Constriction Of Blood Vessels Research Articles

Objective Assessment of the Rheological Muscle Property in the Treatment of Fibromyalgia.

Fibromyalgia (FM), clinical condition characterized by several signs and symptoms such as widespread pain, trigger point, morning stiffness and extreme tiredness for scarce hours of sleep, is linked to several changes in several brain neurotransmitters, particularly serotonin and norepinephrine. Consequently, the Neural Vegetative System works more and so it generates an exaggerated muscular contraction, sweating and constriction of blood vessels. The aim of our study was to treat a selected group of female patients suffering from FM with duloxetine with physiotherapy. We used two clinical scales (VAS and FIQ) and an objective evaluation such as myometric. The analysis of the data Myoton used during any inspection showed a statistically significant reduction in the values of muscle tone in each district analyzed. This finding was also confirmed by the patients themselves who have experienced a significant welfare and less muscle tension in different locations, as evidenced by data obtained from the clinical scales used by us. In addition, our patients were thought to be satisfied with the improvements not only subjective, but also with the objective witnessed myometry, making them a share of the study and feeling constantly monitored for treatment aimed at a real reduction in muscle stiffness. In conclusion, our study demonstrates combined treatment duloxetine- physiotherapy effectively reduces a symptom often disabling and particularly troublesome in patients with FM as the exaggerated muscle contraction.

Abstract 5119: Mechanisms associated with blood flow modifying effects of electric pulses used for electrochemotherapy on normal and tumor blood vessels

Abstract Electropermeabilization/electroporation (EP) is a physical method that by applying external electric pulses to cells increases cell membrane permeability and thus enables the introduction of molecules into the cells. Nowadays, it is used in treatment of tumors, where its benefits are exploited in electrochemotherapy (ECT). In vivo EP also modifies blood flow, resulting in a decreased blood flow and increased permeability of blood vessel walls; whereas ECT has a vascular disrupting effect. The aim of our study was to evaluate the effects of EP on normal blood vessels and the effects of EP and ECT with bleomycin on tumor vasculature with the use of in vivo microscopy. The effects of pulse parameters used for ECT (8 pulses, 1300 V/cm, 100 μs, 1 Hz) on normal blood vessels were determined via a dorsal skinfold window chamber (DWC) with intravital two-photon microscopy after in vivo labelling of CD31 with fluorescently labeled antibodies. Furthermore, 70 kDa fluorescently labeled dextrans was used to visualize the increased permeability of blood vessel walls. Additionally, Fluorescence Lifetime Imaging (FLIM) was used to determine the stability of the used fluorochrome. In tumors the effects of ECT pulse parameters on tumor blood vessels after EP or ECT with bleomycin were determined using 70 kDa fluorescently labeled dextrans either with two-photon or widefield intravital microsocopy via DWC. Solid mouse sarcoma SA-1 tumors were induced by a subcutaneous injection of dense cell suspension into the area of DWC in mice and an intravenous injection of bleomycin (100 μg/mouse) was performed 3 min before the application of electric pulses. EP resulted in immediate constriction of the affected normal blood vessels and in a rapid increase of vascular permeability. This was accompanied by the change of the endothelial cells’ shape and a decrease of CD31 labelling in the cell-to-cell junctions. In vivo 3D FLIM showed no difference in the lifetime of the used fluorochrome before and after EP. When electric pulses or ECT were applied to tumors the increase in vascular permeability and the constriction of tumor blood vessels were not as pronounced as in normal blood vessels. However, there was a complete vascular lock that lasted for more than 30 min. Furthermore, ECT had a differential vascular disrupting effect on tumor blood vessels, leaving the larger normal blood vessels surrounding the tumors functional after the therapy. In conclusion, the results of our study provide direct in vivo evidence of the difference in vascular effects of electric pulses used for ECT in normal and tumor blood vessels, show the response of normal endothelial cells to EP with two-photon microscopy and 3D FLIM, and provide evidence of the differential vascular disrupting action of ECT. Citation Format: Bostjan Markelc, Elisabeth Bellard, Gregor Sersa, Tanja Dolinsek, Justin Teissie, Muriel Golzio, Maja Cemazar. Mechanisms associated with blood flow modifying effects of electric pulses used for electrochemotherapy on normal and tumor blood vessels. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5119. doi:10.1158/1538-7445.AM2015-5119

Administering iloprost for severe Raynaud's phenomenon

T topic of this month’s Calculation Skills is iloprost, a synthetic analogue of prostacyclin, which is known to dilate pulmonary and arterial vascular beds. Iloprost has been used via a nebulizer to treat pulmonary hypertension and by intravenous (IV) infusion to treat other diseases where the constriction of blood vessels interferes with blood supply to the tissues, such as scleroderma and Raynaud’s phenomenon. This instalment looks at intravenous administration of iloprost in patients with severe Raynaud’s phenomenon. In the UK, the iloprost nebulizer solution is licensed as Ventavis (electronic Medicines Compendium, 2014). Iloprost injection is available as an unlicensed product in the UK but is licensed (Ilomedin) in other parts of the world (Bayer New Zealand Limited, 2012). Raynaud’s phenomenon is characterized by paroxysmal vasospasm followed by vasodilation of the peripheral arterioles, most commonly of the hands and feet (Tidy, 2013). The term ‘Raynaud’s phenomenon’ encompasses both Raynaud’s disease and Raynaud’s syndrome, although there is some overlap between them: ■ Primary Raynaud’s phenomenon (Raynaud’s disease) has no known cause. It occurs mostly in younger people (usually under the age of 30 years, although it can occur at any age) and is more common in women. It often has a genetic component— about a third of patients have a firstdegree relative affected ■ Secondary Raynaud’s phenomenon (Raynaud’s syndrome) is less common but has a known cause. It occurs mostly in people over the age of 30 years, but can occur at any age. It is linked to multiple causes including autoimmune disease; arterial and vasospastic disorders; haematological, endocrine and metabolic disorders; mechanical and environmental factors, such as vibration and smoking; malignant disease; infection; and some drugs, including betablockers and certain cytotoxics. Intravenous iloprost infusion can be used to treat primary and secondary Raynaud’s phenomenon. It reduces the frequency and severity of attacks and Alison Eggleton

Role of Peptide YY in blood vessel function and atherosclerosis in a rabbit model

Cardiovascular disease remains a burden for Westernized countries. Peptide YY (PYY) raises blood pressure, yet its role has not yet been determined in diseased arteries. This study aimed at identifying PYY and eNOS in diseased blood vessels and to determine which blood vessels respond to PYY. New Zealand White rabbits were fed an atherogenic diet (n = 6, 0.5% cholesterol + 1% methionine + 5% peanut oil) and control animals fed a normal diet (n = 6) for 4 weeks. Immunohistochemistry was used to determine the localization of PYY and eNOS in the aorta. The aorta, carotid, renal, iliac, inferior mesenteric, and renal interlobular arteries were removed, mounted in organ baths, and subjected to doses of PYY (10(-9) -10(-7) mol/L) and then acetylcholine (10(-6) mol/L). Immunohistochemistry of the aorta shows PYY staining in plaque macrophages, smooth muscle cells and endothelium, and these cells co-expressed eNOS. PYY caused a minor vasoconstrictive response in all blood vessels studied but was blunted in arteries from control animals. Acetylcholine caused relaxation of PYY constricted blood vessels. This data clearly shows that PYY is present in atherosclerotic plaque and is a minor constrictor of the vasculature tree. Further studies aimed at understanding the role of PYY in cardiovascular disease are warranted.

Patient-specific computational modeling of blood flow in the pulmonary arterial circulation

Computational fluid dynamics (CFD) modeling of the pulmonary vasculature has the potential to reveal continuum metrics associated with the hemodynamic stress acting on the vascular endothelium. It is widely accepted that the endothelium responds to flow-induced stress by releasing vasoactive substances that can dilate and constrict blood vessels locally. The objectives of this study are to examine the extent of patient specificity required to obtain a significant association of CFD output metrics and clinical measures in models of the pulmonary arterial circulation, and to evaluate the potential correlation of wall shear stress (WSS) with established metrics indicative of right ventricular (RV) afterload in pulmonary hypertension (PH). Right Heart Catheterization (RHC) hemodynamic data and contrast-enhanced computed tomography (CT) imaging were retrospectively acquired for 10 PH patients and processed to simulate blood flow in the pulmonary arteries. While conducting CFD modeling of the reconstructed patient-specific vasculatures, we experimented with three different outflow boundary conditions to investigate the potential for using computationally derived spatially averaged wall shear stress (SAWSS) as a metric of RV afterload. SAWSS was correlated with both pulmonary vascular resistance (PVR) (R2=0.77, P<0.05) and arterial compliance (C) (R2=0.63, P<0.05), but the extent of the correlation was affected by the degree of patient specificity incorporated in the fluid flow boundary conditions. We found that decreasing the distal PVR alters the flow distribution and changes the local velocity profile in the distal vessels, thereby increasing the local WSS. Nevertheless, implementing generic outflow boundary conditions still resulted in statistically significant SAWSS correlations with respect to both metrics of RV afterload, suggesting that the CFD model could be executed without the need for complex outflow boundary conditions that require invasively obtained patient-specific data. A preliminary study investigating the relationship between outlet diameter and flow distribution in the pulmonary tree offers a potential computationally inexpensive alternative to pressure based outflow boundary conditions.

Diabetes and cardiac autonomic neuropathy: Clinical manifestations, cardiovascular consequences, diagnosis and treatment.

Cardiac autonomic neuropathy (CAN) is a frequent chronic complication of diabetes mellitus with potentially life-threatening outcomes. CAN is caused by the impairment of the autonomic nerve fibers regulating heart rate, cardiac output, myocardial contractility, cardiac electrophysiology and blood vessel constriction and dilatation. It causes a wide range of cardiac disorders, including resting tachycardia, arrhythmias, intraoperative cardiovascular instability, asymptomatic myocardial ischemia and infarction and increased rate of mortality after myocardial infarction. Etiological factors associated with autonomic neuropathy include insufficient glycemic control, a longer period since the onset of diabetes, increased age, female sex and greater body mass index. The most commonly used methods for the diagnosis of CAN are based upon the assessment of heart rate variability (the physiological variation in the time interval between heartbeats), as it is one of the first findings in both clinically asymptomatic and symptomatic patients. Clinical symptoms associated with CAN generally occur late in the disease process and include early fatigue and exhaustion during exercise, orthostatic hypotension, dizziness, presyncope and syncope. Treatment is based on early diagnosis, life style changes, optimization of glycemic control and management of cardiovascular risk factors. Medical therapies, including aldose reductase inhibitors, angiotensin-converting enzyme inhibitors, prostoglandin analogs and alpha-lipoic acid, have been found to be effective in randomized controlled trials. The following article includes the epidemiology, clinical findings and cardiovascular consequences, diagnosis, and approaches to prevention and treatment of CAN.

Kinetics of Mechanoresponse in the Mammalian Actin Cytoskeleton

Cells have a remarkable ability to sense and respond to their mechanical environment; this ability directs a host of cellular and global processes, such as metastasis, engulfment, blood vessel constriction, and tissue development. However, the direct mechanism by which the dynamic network of actin filaments, myosin motors, and actin crosslinking proteins assemble and interact to exert force on the membrane in response to mechanical perturbations remains unclear. Here, we define the in vivo kinetics of 20 cytoskeletal and signaling proteins in response an applied external stress and identify a number of structural elements that accumulate to regions of the cell under shear or dilational forces. Prominent among these are the three non-muscle myosin II paralogs, the actin bundling protein α-actinin 4, and the orthogonal actin crosslinking protein filamin B. All three myosin paralogs, as well as α-actinin 4, accumulate to the tip region of the aspirated cell, which experiences primarily dilational force. Filamin B, however, accumulates to the tip and the neck region, demonstrating that it responds to both sheared and dilated microenvironments. These differences can be directly related to the actin binding geometries and distinct mechanism of force response for each protein. In support of a proposed model for an increased actin affinity state under load, a disease-relevant point mutation K255E in α-actinin 4, which abolishes the structural low affinity state, greatly slows its accumulation kinetics to dilational stress. The accumulation of cytoskeletal motors and crosslinking proteins under mechanical load represents a mechanism by which cells can concentrate structural components to reduce strain or retract from a local environment of high stress. Understanding how cortical protein dynamics intrinsically give rise to the self-tuning nature of the cell will offer insight into the nature of mechanically-dependent cell processes.

Intramyometrial vasopressin as a haemostatic agent: Is it really safe?

Vasopressin when given intramyometrially during myomectomy results in good surgical haemostasis.[1,2] At the same time, there are published reports of adverse cardiac events following vasopressin injection.[3,4] Resuscitation measures following such adverse cardiac events require understanding of pharmacodynamics of vasopressin administration.[5] We present a case of successful resuscitation of complete heart block following intramyometrial vasopressin injection during myomectomy and the associated implications.

Five Things to Know About Orthostatic Hypotension and Aging

To the Editor: Orthostatic hypotension is an important condition to diagnose and manage in elderly adults. This letter provides a concise, evidence-based update on five things a clinician should know about orthostatic hypotension and aging. A large prospective study identified the presence of OH as an independent risk factor for recurrent falls in elderly adults (aged ≥60) who had experienced falls in the last 6 months (relative risk = 2.6; 95% confidence interval = 1.7–4.6).1 Because falls in elderly adults can result in hip fracture, head trauma, and functional decline, clinicians should screen for and manage OH in these high-risk individuals. There is also recent evidence that OH may contribute to cognitive decline that can occur with aging.2 The Consensus Committee of the American Autonomic Society and the American Academy of Neurology have defined OH as a sustained reduction of systolic blood pressure (SBP) of 20 mmHg or of diastolic blood pressure (DBP) of 10 mmHg or more within 3 minutes of standing.3 However, the most-recent 2011 consensus statement update includes definitions for other variants of OH, including initial and delayed OH. Initial OH was defined as a transient blood pressure decrease (≥40 mmHg SBP or ≥20 mmHg DBP) within 15 seconds of standing, and delayed OH was defined as OH that occurs more than 3 minutes after a postural challenge.4 These types of OH need to be considered when screening high-risk individuals, especially because delayed OH may be more difficult to detect in the setting of clinical time restrictions. An observational study of 342 individuals aged 75 and older found the prevalence of OH in those receiving zero, one, two, or three or more potentially causative medications was 35%, 58%, 60%, and 65%, respectively.5 High-risk medications were identified as antihypertensives, diuretics, antidepressants, and alpha-blocker prostate medications.5 Diseases affecting the central (e.g., Parkinson's disease) and peripheral (e.g., diabetes mellitus) nervous systems are more prevalent and increase the risk of OH in elderly adults. OH associated with type 1 and type 2 diabetes mellitus is primarily due to peripheral neuropathy with damage of the small diameter fibers, for which poor glycemic control is an established risk factor.6 OH was present in 18.2% of individuals aged 65 and older in a large observational study, of whom 87% were asymptomatic.7 Even with profound OH (drop in systolic blood pressure ≥60 mmHg), up to 43% had typical symptoms (e.g., dizziness, visual symptoms, shoulder “coat-hanger” pain), whereas 33% had no symptoms at all, and 24% had atypical symptoms including backache and lower extremity discomfort.8 Start by correcting reversible causes (e.g., anemia, hypovolemia), initiating nonpharmacological measures, and removing or reducing high-risk medications when possible; if these measures fail, pharmacological management of OH should be considered (Table 1). The goal of treatment is to improve the individual's functional capacity and quality of life and to prevent injury, rather than to achieve a target blood pressure.9 Target water intake to 2–2.5 L/d.10 When symptomatic, rapidly drinking 500 mL of water can quickly expand plasma volume.10 Midodrine 2.5–10 mg orally up to three times per day.10 Short-acting alpha adrenomimetic (up to 4 hours); acts through direct blood vessel constriction. Conflict of Interest: The authors have no conflict of interest with the contents of this manuscript. Dr. P. Mills received research salary funding from the Vancouver Coastal Health Research Institute, TD Grants in Medical Excellence, and VGH & UBC Hospital Foundation during the writing of this manuscript. Author Contributions: All authors contributed equally to the conception and writing of this manuscript. Sponsor's Role: None.

Magnetic sensor for arterial distension and blood pressure monitoring

A novel sensor for measuring arterial distension, pulse and pressure waveform is developed and evaluated. The system consists of a magnetic sensor which is applied and fixed to arterial vessels without any blood vessel constriction, hence avoiding stenosis. The measurement principle could be validated by in vitro experiments on silicone tubes, and by in vivo experiments in an animal model, thereby indicating the non-linear viscoelastic characteristics of real blood vessels. The sensor is capable to provide absolute measurements of the dynamically varying arterial diameter. By calibrating the sensor, a long-term monitoring system for continuously measuring blood pressure and other cardiovascular parameters could be developed based on the method described. This will improve diagnostics for high risk patients and enable a better, specific treatment.

Use of Advanced Bleeding Control Mechanisms in Athletic Training: A Shift in the Thought Process of Prehospital Care—Part 1: Tourniquets

Two other competencies(Table 1), although not necessarily new to the list ofimmediate emergency management care skills, do requirefurther examination based on the current available scienceand standard of care in prehospital medicine. The purposeof this column is to provide athletic training educators(ATE) with evidence regarding the use of tourniquets in theprehospital setting as well as to be a resource on how toteach the management of external hemorrhage usingtourniquets.Trauma resulting in disruption of soft tissue is classified asan open or closed wound, and any significant loss ofintravascular volume may lead sequentially to hemodynam-ic instability, decreased tissue perfusion, cellular hypoxia,organ damage, and death.

Complex regional pain syndrome: recent updates

Complex regional pain syndrome (CRPS) may be defined as a painful and disabling disorder affecting one or more extremities showing signs of vasomotor (relating to the constriction and dilatation of blood vessels), sudomotor (stimulation of sweat glands), inflammatory, and trophic changes (changes brought about in tissues from interruption or destruction of nerve, blood supply or both) in the affected extremity. CRPS can occur after even trivial injury and, on occasion, can develop spontaneously. It was first described as a spectrum of symptoms during the American Civil War by Silas Weir Mitchell and colleagues in their book entitled Gunshot Wounds and Other Injuries of Nerves, and named it causalgia. The gamut of symptoms stretches from a self-limiting mild condition to a severe, debilitating condition affecting the quality of life and having a high impact on activity. Owing to the varied manifestation, the patient can present to any specialty be it orthopaedics, rheumatology, neurology, dermatology, or pain medicine. Pain is an early presenting feature and can be the most prominent of symptoms. A high index of suspicion is needed as early diagnosis and treatment may prevent the progression of symptoms and prevent disability. It has been known by many names in the past, including reflex sympathetic dystrophy, algodystrophy, algoneurodystrophy, Sudeck’s dystrophy, and causalgia. In 1994, the International Association for the Study of Pain (IASP) came up with a standardized set of criteria to diagnose CRPS. Until then, numerous different diagnostic and clinical criteria were used. As IASP criteria lacked specificity, a new set of diagnostic criteria were adapted at a closed conference of leading experts from around the world in the Fall of 2004 in Budapest, Hungary—these were called the ‘Budapest criteria’ (Table 1). The Budapest criteria were compared with the former IASP criteria and found to have a higher specificity while maintaining sensitivity, and were validated. Clinical presentation

Necrotizing sialometaplasia of the palatal mucosa in patient with history of anorexia: Review and case report

Necrotizing sialometaplasia is a self-limiting disorder affecting minor salivary glands resembling a malignant process both clinically and histopathologically. The etiology of this rare inflammatory` disorder is related to an ischemic event. Identified risk factors include alcohol abuse, smoking, drugs, denture wearing, injury and systemic diseases. Also reported are cases of necrotizing sialometaplasia associated with bulimia. This paper identifies the whole body incitement among additional risk factors by presenting a case of necrotizing sialometaplasia in an 18year old patient with the history of anorexia nervosa. Furthermore it describes the effects of extreme cooling of palatal mucosa with ice chips resulting in constriction of blood vessels as the direct cause, reinforcing ischemic etiology of necrotizing sialometaplasia.

Influence of celecoxib on the vasodilating properties of human mesenteric arteries constricted with endothelin-1.

The mitogenic and vasoconstrictive properties of the vascular system are attributed to endothelin-1 (ET-1). ET-1 serum concentration increases in a number of pathological conditions, particularly in those associated with blood vessel constriction. ET-1 is also associated with the underlying pathomechanisms of primary pulmonary hypertension, arterial hypertension and eclampsia. The aim of this study was to compare the vasodilating properties of selected phosphodiesterase (PDE) inhibitors and celecoxib in human mesenteric arteries constricted with ET-1, and investigate the role of the endothelium in relaxation. Perfused human mesenteric arteries were collected and stored under the same conditions as organs for transplantation. The mesenteric arteries (with and without the endothelium) were constricted by the addition of ET-1 and treated with one of the following: sildenafil (PDE5 inhibitor), zaprinast (PDE5 and 6 inhibitor), rolipram (PDE4 inhibitor) and celecoxib [cyclooxygenase-2 (COX-2) inhibitor]. Based on the observed changes of the perfusion pressure, concentration response curves (CRCs) were prepared for the respective inhibitors and the EC50 (concentration causing an effect equal to half of the maximum effect), pD2 (negative common logarithm of EC50) and relative potency (RP) were calculated. The results suggested that all the inhibitors triggered a concentration-dependent decrease in the perfusion pressure in isolated human superior mesenteric arteries with endothelium constricted by the addition of ET-1. In the arteries without endothelium, CRCs for celecoxib and rolipram were shifted to the right without a significant decrease in the maximum dilating effect. Moreover, CRCs for sildenafil and zaprinast were shifted to the right with a simultaneous significant decrease in the maximum dilating effect and with an increased inclination angle in reference to the concentration axis. In the presence of the endothelium, all of the evaluated PDE inhibitors, as well as celecoxib, reduced the reactivity of the mesenteric arteries caused by ET-1. Sildenafil indicated the lowest efficacy in the presence of the endothelium, but showed a higher potency compared to that of the other compounds. Removing the endothelium significantly reduced the vasodilating efficacy of PDE5 and 6 inhibitors and a statistically significant influence on the vasodilating efficacy of PDE4 inhibitor and celecoxib was observed. The high vasorelaxing efficacy of celecoxib at the background of the PDE inhibitors was observed, not only in the presence, but also in the absence of the endothelium and may be evidence for the relaxation induced by this COX-2 inhibitor in the cAMP- and cGMP-dependent pathways.

The effect of intranasal oxytocin versus placebo treatment on the autonomic responses to human sounds in autism: a single-blind, randomized, placebo-controlled, crossover design study

BackgroundMany individuals with autism spectrum disorders (ASD) have difficulty with verbal communication, which might be due to a lack of spontaneous orientation toward social auditory stimuli. Previous studies have shown that a single dose of oxytocin improves speech comprehension in autism. The primary aim of this study was to investigate whether the orientation behaviors toward human sounds are different for neurotypical (NT) adults and adults with ASD and whether oxytocin has an effect on their orientation behaviors toward human sounds.MethodsThis was a randomized, placebo-controlled, within-subject, crossover design study of intranasal oxytocin versus placebo in 13 NT adults and 16 adults with ASD. Subjects were randomized to 24 IU intranasal oxytocin or placebo on different days, and they were blind to the treatment. The participants then listened passively to human and non-human affective sounds while their skin conductance responses (SCRs) and the changes in peripheral blood vessel constriction were monitored as an indicator of spontaneous orientation. The monitored data were analyzed by a mixed-design ANOVA.ResultsOxytocin enhanced the difference between the SCRs to human and non-human sounds in both the NT and ASD groups (F(1,56) = 6.046, p = 0.017). Further correlation coefficient analysis showed significant correlations between this SCR difference and the scores in the autism spectrum quotient ‘attention to detail’ and ‘social skill’ subscales and interpersonal reactivity index and social functioning scale in the ASD group. Oxytocin was well tolerated, and no serious adverse effects were reported.ConclusionsThe difference in SCRs implies that oxytocin nasal spray may enhance orientation behaviors toward human sounds in the presence of other environmental sounds in both ASD and NT adults.Trial registrationUMIN-CTR Clinical Trial, Unique trial number: UMIN000005809

What can data mining teach us about triptan safety that we don’t already know?

Triptans are a mainstay of migraine treatment. They were hailed as a breakthrough when they became available in the early 1990s, but excitement about their obvious value was tempered by concern about possible adverse vascular events. From a physiological standpoint this worry was well founded, since triptans have agonist effects at serotonin receptor subtypes that mediate blood vessel constriction (1). Moreover, the limited power of pre-approval clinical trials to detect safety problems was widely recognized. The number of vascular complications identified in post-marketing surveillance after the drugs became widely available, however, proved small in comparison with their extensive use. Large-scale observational studies provided further evidence of a good record of vascular safetywhen physicians prescribed triptans in the course of routine practice (2). In some countries, although not the United States, triptans became available without physician prescription. Even so, no apparent epidemic of vascular complications emerged. What, then, remains to be learned about the vascular safety of triptans? Although one might expect that any controversy has been settled, the limitations of traditional methods of preand post-marketing drug safety surveillance are well known. The vascular risks of commonly used nonsteroidal anti-inflammatory drugs (NSAIDs), for example, have only recently been recognized. Reassessment of their safety was prompted by complications observed in trials of Cox-2 inhibitors; eventually it became clear that these problems were not limited to newer drugs but instead were class effects (3). The NSAID situation teaches us that post-marketing surveillance is never ‘‘finished’’ and that previously unrecognized risks may emerge even with drugs that have been on the market for a long time. The lesson is that we should never stop looking. For this reason, the study by Roberto et al. (4) published in the current issue of Cephalalgia provides a welcome new perspective on the matter of the vascular safety of triptans. The authors used data from the Food and Drug Administration Adverse Event Reporting System (FDA_AERS) from 2004 to 2012 to examine whether triptan use was disproportionately associated with reports of vascular events. Reports of drug-associated adverse events in the AERS database are submitted voluntarily by pharmaceutical manufacturers, healthcare providers, or patients. They typically include a description of the adverse event and the drug or drugs suspected of causing it, as well as patient characteristics such as age, sex and other prescribed medications. Reported events are grouped using a four-level hierarchy. This study evaluated adverse events within the highest level categories of ‘‘Cardiac disorder’’ or ‘‘Vascular disorders.’’ In each category, reports describing patients who experienced vascular events in association with triptan use were classified as cases. Reports describing the same type of vascular events in association with non-triptan drugs were designated noncases. The authors then calculated a reporting odds ratio (ROR) and 95% confidence interval (CI) of cases to non-cases, defining a disproportionality signal of interest as one in which there were more than three reported cases and the lower limit of the 95% CI for the ROR was above one. The researchers addressed the problem of confounding by pre-existing vascular risk by adjusting RORs for the proxy measure of co-prescribed cardiac medications. Of 7800 adverse events in which a triptan was identified as the suspected drug or one of several suspected drugs, almost 2600 were categorized as cardiac or vascular disorders. Disproportionality signals were identified for the subcategories of coronary artery disorders (ROR 2.0, 95% CI 1.85–2.16), cardiac disorders signs

Abstract 053: Carbaprostacyclin Promotes Vascular Growth in Mouse Hindlimb Ischemia

Background: Prostacyclin and its stable analogues are vascular protective agents that have been used clinically to reduce blood vessel constriction. Recent studies indicate they stimulate angiogenesis in response to tissue ischemia, but their role in arteriolar growth remains unclear. In the current study, we test the hypothesis that the prostacyclin stable analogue carbaprostacyclin (cPGI2) facilitates arteriolar growth in ischemic hindlimbs. Methods and Results: Catheters were attached to osmotic pumps in order to continuously deliver either cPGI2 or saline (control) locally into ischemic mouse hindlimbs for 7 and 14 days (n=5/group). At 7 days of cPGI2 delivery, live microscopic images showed more distinct structural remodeling at the arteriolar level in the cPGI2 group than in the saline group, including tortuosity of arteriolar-to-arteriolar connections and increased intersecting of adjacent arterioles. Vascular casting with a silicone radiopaque agent into the distal region of the infrarenal abdominal aorta revealed a more pronounced arterial anastomoses in the cPGI2 treated versus the saline treated ischemic legs. After immunofluorescence staining, laser scanning confocal microscopic analysis found more transmembrane proteoglycan NG2 positive vessels in cross sections of anterior thigh muscles in cPGI2-treated mice than in saline-treated mice. At 14 days, quantitative micro-computed tomography analysis indicated cPGI2-treated legs had markedly increased vascular volume (41.28 ± 2.22 vs 27.11 ± 2.85 mm3), significantly more blood vessels (0.16 ± 0.014 vs 0.09± 0.011 1/mm) and less distance between vessels (6.60 ± 0.52 vs 10.15 ±1.14 mm) than did saline-treated legs. To further verify the pro-arteriogenic effect of cPGI2, a quantitative histogram was generated and exhibited that cPGI2-treated ischemic legs have a significant increase in small vessels, with vessel diameter bins ranging from 40-60 microns. We similarly evaluated contralateral nonischemic legs and found no significant differences in vessel distribution in the cPGI2 and saline groups. Conclusion: Multi-imaging technical analyses indicated that local delivery of carbaprostacylin promotes arteriolar growth in mouse hindlimb ischemia.

A polymorphism in the protein kinase C gene PRKCB is associated with α2-adrenoceptor-mediated vasoconstriction

α2-Adrenoceptors (α2-AR) mediate both constriction and dilatation of blood vessels. There is considerable interindividual variability in dorsal hand vein (DHV) constriction responses to α2-AR agonist activation. Genetic factors appear to contribute significantly to this variation. The present study was designed to identify the genetic factors contributing toward the interindividual variability in α2-AR-mediated vascular constriction induced by the selective α2-AR agonist dexmedetomidine. DHV constriction responses to a local infusion of dexmedetomidine were assessed by measuring changes in vein diameter with a linear variable differential transformer. The outcome variable for constriction was log-transformed dexmedetomidine ED50. A genome-wide association study (GWAS) of 433 378 single-nucleotide polymorphisms (SNPs) was carried out for determining the sensitivity of DHV responses in 64 healthy Finnish individuals. Twenty SNPs were selected on the basis of the GWAS results and their associations with the ED50 of dexmedetomidine were tested in an independent North American study population of 68 healthy individuals. In both study populations (GWAS and replication samples), the SNP rs9922316 in the gene for protein kinase C type β was consistently associated with dexmedetomidine ED50 for DHV constriction (unadjusted P=0.00016 for the combined population). Genetic variation in protein kinase C type β may contribute toward the interindividual variation in DHV constriction responses to α2-AR activation by the agonist dexmedetomidine.

Smoking Cessation After Acute Myocardial Infarction

Cigarette smoking produces endothelial dysfunction, constricts blood vessels, activates platelets, creates a chronic inflammatory state, and causes dyslipidemia ([1][1]). These effects accelerate atherosclerosis, destabilize coronary artery plaques, and precipitate acute coronary events and sudden

Contribution of systemic factors in the pathophysiology of repeated blast-induced neurotrauma

Blast-induced traumatic brain injury is complex and involves multiple factors including systemic pathophysiological factors in addition to direct brain injuries. We hypothesize that systemic activation of platelets/leukocytes plays a major role in the development and exacerbation of brain injury after blast exposure. A mouse model of repeated blast exposure that results in significant neuropathology, neurobehavioral changes and regional specific alterations in various biomolecules in the brain was used for the proposed study. Activation of platelets was evaluated by flow cytometry and serotonin content was analyzed by ELISA. Expression of myeloperoxidase was analyzed by Western blotting. Histopathology of the brain was used to assess blast-induced cerebral vasoconstriction. The data showed an increase in the activation of platelets at 4h after repeated blast exposures, indicating changes in platelet phenotype in blast neurotrauma. Platelet serotonin concentration showed a significant decrease at 4h after blast with a concurrent increase in the plasma serotonin levels, confirming the early onset of platelet activation after repeated blast exposures. Blood, plasma and brain myeloperoxidase enzyme activity and expression was increased in repeated blast exposed mice at multiple time points. Histopathological analysis of the brains of blast exposed mice showed constriction of blood vessels compared to the respective controls, a phenomenon similar to the reported cerebral vasoconstriction in blast affected victims. These results suggest that repeated blast exposure leads to acute activation of platelets/leukocytes which can augment the pathological effects of brain injury. Platelet/leukocyte targeted therapies can be evaluated as potential acute treatment strategies to mitigate blast-induced neurotrauma.