Beta-adrenergic Receptor Antagonist Research Articles

Genome-Wide Transposon Mutagenesis Identifies a Role for Host Neuroendocrine Stress Hormones in Regulating the Expression of Virulence Genes inSalmonella

Bacterial sensing of environmental signals plays a key role in regulating virulence and mediating bacterium-host interactions. The sensing of the neuroendocrine stress hormones epinephrine (adrenaline) and norepinephrine (noradrenaline) plays an important role in modulating bacterial virulence. We used MudJ transposon mutagenesis to globally screen for genes regulated by neuroendocrine stress hormones in Salmonella enterica serovar Typhimurium. We identified eight hormone-regulated genes, including yhaK, iroC, nrdF, accC, yedP, STM3081, and the virulence-related genes virK and mig14. The mammalian alpha-adrenergic receptor antagonist phentolamine reversed the hormone-mediated effects on yhaK, virK, and mig14 but did not affect the other genes. The beta-adrenergic receptor antagonist propranolol had no activity in these assays. The virK and mig14 genes are involved in antimicrobial peptide resistance, and phenotypic screens revealed that exposure to neuroendocrine hormones increased the sensitivity of S. Typhimurium to the antimicrobial peptide LL-37. A virK mutant and a virK mig14 double mutant also displayed increased sensitivity to LL-37. In contrast to enterohemorrhagic Escherichia coli (EHEC), we have found no role for the two-component systems QseBC and QseEF in the adrenergic regulation of any of the identified genes. Furthermore, hormone-regulated gene expression could not be blocked by the QseC inhibitor LED209, suggesting that sensing of hormones is mediated through alternative signaling pathways in S. Typhimurium. This study has identified a role for host-derived neuroendocrine stress hormones in downregulating S. Typhimurium virulence gene expression to the benefit of the host, thus providing further insights into the field of host-pathogen communication.

Maintained cerebral metabolic ratio during exercise in patients with β‐adrenergic blockade

Decreased cerebral metabolic ratio (CMR) [molar uptake of O(2) versus molar uptake of (glucose + (1/2) lactate)] during exercise is attenuated by intravenous administration of the non-selective beta-adrenergic receptor antagonist propranolol. We evaluated to what extent cirrhotic patients in oral treatment with propranolol are able to mobilize brain non-oxidative carbohydrate metabolism. Incremental cycle ergometry to exhaustion (86 +/- 4.2 W; mean +/- SD) was performed in eight cirrhotic patients instrumented with a catheter in the brachial artery and one retrograde in the right internal jugular vein. Healthy subjects form the control group. In beta-blocked cirrhotic patients arterial lactate increased from 1.5 +/- 0.3 to 5.1 +/- 0.8 mM (P<0.05) and the arterial-jugular venous difference (a-v diff) from -0.01 +/- 0.03 to 0.30 +/- 0.05 mM (P<0.05) at rest and during exercise, respectively. During exercise the glucose a-v diff of 0.46 +/- 0.06 mM remained at a level similar to rest (0.54 +/- 0.03 mM) and at exhaustion the CMR was not significantly changed (5.8 +/- 1.1 versus 6.0 +/- 0.6). In controls, CMR decreased from 5.6 +/- 0.9 at rest to 3.4 +/- 0.7 (P<0.05) during maximal exercise and at a lactate level comparable to that achieved by the patients it was 3.8 +/- 0.4. During exhaustive exercise in cirrhotic patients the CMR is maintained and a significant cerebral uptake of lactate is demonstrated. The data suggest that oral treatment with a non-selective beta-adrenergic receptor antagonist attenuates cerebral non-oxidative metabolism.

About strawberry, crab claws, and the Sir James Black’s invention. Hypothesis: Can we battle keloids with propranolol?

The cutaneous hemangiomas of infancy or infantile hemangiomas are the most common benign tumor of childhood. They were formerly known as strawberry hemangiomas in reason of its typical appearance although uncommon morphologic variations can be found. Usually hemangiomas are harmless growths that are the result of proliferation of endothelial cells during early childhood. Involution of the lesion occurs at 12–18 months and can last up to 7 years. Occasionally, infantile hemangiomas suffer dramatic overgrowth causing esthetical damages, as well compromises to vital structures that requires prompt intervention. Propranolol, a beta-adrenergic receptor antagonist that was invented by Sir James Black in 1960s, appears to be an effective treatment for infantile hemangiomas and should now be used as a first-line treatment in hemangiomas when intervention is required. Keloids (that resembles crab claws) and hypertrophic scars are fibrous tissue outgrowths that result from a derailment in the normal wound-healing process. Systemic or intralesional propranolol may play a role in the amelioration of keloids and hypertrophic scars due to their potential to induce vasoconstriction of over proliferating tissues, triggering apoptosis of endothelial cells and also to their effect as modulator of inflammatory process during wound healing. In adding the propranolol to the melting pot of abnormal (or supra-normal) wound healing, we hypothesized that we can battle keloids with propranolol.

Noradrenergic modulation of neuronal responses to glutamate in the vestibular complex

Increases in firing rate induced in secondary vestibular neurons by microiontophoretic application of glutamate were studied during long-lasting applications of noradrenaline (NA) and/or its antagonists and agonists. Sixty-nine percent of the tested neurons, scattered through all nuclei of the vestibular complex, modified their responsiveness to glutamate in the presence of NA. The effects were depressive in a majority (40%) and enhancing in a minority (29%) of cases. NA application depressed responses to glutamate more often than it increased them in lateral, medial and superior vestibular nuclei, while the reverse was true for the spinal nucleus. The mean intensities of NA-evoked effects were comparable in the various nuclei. The enhancing effects of NA were antagonized by application of the alpha2 receptor antagonist yohimbine, and their depressive effects were enhanced by the beta receptor antagonist timolol. It is concluded that NA exerts a control on the processing of vestibular information and that this modulation is exerted by at least two mechanisms involving alpha2 and beta noradrenergic receptors.

Nebivolol

Nebivolol is a beta-adrenergic receptor antagonist with a dual mechanism of action. It shows high selectivity for beta(1)-adrenergic receptors and appears to have nitric oxide-mediated vasodilatory activity. Once-daily nebivolol effectively lowered BP in patients with mild to moderate hypertension in four randomized, double-blind, placebo-controlled, 12-week trials. Trough sitting DBP and SBP were reduced to a significantly greater extent in nebivolol than in placebo recipients in trials in demographically heterogenous hypertensive patient groups, as well as in trials involving only Black patients and in patients continuing previous stable antihypertensive drug therapies. Treatment response (defined as a mean sitting DBP <90 mmHg or a >or=10 mmHg reduction from baseline) rates were significantly higher in nebivolol versus placebo recipients in trials enrolling patient groups considered representative of the US hypertensive population (46-65% vs 25%), in Black patients (57-64% vs 27%), and in patients concurrently treated with other antihypertensive drugs (53-65% vs 41%). Nebivolol was generally well tolerated in the treatment of hypertension, with the majority of adverse events described as being mild or moderate in severity. The incidences of fatigue, bradycardia, dyspnea, depression, and erectile dysfunction (events commonly associated with beta-adrenergic receptor antagonist use) did not significantly differ between nebivolol and placebo recipients in the 12-week trials.

Statins and Erectile Dysfunction

HMG-CoA reductase inhibitors, more commonly called statins, are widely used in the pharmacological management of hyperlipidaemias. The most common adverse drug reactions (ADRs) of statins are muscular. Other reported ADRs of statins along with other lipid-lowering drugs, namely fibrates, include erectile dysfunction (ED). The relationship between ED and exposure to statins has not clearly been established even though a number of significant case reports have associated ED with exposure to statins. To investigate the association between exposure to statins and the occurrence of ED on the French Pharmacovigilance System Database. Within the French Pharmacovigilance System Database, the case/non-case method was used to measure the disproportionality of combination between a statin and ED. Cases are defined as those reports corresponding to the ADR of interest (i.e. ED) and non-cases are all reports of ADRs other than that being studied. The study period was from 1 January 1985 to 31 December 2006, limited to males aged 13-80 years. We estimated the association between ED and statins by calculating a reporting odds ratio (ROR) of exposure to each drug, with its 95% confidence interval (CI). Among the total of spontaneous reports selected (110 685), exposure to statins was identified in 4471 cases (4%), of which 51 reports (1.1%) concerned ED, whereas 431 (0.4%) cases of ED were found in the 106 214 reports without exposure to statins (p < 0.0001). The mean delay of onset of ED after starting statins, known for 19 cases, was 62 days (median 29 days). In 56.9% of cases, recovery occurred after withdrawal of statin, and rechallenge was positive in five cases. The association was statistically significant for all statins (adjusted ROR [aROR] = 2.4; 95% CI 1.8, 3.3), simvastatin (aROR = 2.6; 1.6, 4.1), atorvastatin (aROR = 3.4; 2.1, 5.4) and rosuvastatin (aROR = 7.1; 2.6, 19.4) [p < 0.001 for all] but not for pravastatin and fluvastatin. We did not find any relationship between the occurrence of ED and the daily dose or the duration of exposure to statins (data not shown). Assessment of the association between drugs other than statins known to be at risk of ED confirmed a significant association for finasteride (aROR = 14.5; 95% CI 8.3, 25.4), fibrates (aROR = 3.6; 2.6, 5.1), beta-adrenergic receptor antagonists (aROR = 1.5; 1.01, 2.1) and tricyclic antidepressants (aROR = 2.0; 1.2, 3.4) [all p < 0.05]. Despite some methodological limitations, the present study suggests that statins may induce or worsen ED in accordance with other data. Further pharmacoepidemiological studies are necessary to confirm this conclusion and to improve the precision of the prevalence and/or the risk factors of this ADR.

Interleukin-1 cluster gene polymorphisms in childhood IgA nephropathy

We have carried out a study with the aim of investigating the association between single nucleotide polymorphisms (SNPs) of the IL-1 gene cluster and childhood IgA nephropathy (IgAN). SNPs of the IL-1 alpha, IL-1 beta, and IL-1 receptor antagonist (RN) genes (IL1A, IL1B, and IL1RN, respectively) were analyzed in 182 patients with childhood IgAN and in 500 healthy controls. The IgAN patients were also dichotomized and compared with respect to proteinuria (<4 mg and >or=4 mg/m(2) per hour, respectively), the presence or absence of podocyte foot process effacement, and the presence of pathologically early and advanced disease markers, such as interstitial fibrosis, tubular atrophy, or global sclerosis. Significant differences in SNP frequencies were observed for the IL1B and IL1RN genes (rs1143627, rs3917356, and rs1143633 in the IL1B gene, and rs928940, rs439154, and rs315951 in the IL1RN gene). Moreover, rs1143627, rs3917356, and rs1143633 of IL1B were found to be significantly associated with the presence of podocyte foot process effacement. Our results suggest that the IL1B and IL1RN genes are associated with increased susceptibility to IgAN in children. They also suggest that the development of proteinuria in IgAN is related to IL1A and that podocyte foot process effacement is associated with IL1B.

Brinzolamide/Timolol

Brinzolamide 1%/timolol 0.5% fixed combination (brinzolamide/timolol) is a twice-daily eyedrops suspension comprising the carbonic anhydrase-II inhibitor brinzolamide and the beta-adrenergic receptor antagonist timolol. Brinzolamide/timolol produced clinically relevant reductions in mean intraocular pressure (IOP) from baseline and was more effective than brinzolamide or timolol monotherapy in lowering IOP in a 6-month, randomized, phase III trial in patients with open-angle glaucoma or ocular hypertension (n = 523). The proportion of patients achieving a mean IOP of <18 mmHg was significantly greater in recipients of brinzolamide/timolol than in recipients of brinzolamide or timolol monotherapy. The IOP-lowering efficacy of brinzolamide/timolol was maintained for up to 12 months, and was no less effective than dorzolamide 2%/timolol 0.5% solution (dorzolamide/timolol) in a randomized, phase III, noninferiority trial (n = 437). Brinzolamide/timolol was generally well tolerated and was associated with significantly lower ocular discomfort scores than dorzolamide/timolol. Moreover, a significantly greater number of patients expressed a preference for brinzolamide/timolol over dorzolamide/timolol. The main ocular adverse event was blurred vision, and was not considered to be a safety issue.

Cerebral non‐oxidative carbohydrate consumption in humans driven by adrenaline

During brain activation, the decrease in the ratio between cerebral oxygen and carbohydrate uptake [6 O2/(glucose + 1/2lactate); OCI] is attenuated by the non‐selective beta‐adrenergic receptor antagonist propranolol, whereas OCI remains unaffected by the beta1‐adrenergic receptor antagonist metroprolol. These observations suggest involvement of a beta2‐adrenergic mechanism in non‐oxidative metabolism for the brain. Therefore, we evaluated the effect of adrenaline (0.08 micrograms kg‐1 min‐1 iv. for 15 min) and noradrenaline (0.5, 0.1 and 0.15 micrograms kg‐1 min‐1 iv. for 20 min) on the arterial to internal jugular venous concentration differences (a‐v diff) of O2, glucose, and lactate in healthy humans. Adrenaline (n=10) increased the arterial concentrations of O2, glucose and lactate (P &lt; 0.05) and also increased the a‐v diff for glucose from 0.6 ± 0.1 to 0.8 ± 0.2 mM (mean ± SD; P &lt; 0.05). The a‐v diff for lactate shifted from a net cerebral release to an uptake and OCI was lowered from 5.1 ± 1.5 to 3.6 ± 0.4 (P &lt; 0.05) indicating a 8‐fold increase in the rate of non‐oxidative carbohydrate uptake during adrenaline infusion (P &lt; 0.01). Conversely, noradrenaline (n=8) did not affect the OCI despite an increase in the a‐v diff for glucose (P &lt; 0.05). These results support that non‐oxidative carbohydrate consumption for the brain is driven by a beta2‐adrenergic mechanism, making neurons abundantly provided with energy when plasma adrenaline increases.

Expression of β2‐adrenergic receptor in oral squamous cell carcinoma

It has been speculated that chemokines and neurotransmitters might be involved in the organ-specific development of metastases because cancer metastasis is similar to the regulation of migratory activity in leukocytes. Here, we aimed to examine the expression of beta(2)-adrenergic receptor (beta(2)-AR) in oral squamous cell carcinoma (OSCC), and to investigate its correlation with tumor development and metastasis. Expression of beta(2)-AR was examined in 65 cases of OSCC specimens, 10 cases of normal oral mucosa, and two cell lines using immunohistochemistry, Western blot and RT-PCR. The differences in beta(2)-AR expression between various groups were evaluated using SPSS 13.0 Statistical Software. Cell proliferation assays were assayed by beta-adrenergic receptors agonists (norepinephrine) and antagonists (propranolol). Norepinephrine-mediated cell migration was assayed in Matrigel-coated chemotaxis chamber. beta(2)-AR was highly expressed on OSCC compared to normal controls. In OSCC, positive beta(2)-AR expression was significantly correlated with cervical lymph node metastasis (P = 0.001), age (P = 0.003), tumor size (P = 0.001) and clinical stage (P = 0.001), but not with gender. RT-PCR and Western blot also confirmed positive beta(2)-AR expression in OSCC and TCa8113 cell line, and negative beta(2)-AR expression in normal oral mucosa and ACC cell line. beta-adrenoreceptor agonist (norepinephrine) was a potent mitogen for TCa8113 and ACC cell lines, and completely inhibited by the selective antagonist of beta-adrenergic receptors (propranolol). Norepinephrine induced migratory activity of OSCC cells in a dose-dependent manner. Increased expression of beta(2)-AR may play an important role in the formation and metastasis of OSCC.

Strain-dependent differences of restraint stress-induced hypertension in WKY and SHR

The aim of our study was to investigate differences in restraint stress-response between normotensive Wistar Kyoto rats (WKY) and spontaneously hypertensive rats (SHR) and the consequences for tail-cuff (TC) blood pressure measurements. We therefore radiotelemetrically collected cardiovascular data from WKY and SHR that underwent TC procedures and measured plasma norepinephrine (NE) and angiotensin II (ATII) levels as well as gene expression of the adrenal and hypothalamic tyrosine-hydroxylase, the rate-limiting enzyme in NE synthesis. Furthermore, we determined the effects of antihypertensive therapy using the beta 1-receptor antagonist metoprolol, the alpha 1-receptor antagonist doxazosin and the AT 1-receptor antagonist telmisartan as mono- or combination therapies during the TC procedure. Results show that the TC procedure induced a stress reaction characterised by greatly increasing heart rate (HR) and blood pressure (BP) and elevating plasma norepinephrine and angiotensin II concentrations. Strain-dependent differences were found concerning stress reactions during rest (more pronounced effects) and activity of the two rat strains. In both strains, metoprolol inhibited the TC-induced increase in HR and doxazosin the TC-induced increase in BP. Telmisartan, in addition, reduced hypertension in SHR, slightly reduced the TC-induced increase of BP in SHR but had no effect in WKY. The cardiovascular data as well as those on NE, ATII and TH expression clearly show that SHR are less able to cope with stress-related mechanisms than the normotensive WKY. Since TC activates both the sympathetic as well as renin–angiotensin system this method is not appropriate to evaluate neither physiological nor drug-induced effects on BP and HR.

Changes in the Rhythmoinotropic Dependence of the Myocardium in Rats with Postinfarction Cardiosclerosis after β1-Adrenoreceptor Blocking

The rhythmoinotropic dependence of the papillary muscles was studied in rats with postinfarction cardiosclerosis after blocking of beta(1)-adrenoreceptors by concor (7 mg/kg daily). The development of postinfarction cardiosclerosis led to a reduction of the postextrasystolic potentiation and of potentiation induced by periods of rest. Preliminary blocking of beta(1)-adrenoreceptors stimulated the postextrasystolic contractions and contractions after periods of rest in the myocardium of rats with postinfarction cardiosclerosis. These results suggest that blocking of beta(1)-adrenoreceptors promotes an improvement of calcium-accumulating function of the cardiomyocyte sarcoplasmatic reticulum in the myocardium of rats with postinfarction cardiosclerosis.

P.4.10 Effects of early exposure to ethanol and/or a cannabinoid receptor agonist on alcohol preference at adult age in mice

in which each instrumental response was reinforced with the drug CS in the absence of cocaine. One group received a systemic injection of the NMDA receptor antagonist MK-801 in conjunction with memory reactivation, another received the beta-adrenergic receptor antagonist propranolol, and control groups received saline. At subsequent test, in which instrumental responding was reinforced with the CS alone, the MK-801-treated group showed a reduction in drug-seeking responses compared to the saline control group. The responding of the MK801-treated group was equivalent to the responding of another control group, for which the CS was omitted at test. By contrast, injections of propranolol in conjunction with memory reactivation did not reduce instrumental responding at subsequent test.

Postural Tachycardia Syndrome (POTS)

POTS is defined as the development of orthostatic symptoms associated with a heart rate (HR) increment >or=30, usually to >or=120 bpm without orthostatic hypotension. Symptoms of orthostatic intolerance are those due to brain hypoperfusion and those due to sympathetic overaction. We provide a review of POTS based primarily on work from the Mayo Clinic. Females predominate over males by 5:1. Mean age of onset in adults is about 30 years and most patients are between the ages of 20-40 years. Pathophysiologic mechanisms (not mutually exclusive) include peripheral denervation, hypovolemia, venous pooling, beta-receptor supersensitivity, psychologic mechanisms, and presumed impairment of brain stem regulation. Prolonged deconditioning may also interact with these mechanisms to exacerbate symptoms. The evaluation of POTS requires a focused history and examination, followed by tests that should include HUT, some estimation of volume status and preferably some evaluation of peripheral denervation and hyperadrenergic state. All patients with POTS require a high salt diet, copious fluids, and postural training. Many require beta-receptor antagonists in small doses and low-dose vasoconstrictors. Somatic hypervigilance and psychologic factors are involved in a significant proportion of patients. POTS is heterogeneous in presentation and mechanisms. Major mechanisms are denervation, hypovolemia, deconditioning, and hyperadrenergic state. Most patients can benefit from a pathophysiologically based regimen of management.

Beyond extinction: erasing human fear responses and preventing the return of fear

Animal studies have shown that fear memories can change when recalled, a process referred to as reconsolidation. We found that oral administration of the beta-adrenergic receptor antagonist propranolol before memory reactivation in humans erased the behavioral expression of the fear memory 24 h later and prevented the return of fear. Disrupting the reconsolidation of fear memory opens up new avenues for providing a long-term cure for patients with emotional disorders.

Catecholamine-secreting neuroblastoma in a 4-month-old infant: perioperative management

Preoperative alpha- and beta-adrenergic receptor block with phenoxybenzamine and labetalol, the intraoperative course of a 4-month-old infant with neuroblastoma and elevated catecholamines causing sweating, hypertension, and tachycardia, are presented. We recommend determination of catecholamine levels and pretreatment with alpha-adrenergic and–if needed–beta-adrenergic receptor antagonists in infants with neuroblastoma and hypertension, tachycardia, or sweating.

A dose–response study of the effects of pre-test administration of beta-adrenergic receptor antagonist propranolol on the learning of active place avoidance, a spatial cognition task, in rats

The involvement of various neurotransmitter receptors in the brain in the regulation of spatial behavior is a focus of interest for many cognitive neuroscientists. Active allothetic place avoidance (AAPA) task have been demonstrated to require spatial mapping and cognitive coordination and is highly dependent upon hippocampus. The present study was designed to evaluate the role of beta-adrenergic receptors in the modulation of locomotor and spatial behavior in this task. Four doses of centrally active beta-adrenergic antagonist propranolol (5, 20, 25 and 30 mg/kg) were administered intraperitoneally 30 min prior to testing in the place avoidance task. Four daily sessions were pursued, each lasting 20 min. A dose of 25 mg/kg was found to induce a deficit in spatial behavior (measured by number of entrances into the shock sector) without altering locomotion; lower doses were without effect. The highest dose (30 mg/kg) impaired both locomotion and avoidance behavior. The results suggest that beta-adrenoceptors are involved in the regulation of behavior in the place avoidance task and that it is possible to dissociate the effect of propranolol on the spatial performance and locomotion in the AAPA using dose-selection.

Peanuts can contribute to anaphylactic shock by activating complement

Peanut allergy is the most common food-related cause of lethal anaphylaxis and, unlike other food allergies, typically persists into adulthood. Resistance to digestion and dendritic cell activation by the major peanut allergen Ara h 1 are reported to contribute to its allergenicity. We sought to evaluate whether peanut molecules might also promote anaphylaxis through an innate immune mechanism. Naive mice were treated with a beta-adrenergic receptor antagonist and long-acting IL-4 to increase sensitivity to vasoactive mediators and injected with peanut extract (PE). Shock was detected and quantified by means of rectal thermometry. Gene-deficient mice and specific antagonists were used to determine the roles of specific cell types, complement, Fc receptors, and vasoactive mediators in shock pathogenesis. PE induces dose-dependent shock. PE activates complement in vivo in mice and in vitro in mice and human subjects. C3a and, to a lesser extent, stimulatory immunoglobulin receptors contribute to PE-induced shock. PE-induced shock depends more on macrophages and basophils than on mast cells. Platelet-activating factor and, to a lesser extent, histamine contribute to PE-induced shock. PE induces shock in the absence of the adaptive immune system. LPS contamination is not responsible for PE-induced shock. PE and IgE-mediated mast cell degranulation synergistically induce shock. Tree nuts have similar effects to PE, and skim milk and egg white do not. Peanuts can contribute to shock by causing production of C3a, which stimulates macrophages, basophils, and mast cells to produce platelet-activating factor and histamine.

Goshuyuto, a Traditional Japanese Medicine, and Aqueous Extracts of Evodiae Fructus Constrict Isolated Rat Aorta via Adrenergic and/or Serotonergic Receptors

Effects of goshuyuto, a traditional Japanese medicine, on vascular constriction were examined using isolated strips of rat aorta. Goshuyuto (1 x 10(-5) to 1 x 10(-3) g/ml) caused constriction of aorta strips in a dose-dependent manner. The vasoconstrictive effects of goshuyuto were significantly inhibited by pretreatment with prazosin, an adrenergic alpha(1) receptor antagonist. The constrictive effects were partially inhibited by pretreatment with BRL15572, a 5-HT(1D) antagonist, and ketanserin, a 5-HT(2A) antagonist. However, the constrictive effects were not inhibited by pretreatment with SB216641, a 5-HT(1B) antagonist, or propranolol, an adrenergic beta receptor antagonist. In addition, aqueous extracts of Evodiae Fructus, one of the constituent medicinal herbs of goshuyuto, caused constriction of aorta strips strongly, but aqueous extracts of Zizyphi Fructus, Ginseng Radix, and Zingiberis Rhizoma, the other constituents of goshuyuto, did not have much effect on the vascular response of rat aorta strips. Also, synephrine, which is one of the ingredients of Evodiae Fructus, constricted the rat aorta. These results suggest that goshuyuto constricts rat aorta strips and that the mechanisms involve the adrenergic and/or serotonergic receptors. Also, it may be suggested that Evodiae Fructus and synephrine play the important role in the vasoconstrictive effects of goshuyuto on rat aorta strips.

Antidepressants in Long-Term Migraine Prevention

Migraine and depression coincide in some 20-30% of patients. Although antidepressants (namely tricyclics) are not considered as first-line prophylactic compounds in patients with migraine alone, several clinical trials support a remarkable benefit in the treatment of migraine and related headache disorders. However, treatment with one antidepressant alone often does not suffice to treat both disorders effectively. Therefore, combinations of classical antidepressants with both newer antidepressants and established prophylactic drugs (e.g. beta-adrenergic receptor antagonists [beta-blockers], topiramate and sodium valproate) are required. In addition, acute attack medication (such as triptans, ergotamines or analgesics) is regularly combined with the preventive medication, thus requiring elaborate knowledge about the complex network of potential interactions and contraindications. Fear of potentially serious interactions can frequently lead to insufficient treatment of both underlying disorders, with an enormous impact on the patient's life. Pathophysiologically, multiple neurotransmitters have been attributed an important role in the aetiology of migraine (mainly serotonin and calcitonin gene-related peptide) and depression (among others, serotonin, dopamine and noradrenaline [norepinephrine]). Most drugs used to treat both disorders influence at least one of these transmitter systems, such as classical tricyclics. This review discusses the efficacy of antidepressants in migraine prevention. In addition, recommended combinations in patients with concomitant depression and migraine are presented with regard to their proposed pharmacological mechanism of action and their potential interactions.