The endogenous cannabinoid receptor agonist anandamide is a powerful vasodilator of isolated vascular preparations, but its mechanism of action is unclear. Here we show that the vasodilator response to anandamide in isolated arteries is capsaicin-sensitive and accompanied by release of calcitonin-gene-related peptide (CGRP). The selective CGRP-receptor antagonist 8-37 CGRP, but not the cannabinoid CB1 receptor blocker SR141716A, inhibited the vasodilator effect of anandamide. Other endogenous (2-arachidonylglycerol, palmitylethanolamide) and synthetic (HU 210, WIN 55,212-2, CP 55,940) CB1 and CB2 receptor agonists could not mimic the action of anandamide. The selective 'vanilloid receptor' antagonist capsazepine inhibited anandamide-induced vasodilation and release of CGRP. In patch-clamp experiments on cells expressing the cloned vanilloid receptor (VR1), anandamide induced a capsazepine-sensitive current in whole cells and isolated membrane patches. Our results indicate that anandamide induces vasodilation by activating vanilloid receptors on perivascular sensory nerves and causing release of CGRP. The vanilloid receptor may thus be another molecular target for endogenous anandamide, besides cannabinoid receptors, in the nervous and cardiovascular systems.

Background Intracerebral hemorrhage (ICH) accounted for 9% to 27% of all strokes worldwide in the last decade, with high early case fatality and poor functional outcome. In view of recent randomized controlled trials (RCTs) of the management of ICH, the European Stroke Organisation (ESO) has updated its evidence-based guidelines for the management of ICH. Method A multidisciplinary writing committee of 24 researchers from 11 European countries identified 20 questions relating to ICH management and created recommendations based on the evidence in RCTs using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. Results We found moderate-to high-quality evidence to support strong recommendations for managing patients with acute ICH on an acute stroke unit, avoiding hemostatic therapy for acute ICH not associated with antithrombotic drug use, avoiding graduated compression stockings, using intermittent pneumatic compression in immobile patients, and using blood pressure lowering for secondary prevention. We found moderate-quality evidence to support weak recommendations for intensive lowering of systolic blood pressure to <140 mmHg within six-hours of ICH onset, early surgery for patients with a Glasgow Coma Scale score 9-12, and avoidance of corticosteroids. Conclusion These guidelines inform the management of ICH based on evidence for the effects of treatments in RCTs. Outcome after ICH remains poor, prioritizing further RCTs of interventions to improve outcome.

The original version of this consensus statement on mechanical thrombectomy was approved at the European Stroke Organisation (ESO)-Karolinska Stroke Update conference in Stockholm, 16-18 November 2014. The statement has later, during 2015, been updated with new clinical trials data in accordance with a decision made at the conference. Revisions have been made at a face-to-face meeting during the ESO Winter School in Berne in February, through email exchanges and the final version has then been approved by each society. The recommendations are identical to the original version with evidence level upgraded by 20 February 2015 and confirmed by 15 May 2015. The purpose of the ESO-Karolinska Stroke Update meetings is to provide updates on recent stroke therapy research and to discuss how the results may be implemented into clinical routine. Selected topics are discussed at consensus sessions, for which a consensus statement is prepared and discussed by the participants at the meeting. The statements are advisory to the ESO guidelines committee. This consensus statement includes recommendations on mechanical thrombectomy after

1 In the presence of N G -nitro-L-arginine (L-NOARG, 0.3 mM) and indomethacin (10 mM), the relaxations induced by acetylcholine and the calcium (Ca) ionophore A23187 are considered to be mediated by endothelium-derived hyperpolarizing factor (EDHF) in the guinea-pig basilar artery. 2 Inhibitors of adenosine 5'-triphosphate (ATP)-sensitive potassium (K)-channels (K ATP ; glibenclamide, 10 mM), voltage-sensitive K-channels (K V ; dendrotoxin-I, 0.1 mM or 4-aminopyridine, 1 mM), small (SK Ca ; apamin, 0.1 mM) and large (BK Ca ; iberiotoxin, 0.1 mM) conductance Ca-sensitive K-channels did not a ect the L-NOARG/indomethacin-resistant relaxation induced by acetylcholine. 3 Synthetic charybdotoxin (0.1 mM), an inhibitor of BK Ca and K V , caused a rightward shift of the concentration-response curve for acetylcholine and reduced the maximal relaxation in the presence of L-NOARG and indomethacin, whereas the relaxation induced by A23187 was not signi®cantly inhibited. 4 A combination of charybdotoxin (0.1 mM) and apamin (0.1 mM) abolished the L-NOARG/ indomethacin-resistant relaxations induced by acetylcholine and A23187. However, the acetylcholineinduced relaxation was not a ected by a combination of iberiotoxin (0.1 mM) and apamin (0.1 mM). 5 Ciclazindol (10 mM), an inhibitor of K V in rat portal vein smooth muscle, inhibited the L-NOARG/ indomethacin-resistant relaxations induced by acetylcholine and A23187, and the relaxations were abolished when ciclazindol (10 mM) was combined with apamin (0.1 mM). 6 Human pial arteries from two out of four patients displayed an L-NOARG/indomethacin-resistant relaxation in response to substance P. This relaxation was abolished in both cases by pretreatment with the combination of charybdotoxin (0.1 mM) and apamin (0.1 mM), whereas each toxin had little e ect alone. 7 The results suggest that K V , but not K ATP and BK Ca , is involved in the EDHF-mediated relaxation in the guinea-pig basilar artery. The synergistic action of apamin and charybdotoxin (or ciclazindol) could indicate that both K V and SK Ca are activated by EDHF. However, a single type of K-channel, which may be structurally related to K V and allosterically regulated by apamin, could also be the target for EDHF.

Objectives: The aim of this study was to investigate for the first time the association between body fat and risk of amyotrophic lateral sclerosis (ALS) with an appropriate prospective study design. Methods:The EPIC (European Prospective Investigation into Cancer and Nutrition) study included 518,108 individuals recruited from the general population across 10 Western European countries. At recruitment, information on lifestyle was collected and anthropometric characteristics were measured. Cox hazard models were fitted to investigate the associations between anthropometric measures and ALS mortality.Results: Two hundred twenty-two ALS deaths (79 men and 143 women) occurred during the followup period (mean follow-up 5 13 years). There was a statistically significant interaction between categories of body mass index and sex regarding ALS risk (p 5 0.009): in men, a significant linear decrease of risk per unit of body mass index was observed (hazard ratio 5 0.93, 95% confidence interval 0.86-0.99 per kg/m 2 ); among women, the risk was more than 3-fold increased for underweight compared with normal-weight women. Among women, a significant risk reduction increasing the waist/hip ratio was also evident: women in the top quartile had less than half the risk of ALS compared with those in the bottom quartile (hazard ratio 5 0.48, 95% confidence interval 0.25-0.93) with a borderline significant p value for trend across quartiles (p 5 0.056). Conclusion:Increased prediagnostic body fat is associated with a decreased risk of ALS mortality.