Pro-contractile effects of perivascular fat in health and disease.

Perivascular adipose tissue (PVAT) is now recognised as an active player in vascular homeostasis. Expansion of PVAT in obesity and the possible role of PVAT in vascular dysfunction has attracted much interest. In terms of the regulation of vascular tone and blood pressure, PVAT has been shown to release vasoactive mediators, for instance angiotensin peptides, reactive oxygen species, chemokines and cytokines. The secretory profile of PVAT is altered by obesity, hypertension and other cardiovascular diseases, leading to imbalance between its pro-contractile and anti-contractile effects. PVAT adipocytes represent an important source of the mediators, but infiltrating immune cells may become more important under conditions of hypoxia and inflammation. This review describes recent advances on the effects of PVAT on vascular tone regulation, highlighting the evidence for a pro-contractile action in health and disease. The role of the endothelium, vascular smooth muscle, immune cells and probably perivascular nerves in PVAT function is also discussed

A multi agent based model for airport service planning

Author name used in this publication: Vincent ChoAuthor name used in this publication: George Ho2010-2011 > Academic research: refereed > Publication in refereed journalVersion of RecordPublishe

Big conductance calcium-activated potassium channel openers control spasticity without sedation.

BACKGROUND AND PURPOSE: Our initial aim was to generate cannabinoid agents that control spasticity, occurring as a consequence of multiple sclerosis (MS), whilst avoiding the sedative side effects associated with cannabis. VSN16R was synthesized as an anandamide (endocannabinoid) analogue in an anti-metabolite approach to identify drugs that target spasticity. EXPERIMENTAL APPROACH: Following the initial chemistry, a variety of biochemical, pharmacological and electrophysiological approaches, using isolated cells, tissue-based assays and in vivo animal models, were used to demonstrate the activity, efficacy, pharmacokinetics and mechanism of action of VSN16R. Toxicological and safety studies were performed in animals and humans. KEY RESULTS: VSN16R had nanomolar activity in tissue-based, functional assays and dose-dependently inhibited spasticity in a mouse experimental encephalomyelitis model of MS. This effect occurred with over 1000-fold therapeutic window, without affecting normal muscle tone. Efficacy was achieved at plasma levels that are feasible and safe in humans. VSN16R did not bind to known CB1 /CB2 /GPPR55 cannabinoid-related receptors in receptor-based assays but acted on a vascular cannabinoid target. This was identified as the major neuronal form of the big conductance, calcium-activated potassium (BKCa ) channel. Drug-induced opening of neuronal BKCa channels induced membrane hyperpolarization, limiting excessive neural-excitability and controlling spasticity. CONCLUSIONS AND IMPLICATIONS: We identified the neuronal form of the BKCa channel as the target for VSN16R and demonstrated that its activation alleviates neuronal excitability and spasticity in an experimental model of MS, revealing a novel mechanism to control spasticity. VSN16R is a potential, safe and selective ligand for controlling neural hyper-excitability in spasticity

The Endocannabinoid System: A Dynamic Signalling System at the Crossroads Between Metabolism and Disease

The discovery of the endocannabinoid system (ECS) in the early 1990s of last century generated high expectations of new therapeutic opportunities. Its central role and pleiotropic character seemed to offer promising indications in the fields of pain, inflammation, CNS disorders, weight management and metabolic diseases. However, around 2007 the tide began to turn when several cannabinoid receptor type 1 (CB1) antagonists/inverse agonists failed as therapeutics against overweight and its complications. More recently, the development of FAAH (Fatty Acid Amide Hydrolase) inhibitors against pain has also faced serious setbacks. In retrospect the much greater complexity of the ECS than originally assumed has played a fundamental role in these difficulties. Although there is no doubt that endocannabinoids and their receptors are of great (patho-)physiological relevance, it has become clear that the ECS is intimately intertwined with other biological systems. Endocannabinoids exist in equilibrium with fatty acids and their metabolic derivatives, including eicosanoids and prostamides. Furthermore, there are several biologically active analogues of endocannabinoids, in particular fatty acid amides, with metabolic pathways overlapping those of the ECS. Finally, endocannabinoids per se and their congeners show “promiscuous” behaviour going beyond interactions with CB1 and CB2 receptors. It has become clear that the complexity of what may be called the “endocannabinoidome” demands for pharmacological approaches that take into account these dynamics. Targeting the “endocannabinoidome” continues to offer opportunities for prevention and therapy, in particular for chronic diseases. However, chances for success are more likely to come from “multiple-target” than from “single-target” approaches