to active phase interval and the duration of active stage of labor were significantly shorter among Isosorbide dinitrate group than among Control group. Conclusion As evident from the current study, both intravaginal misoprostol and combination of vaginal Isosorbide dinitrate and misoprostol are safe and effective modes of labor induction. Vaginal isosorbide dinitrate and misoprostol is more effective than misoprostol alone in terms of post induction Bishop Score, shorter induction to active phase interval and induction to delivery interval. Thus, the combined use of vaginal isosorbide dinitrate with misoprostol for preinduction cervical ripening at term may prove to be a major therapeutic advance.

Dual enkephalinase inhibitor PL37 as a potential novel treatment of migraine: evidence from a rat model.

The dual enkephalinase inhibitor PL37, a small molecule that protects enkephalins from rapid degradation, has demonstrated analgesic properties in animal pain models and in early human clinical trials. This study tested the antimigraine potential of PL37 on cutaneous mechanical hypersensitivity affecting cephalic regions in migraineurs. Using behavioural testing and c-Fos immunoreactivity in male rats, we investigated the effects of single (oral or intravenous) and repeated oral administration of PL37 on changes in cutaneous mechanical sensitivity and sensitization of the trigeminocervical complex induced by repeated administration of the nitric oxide donor, isosorbide dinitrate. In naïve rats, single or repeated administration of PL37 or vehicle had no effect on cephalic mechanical sensitivity. However, single oral PL37 treatment effectively inhibited isosorbide dinitrate-induced acute cephalic mechanical hypersensitivity. Single intravenous but not oral PL37 administration inhibited chronic cephalic mechanical hypersensitivity. Daily oral administration of PL37 prevented cephalic mechanical hypersensitivity and decreased touch-induced c-Fos expression in trigeminocervical complex following repeated isosorbide dinitrate administration. These data reveal the therapeutic potential of the dual enkephalinase inhibitor PL37 as an acute and prophylactic treatment for migraine. Protecting enkephalins from their degrading enzymes therefore appears to be an innovative approach to treat migraine.

A Pilot Evaluation Study of Diffuse Coronary Arterial Contraction Causing Ischemia by Double Measurement of Left Ventriculography Before and After Intracoronary Administration of Nitrates.

Background: Abnormal diffuse coronary artery contraction is not easily diagnosed. In order to evaluate its true risk, we performed double left ventriculography (LVG) before and after intracoronary administration of isosorbide dinitrate (ISDN). We also investigated the relationship between changes in coronary lumen area and changes in left ventricular ejection fraction (LVEF) after ISDN.Methods and Results: The study included 53 patients who underwent an acetylcholine (ACh) provocation test after coronary angiogram and LVG. The second LVG was performed after intracoronary ISDN administration. Coronary lumen area was measured by quantitative coronary arteriography (QCA). Simple and multiple regression analyses showed a significant correlation between changes in total QCA area before and after ISDN administration (pre-and post-total QCA area, respectively) and changes in LVEF. Using structural equation modeling, we observed a negative effect of pre-total QCA area and a positive effect of post-total QCA area on LVEF improvement. Importantly, LVEF improvement was similar between the ACh-positive and -negative groups on the coronary artery spasm test. Receiver operating characteristic curves indicated that the cut-off value at which changes in total QCA area affected changes in LVEF was 5%.Conclusions: Performing double LVG tests before and after ISDN administration may detect myocardial ischemia caused by diffuse coronary artery contraction. The addition of this method to the conventional ACh provocation test may detect the presence of local and/or global myocardial ischemia.

Physiological Impact of Afterload Reduction on Cardiac Mechanics and Coronary Hemodynamics Following Isosorbide Dinitrate Administration in Ischemic Heart Disease

Understanding the cardiac-coronary interaction is fundamental to developing treatment strategies for ischemic heart disease. We sought to examine the impact of afterload reduction following isosorbide dinitrate (ISDN) administration on LV properties and coronary hemodynamics to further our understanding of the cardiac-coronary interaction. Novel methodology enabled real-time simultaneous acquisition and analysis of coronary and LV hemodynamics in vivo using coronary pressure-flow wires (used to derive coronary wave energies) and LV pressure-volume loop assessment. ISDN administration resulted in afterload reduction, reduced myocardial demand, and increased mechanical efficiency (all P<0.01). Correlations were demonstrated between the forward compression wave (FCW) and arterial elastance (r=0.6) following ISDN. In the presence of minimal microvascular resistance, coronary blood flow velocity exhibited an inverse relationship with LV elastance. In summary this study demonstrated a reduction in myocardial demand with ISDN, an inverse relationship between coronary blood flow velocity and LV contraction-relaxation and a direct correlation between FCW and arterial elastance.Graphical abstractThe pressure volume-loop and corresponding parameters b The pressure volume loop before (solid line) and after (broken line) Isosorbide dintrate

Coronary microvascular dysfunction: An important interpretation on the clinical significance of transient ischemic dilation of the left ventricle on myocardial perfusion imaging.

To further investigate the clinical significance of transient ischemic dilation (TID) on myocardial perfusion imaging (MPI) by analyzing the effect of anisodamine hydrobromide (a drug that can effectively ameliorate microcirculation) on the patients with isolated TID and the findings of previous literatures. Total 107 patients with isolated TID (TID value≥1.11) were randomly divided into group A (n = 36; intravenous administration of anisodamine hydrobromide), group N (n = 36; intravenous administration of isosorbide dinitrate), and group C (n = 35; intravenous administration of normal saline). MPI and treadmill exercise test (TET) were performed again after 14-day course of intervention. Pre- and post-intervention frequencies of symptom were recorded. In group A, after intervention of anisodamine hydrobromide, the summed stress score (SSS) and TID value on MPI significantly decreased than those before intervention (P < 0.001), the durations of exercise (DEs) and metabolic equivalents (METs) in TET notably ascended (P < 0.001), as well as the symptom remarkably improved. In group N and group C, there were no significant differences in SSS, TID value, DEs, METs, and frequencies of symptom between pre- and post-intervention (P > 0.05). No significant improvement of symptoms in group N before and after treatment. TID with perfusion defect may usually predict a possibility of severe and extensive coronary artery disease (CAD). An isolated TID should be considered as a likelihood of coronary microvascular dysfunction (CMD). TET and coronary CT angiography (cCTA) are extremely helpful for the antidiastole on CAD and CMD. The administration of anisodamine hydrobromide might be an optional treatment for the patients with isolated TID.

Dinitrosyl Iron Complexes with Thiol-Containing Ligands Exist in Living Organisms Mainly in the Binuclear Form

The levels of the mononitrosyl iron complex with diethyldithiocarbamate that form in the liver of mice in vivo and in vitro after intraperitoneal injection of binuclear dinitrosyl iron complexes with N-acetyl-L-cysteine or glutathione, S-nitrosoglutathione, sodium nitrite, or the vasodilating drug isosorbide dinitrate (Isoket®) have been assessed by electron paramagnetic resonance (EPR). The levels of the complex in mice that received binuclear dinitrosyl iron complexes with thiol-containing ligands or S-nitrosoglutathione do not change after the treatment of liver preparations with the strong reducing agent dithionite, in contrast to those formed after nitrite or isosorbide dinitrate administration, whose levels sharply increase after the same treatment. It is inferred that in the latter case an EPR-active mononitrosyl iron complex with diethyldithiocarbamate is produced with the absence or presence of dithionite in the reaction of NO formed from nitrite with Fe2+-diethyldithiocarbamate and Fe3+-diethyldithiocarbamate complexes, respectively. In the former case, the mononitrosyl iron complex with diethyldithiocarbamate is produced by transition of iron-mononitrosyl fragments from already present iron-dinitrosyl groups of binuclear dinitrosyl complexes, whose content is three to four times higher than the content of the mononuclear form of these complexes in the tissue. The results we obtained indicate that when dinitrosyl iron complexes with thiol-containing ligands, either introduced into the body or produced with the participation of endogenous NO, appear in animal tissues in vivo, these complexes are presented in these tissues mainly in their diamagnetic, EPR-silent binuclear form.

A randomized controlled trial comparing isosorbide dinitrate-oxytocin versus misoprostol-oxytocin at management of foetal intrauterine death.

BackgroundThe metabolic activity of endogenous nitric oxide (NO) and the medical use of nitrovasodilatory drugs like isosorbide dinitrate have been shown to be potential inducers inducers of cervical ripening prior to surgical evacuation of the uterus.ObjectiveTo assess the therapeutic efficacy and safety of combined isosorbide dinitrate-oxytocin in the management of intrauterine foetal death (IUFD).MethodsSixty women with IUFD after 20 weeks of gestation requesting uterine evacuation were randomly selected to receive isosorbide dinitrate gel solution (80 mg/1.5 mL; n = 30) or misoprostol gel solution (100 mcg/1.5 mL; n = 30) every 3 h with a maximum of four doses or until a Bishop score >7 was reached. Subsequently, patients received a high dose of intravenous oxytocin until complete uterus evacuation was achieved. Therapeutic efficacy was evaluated by mean the relative risk of the foetal expulsion based on comparison of event rates, and the proportion of women induced to labor at 7, 10 and 15 h after the administration of isosorbide dinitrate or misoprostol. Safety was assessed on the basis of woman´s vital signs and evaluation of adverse effects, including headache, abdominal pain, pelvic pain, lower back pain, nausea, dizziness and vomiting.ResultsThe foetal expulsion rate using the isosorbide dinitrate-oxytocin combination was approximately 4.4 times, and at least 2.1 times, the foetal expulsion rate with the misoprostol-oxytocin regimen at any given point in time. The proportion of women achieved vaginal delivery at 15 hours was 100% for the isosorbide dinitrate-oxytocin group and 86.7% for the misoprostol-oxytocin group. The average delivery induction interval was significantly lower when isosorbide dinitrate-oxytocin was used (8.7 ± 3.1 h) than when misoprostol-oxytocin (11.9 ± 3.1 h) was used. A total of 20% of patients in the isosorbide dinitrate-oxytocin group recorded headache, and no cases of uterine tachysystole, haemorrhage or coagulopathy were recorded.ConclusionThis study indicates that intravaginal isosorbide dinitrate followed by intravenous oxytocin was more effective than the conventional method used to induce labour in the medical management of foetal death in pregnancies after 20 weeks of gestation.Trial registrationClinicaltrials.gov NCT02488642.

Search for Therapeutic Agents for Cardiac Arrest Using a Drug Discovery Tool and Large-Scale Medical Information Database.

The survival rate of cardiac arrest patients is less than 10%; therefore, development of a therapeutic strategy that improves their prognosis is necessary. Herein, we searched data collected from medical facilities throughout Japan for drugs that improve the survival rate of cardiac arrest patients. Candidate drugs, which could improve the prognosis of cardiac arrest patients, were extracted using “TargetMine,” a drug discovery tool. We investigated whether the candidate drugs were among the drugs administered within 1 month after cardiac arrest in data of cardiac arrest cases obtained from the Japan Medical Data Center. Logistic regression analysis was performed, with the explanatory variables being the presence or absence of the administration of those candidate drugs that were administered to ≥10 patients and the objective variable being the “survival discharge.” Adjusted odds ratios for survival discharge were calculated using propensity scores for drugs that significantly improved the proportion of survival discharge; the influence of covariates, such as patient background, medical history, and treatment factors, was excluded by the inverse probability-of-treatment weighted method. Using the search strategy, we extracted 165 drugs with vasodilator activity as candidate drugs. Drugs not approved in Japan, oral medicines, and external medicines were excluded. Then, we investigated whether the candidate drugs were administered to the 2,227 cardiac arrest patients included in this study. The results of the logistic regression analysis showed that three (isosorbide dinitrate, nitroglycerin, and nicardipine) of seven drugs that were administered to ≥10 patients showed significant association with improvement in the proportion of survival discharge. Further analyses using propensity scores revealed that the adjusted odds ratios for survival discharge for patients administered isosorbide dinitrate, nitroglycerin, and nicardipine were 3.35, 5.44, and 4.58, respectively. Thus, it can be suggested that isosorbide dinitrate, nitroglycerin, and nicardipine could be novel therapeutic agents for improving the prognosis of cardiac arrest patients.

Nitroglycerin application and coronary arteriogenesis.

BackgroundIn the presence of a coronary occlusion, pre-existing small collateral vessels (arterioles) develop into much larger arteries (biological bypasses) that have the potential to allow a certain level of perfusion distal to the blockage. Termed arteriogenesis, this phenomenon proceeds via a complex combination of events, with nitric oxide (NO) playing an essential role. The aim of this study was to investigate the effects of supplemental administration of NO donors, i.e., short-acting nitroglycerin (NTG) or slow-release pelleted isosorbide dinitrate (ISDN), on collateral development in a repetitive coronary artery occlusion model in rats.MethodsCoronary collateral growth was induced via a repetitive occlusion protocol (ROP) of the left anterior descending coronary artery (LAD) in rats. The primary endpoints were the histological evaluation of rat heart infarct size and ST-segment elevation (ECG-analysis) upon final permanent occlusion of the LAD (experimentally induced myocardial infarction). The effects of NTG or ISDN were also evaluated by administration during 5 days of ROP. We additionally investigated whether concomitant application of NTG can compensate for the anti-arteriogenic effect of acetylsalicylic acid (ASA).ResultsAfter 5 days of ROP, the mean infarct size and degree of ST-elevation were only slightly lower than those of the SHAM group; however, after 10 days of the protocol, the ROP group displayed significantly less severe infarct damage, indicating enhanced arteriogenesis. Intermittent NTG application greatly decreased the ST-elevation and infarct size. The ISDN also had a positive effect on arteriogenesis, but not to the same extent as the NTG. Administration of ASA increased the infarct severity; however, concomitant dosing with NTG somewhat attenuated this effect.ConclusionIntermittent treatment with the short-acting NTG decreased the size of an experimentally induced myocardial infarct by promoting coronary collateral development. These new insights are of great relevance for future clinical strategies for the treatment of occlusive vascular diseases.

Catastrophic catheter-induced coronary artery vasospasm successfully rescued using intravascular ultrasound imaging guidance

A 46-year-old man underwent coronary angiography for stable angina. He developed inferior ST-segment myocardial infarction during the angiography. Intravascular ultrasound (IVUS) findings suggested coronary vasospasm. Intracoronary administration of isosorbide dinitrate...

Intratracheal administration of isosorbide dinitrate improves pulmonary artery pressure and ventricular remodeling in a rat model of heart failure following myocardial infarction.

Pulmonary hypertension due to left heart disease is associated with poor outcomes. This study investigated the beneficial effects of isosorbide dinitrate (ISDN) inhalation on pulmonary pressure and ventricular remodeling in a rat model of heart failure (HF) following myocardial infarction (MI). To assess the effect of ISDN on pulmonary pressure, 20 male Sprague-Dawley (SD) rats were randomized to four groups: Normal saline (NS) 1 ml/kg, ISDN 1 mg/kg, NS 3 ml/kg or ISDN 3 mg/kg following coronary ligation. Assessments included pulmonary and systemic artery pressure alterations, lung weight/body weight and plasma nitric oxide (NO) concentration. To assess the effect of ISDN on ventricular remodeling, 30 SD rats were randomized to three groups: Sham surgery, MI-NS (intratracheal NS 3 ml/kg for 13 days following coronary ligation), and MI-ISDN (intratracheal ISDN 3 mg/kg for 13 days following coronary ligation). On day 15, all rats underwent echocardiogram and hemodynamic assessments. The area affected by MI was evaluated using microscopy and vascular endothelial growth factor (VEGF) expression was examined using immunohistochemistry. Plasma epinephrine, norepinephrine and brain natriuretic peptide (BNP) levels were assessed by ELISA. Intratracheal ISDN reduced pulmonary and systematic artery pressure without pulmonary edema when compared with NS. The reduction was associated with increased plasma NO levels. ISDN inhalation for 14 days reduced MI size and alleviated left and right ventricular remodeling following MI. These hemodynamic and morphological improvements were associated with decreased plasma epinephrine, norepinephrine and BNP levels, and an increased VEGF positive area at the border of MI region. In conclusion, intratracheal administration of ISDN was effective in improving ventricular remodeling and cardiac function in a rat model of HF following MI.

Recurrent administration of the nitric oxide donor, isosorbide dinitrate, induces a persistent cephalic cutaneous hypersensitivity: A model for migraine progression.

Background A subgroup of migraineurs experience an increase in attack frequency leading to chronic migraine. Methods We assessed in rats the roles of dose and repeat administration of systemic isosorbide dinitrate (ISDN), a nitric oxide donor, on the occurrence and development of cephalic/face and extracephalic/hindpaw mechanical allodynia as a surrogate of migraine pain, and the effect of acute systemic sumatriptan and olcegepant and chronic systemic propranolol on these behavioral changes. Results A single high (H-ISDN) but not low (L-ISDN) dose of ISDN induces a reversible cephalic and extracephalic mechanical allodynia. However, with repeat administration, L-ISDN produces reversible cephalic but never extracephalic allodynia, whereas H-ISDN induces cephalic and extracephalic allodynia that are both potentiated. H-ISDN-induced cephalic allodynia thus gains persistency. Sumatriptan and olcegepant block single H-ISDN-induced behavioral changes, but only olcegepant reduces these acute changes when potentiated by repeat administration. Neither sumatriptan nor olcegepant prevent chronic cephalic hypersensitivity. Conversely, propranolol blocks repeat H-ISDN-induced chronic, but not acute, behavioral changes. Conclusions Repeated ISDN administration appears to be a naturalistic rat model for migraine progression, suitable for screening acute and preventive migraine therapies. It suggests frequent and severe migraine attacks associated with allodynia may be a risk factor for disease progression.

Effectiveness of isosorbide dinitrate in cyanide poisoning as a function of the administration timing

BackgroundBetter and safer antidotes against cyanide poisoning are needed. Prior study has shown a favorable effect of isosorbide dinitrate (ISDN) on the survival of cyanide-poisoned rabbits when administered as early as 1 min after poisoning. The aim of the current study was to further evaluate the efficacy of intravenous ISDN administered in clinically relevant timing for first responders.MethodsA comparative animal study using 24 rabbits in 4 randomized study groups was performed. Animals were poisoned with intravenous potassium cyanide (1 mg/kg). Animals in Group 1 served as controls and received no treatment. Groups 2–4 animals were treated intravenously with ISDN (50 μg/kg) after poisoning; one group after 3 min, another group after 5 min and the last after 7 min. Animals were observed for 30 min after poisoning. The study endpoints included survival rate, clinical status, blood pressure, pulse per minute, blood lactate and pH.ResultsFive of 6 animals (83.3%) from every treatment group survived the whole observation period while all control untreated animals died. All the rabbits collapsed immediately after exposure, showing rapidly deteriorated vital signs with lactic metabolic acidosis (peak blood lactate levels of 18.1 to 19.0 mmol/L on average at 10 min post exposure). Vital signs, clinical scores, and blood gases of treated rabbits gradually improved.ConclusionPoisoned rabbits showed improved short-term survival following the administration of ISDN up to 7 min after lethal cyanide poisoning of. We see a potential for ISDN as an antidote against cyanide poisoning.

The nitric oxide donor, isosorbide dinitrate, induces a cephalic cutaneous hypersensitivity, associated with sensitization of the medullary dorsal horn

Nitric oxide donors are known to produce headache in healthy as well as migraine subjects, and to induce extracephalic cutaneous hypersensitivity in rodents. However, little is known on the effect of nitric oxide donors on cephalic cutaneous sensitivity. Combining behavioral, immunohistochemical, and in vivo electrophysiological approaches, this study investigated the effect of systemic administration of the nitric oxide donor, isosorbide dinitrate (ISDN), on cephalic and extracephalic cutaneous sensitivity and on neuronal activation within the medullary dorsal horn (MDH) in the rat. Systemic administration of ISDN increased selectively the first phase and interphase of the facial formalin test, but had no effect on the hindpaw formalin one. Monitoring neuronal activity within the MDH with phospho-ERK1/2 immunoreactivity revealed that ISDN alone did not activate MDH neurons, but significantly increased the number of formalin-evoked phospho-ERK1/2-immunoreactive cells in the ipsilateral, but not contralateral, MDH. Using in vivo electrophysiological unit recordings, we show that ISDN administration never affected the spontaneous activity of trigeminal wide dynamic range neurons, but, facilitated C-fiber-evoked responses in half the neurons tested. This research demonstrates that a nitric oxide donor, isosorbide dinitrate, induces selectively cephalic hyperalgesia that arises as a consequence of central sensitization in pain pathways that subserve meningeal nociception. This model better mimics the clinical condition and offers another possibility of studying the role of nitric oxide donor in the physiopathology of headache.

Moderate vasomotor response to acetylcholine provocation test as an indicator of long-term prognosis.

The acetylcholine (ACh) provocation test (ACh-test) is used for the diagnosis of vasospastic angina (VSA). However, subjects often show a moderate spasm (MS) response for which diagnosis of VSA is not definitive, and the clinical significance of this response is unknown. We assessed moderate coronary vasomotor response to the ACh test as an indicator of long-term prognosis. A total of 298 consecutive patients who underwent the ACh test for suspected VSA were retrospectively investigated. Coronary spasm severity after intracoronary administration of isosorbide dinitrate was evaluated by measuring epicardial coronary artery diameter reduction after ACh injection. Patients were divided into three groups according to the diameter reduction during the ACh test: severe spasm (SS) showing ≥75% diameter reduction, MS showing ≥50% diameter reduction, and others (N). In Kaplan-Meier analysis, the major adverse cardiac event (MACE) rates with a median follow-up of 4.6years were significantly worse in SS (11.1%) and MS (8.5%) than N (1.9%), (SS vs N; P=0.009, MS vs N; P=0.029). Significant difference in MACE rates was not observed between SS and MS (P=0.534). Cox regression analysis revealed that MS remained an independent predictor of MACE after adjustment for other confounders (HR: 7.18, 95% CI 1.42-36.4, P=0.017). Patients with MS by ACh test had a cardiac event rate comparable with that of patients with SS and significantly worse than that of patients with normal vasomotor responses.

Early administration of isosorbide dinitrate improves survival of cyanide-poisoned rabbits

Context. More effective, rapidly delivered, safer antidotes are needed for cyanide poisoning. Previous study has demonstrated a beneficial effect of isosorbide dinitrate on the survival of cyanide-poisoned mice. Objective. To evaluate the effectiveness of isosorbide dinitrate compared with that of sodium nitrite in cyanide poisoning. Materials and methods. A comparative animal study was performed using 18 rabbits, randomized into 3 study groups. Animals were poisoned intravenously with potassium cyanide (1 mg/kg). The first group was not given any further treatment. The second and third groups were treated intravenously 1 min after poisoning with sodium nitrite (6 mg/kg) and isosorbide dinitrate (50 μg/kg), respectively. The primary outcome was short-term survival of up to 30 min. Secondary outcomes included time to death, a clinical score, mean blood pressure, pulse, blood pH, and lactate and methemoglobin levels. Results. Rabbits treated with isosorbide dinitrate or sodium nitrite survived while only one untreated rabbit survived. Median time to death of the 5 poisoned and untreated animals was 10 min. All the animals collapsed soon after poisoning, exhibiting rapidly disturbed vital signs and developed lactic metabolic acidosis; average peak blood lactate levels were 15.5–19.1 mmol/L at 10 min after poisoning. The treated animals improved gradually with practically full recovery of the clinical scores, vital signs, and blood gas levels. Sodium nitrite administration raised methemoglobin to an average peak of 7.9%, while isosorbide dinitrate did not change methemoglobin levels. Conclusion. Early administration of isosorbide dinitrate improved the short-term survival of cyanide-poisoned rabbits. Isosorbide dinitrate shows potential as an antidote for cyanide poisoning and may exert its effect using a nitric-oxide-dependent mechanism.

Abstract 11863: Enhanced Adventitial Vasa Vasorum Formation in Patients With Vasospastic Angina -Assessment With Optical Frequency Domain Imaging-

Background: We have previously demonstrated that adventitial inflammation, including enhanced formation of adventitial vasa vasorum (VV), is involved in the pathogenesis of coronary spasm in porcine models and that optical frequency domain imaging (OFDI) allows us to visualize adventitial VV in humans in vivo. However, it remains to be elucidated whether adventitial VV is also involved in the coronary hyperconstriction in patients with vasospastic angina (VSA). In this study, we thus examined the extent of VV formation in VSA patients and control subjects by using OFDI. Methods: OFDI image acquisition of the left anterior descending coronary artery (LAD) was performed along the LAD at every 10 mm length after intracoronary administration of isosorbide dinitrate in 21 patients with acetylcholine-induced spasm and 10 control subjects without the spasm. Results: Patient characteristics were comparable between VSA patients and control subjects, including sex, age, cardiovascular risks and medications. OFDI and reconstructed 3D-OFDI images clearly visualized enhanced VV formation in VSA patients as compared with control subjects (Figure). Quantitative analysis showed that VV area was significantly larger in VSA patients than in control subjects (VSA, 0.093±0.006 vs. control, 0.040±0.006 mm 2 , P&lt;0.0001), whereas vessel diameter, wall thickness and coronary lesion types were all comparable between the 2 groups. Conclusions: These results demonstrate for the first time that adventitial VV formation is enhanced at the spastic coronary segment in VSA patients, suggesting the important role of adventitial VV in the pathogenesis of coronary spasm.

A case of vasospastic angina in which the ergonovine provocation test with intracoronary isosorbide dinitrate and nicorandil was effective in the diagnosis of microvascular spasm

A 60-year-old man was admitted with early morning angina while at rest. Coronary angiogram revealed no organic lesions; therefore, a spasm provocation test with ergonovine was performed. Administration of intracoronary ergonovine induced total occlusion of the right coronary artery. The induced total occlusion improved but coronary flow velocity remained severely reduced and chest discomfort with ST-T changes in ECG remained in spite of repeated administration of isosorbide dinitrate (ISDN). Intracoronary administration of nicorandil following ISDN alleviated the chest discomfort, normalized the ST-T change in ECG, and improved the coronary flow. This suggested that microvascular spasm and the epicardial spasm were not relieved by ISDN but by nicorandil. Intracoronary nicorandil injection following ISDN administration may be useful for the diagnosis of microvascular spasm in the ergonovine provocation test.