British Journal of Pharmacology - Volume 165 Issue 5 (March 2012)

1. Different tests for a difference: how do we do research?

Date: Feb 10, 2012, Pages: 1217-1222

2. What makes the α _1A ‐adrenoceptor gene express the α _1L ‐adrenoceptor functional phenotype?

Date: Feb 10, 2012, Pages: 1223-1225

The α1A‐adrenoceptor is therapeutically exploited because of its prevalence in the lower urinary tract. The pharmacology shown by this lower urinary tract α1A‐adrenoceptor is different from that shown by other α1A‐adrenoceptors, which has led to it being subclassified as an α1L‐adrenoceptor. Only in the last few years was it shown that this pharmacologically distinct α1L‐adrenoceptor is a product of the α1A‐adrenoceptor gene. In this issue of the BJP, Nishimune...

3. Phenotype pharmacology of lower urinary tract α ₁ ‐adrenoceptors

Date: Feb 10, 2012, Pages: 1226-1234

α1‐Adrenoceptors are involved in numerous physiological functions, including micturition. However, the pharmacological profile of the α1‐adrenoceptor subtypes remains controversial. Here, we review the literature regarding α1‐adrenoceptors in the lower urinary tract from the standpoint of α1L phenotype pharmacology. Among three α1‐adrenoceptor subtypes (α1A, α1B and α1D), α1a‐adrenoceptor mRNA is the most abundantly transcribed in the prostate, urethra and...

4. Cyclosporin A and cardioprotection: from investigative tool to therapeutic agent

Date: Feb 10, 2012, Pages: 1235-1245

Ischaemic heart disease (IHD) is the leading cause of death and disability worldwide. The pathophysiological effects of IHD on the heart most often result from the detrimental effects of acute ischaemia–reperfusion injury (IRI) on the myocardium. Therefore, novel therapeutic targets for protecting the myocardium against acute IRI are required to reduce injury to the heart, preserve cardiac function and improve clinical outcomes in...

5. Tau‐targeted treatment strategies in Alzheimer's disease

Date: Feb 10, 2012, Pages: 1246-1259

With populations ageing worldwide, the need for treating and preventing diseases associated with high age is pertinent. Alzheimer's disease (AD) is reaching epidemic proportions, yet the currently available therapies are limited to a symptomatic relief, without halting the degenerative process that characterizes the AD brain. As in AD cholinergic neurons are lost at high numbers, the initial strategies were limited to the development of...

6. OATPs, OATs and OCTs: the organic anion and cation transporters of the SLCO and SLC22A gene superfamilies

Date: Feb 10, 2012, Pages: 1260-1287

The human organic anion and cation transporters are classified within two SLC superfamilies. Superfamily SLCO (formerly SLC21A) consists of organic anion transporting polypeptides (OATPs), while the organic anion transporters (OATs) and the organic cation transporters (OCTs) are classified in the SLC22A superfamily. Individual members of each superfamily are expressed in essentially every epithelium throughout the body, where they play a significant...

7. Cyclic nucleotide phosphodiesterase (PDE) isozymes as targets of the intracellular signalling network: benefits of PDE inhibitors in various diseases and perspectives for future therapeutic developments

Date: Feb 10, 2012, Pages: 1288-1305

Cyclic nucleotide phosphodiesterases (PDEs) that specifically inactivate the intracellular messengers cAMP and cGMP in a compartmentalized manner represent an important enzyme class constituted by 11 gene‐related families of isozymes (PDE1 to PDE11). Downstream receptors, PDEs play a major role in controlling the signalosome at various levels of phosphorylations and protein/protein interactions. Due to the multiplicity of isozymes, their...

8. The evolving science of detection of ‘blood doping’

Date: Feb 10, 2012, Pages: 1306-1315

Blood doping practices in sports have been around for at least half a century and will likely remain for several years to come. The main reason for the various forms of blood doping to be common is that they are easy to perform, and the effects on exercise performance are gigantic. Yet another reason for blood doping to be a popular illicit practice is that detection is difficult. For autologous blood transfusions, for example, no direct...

9. TLR4‐MyD88 signalling: a molecular target for alcohol actions

Date: Feb 10, 2012, Pages: 1316-1318

Several studies implicate Toll‐like receptors (TLRs) in alcohol‐induced neuroinflammatory processes. The work reported by Wu et al., in this issue of the British Journal of Pharmacology, indicates that TLR4 along with its intracellular adaptor protein, MyD88, may play crucial roles in the acute actions of alcohol. The deletions of TLR4 or MyD88 gene or pharmacological inhibition of TLR4 by (+)‐naloxone were able to attenuate ...

10. Inhibiting the TLR4‐MyD88 signalling cascade by genetic or pharmacological strategies reduces acute alcohol‐induced sedation and motor impairment in mice

Date: Feb 10, 2012, Pages: 1319-1329

BACKGROUND AND PURPOSE Emerging evidence implicates a role for toll‐like receptor 4 (TLR4) in the CNS effects of alcohol. The aim of the current study was to determine whether TLR4–MyD88‐dependent signalling is involved in the acute behavioural actions of alcohol and if alcohol can activate TLR4‐downstream MAPK and NF‐κB pathways. EXPERIMENTAL APPROACH The TLR4 pathway was evaluated using the TLR4 antagonist...

11. Endothelin and bradykinin: ‘brothers‐in‐arms’ in Chagas vasculopathies?

Date: Feb 10, 2012, Pages: 1330-1332

Reports of Chagas disease are increasing in non‐endemic populations across the globe. Apart from vector eradication and prevention efforts by public health organizations, current pharmacological interventions are sparse and show important side effects. In this issue of the BJP, Andrade et al. elegantly demonstrate a new pharmacological paradigm whereby Trypanosoma cruzi host cell invasion requires significant cross‐talk between receptors for kinins...

12. Trypanosoma cruzi invades host cells through the activation of endothelin and bradykinin receptors: a converging pathway leading to chagasic vasculopathy

Date: Feb 10, 2012, Pages: 1333-1347

BACKGROUND AND PURPOSE Independent studies in experimental models of Trypanosoma cruzi appointed different roles for endothelin‐1 (ET‐1) and bradykinin (BK) in the immunopathogenesis of Chagas disease. Here, we addressed the hypothesis that pathogenic outcome is influenced by functional interplay between endothelin receptors (ETAR and ETBR) and bradykinin B2 receptors (B2R). EXPERIMENTAL APPROACH Intravital microscopy was used to...

13. Azithromycin distinctively modulates classical activation of human monocytes in vitro

Date: Feb 10, 2012, Pages: 1348-1360

BACKGROUND AND PURPOSE Azithromycin has been reported to modify activation of macrophages towards the M2 phenotype. Here, we have sought to identify the mechanisms underlying this modulatory effect of azithromycin on human monocytes, classically activated in vitro. EXPERIMENTAL APPROACH Human blood monocytes were primed with IFN‐γ for 24 h and activated with LPS for 24 h. Azithromycin, anti‐inflammatory and ...

14. Pentoxifylline aggravates fatty liver in obese and diabetic ob/ob mice by increasing intestinal glucose absorption and activating hepatic lipogenesis

Date: Feb 10, 2012, Pages: 1361-1374

BACKGROUND AND PURPOSE Pentoxifylline is in clinical trials for non‐alcoholic fatty liver disease and diabetic nephropathy. Metabolic and hepatic effects of pentoxifylline were assessed in a murine model of obesity and type 2 diabetes. EXPERIMENTAL APPROACH Pentoxifylline (100 mg·kg−1·day−1) was administered for 4 days or 3 weeks in lean and obese/diabetic ob/ob mice. Plasma lipids, glucose, other metabolites and relevant enzymes...

15. Treatment of depressive‐like behaviour in Huntington's disease mice by chronic sertraline and exercise

Date: Feb 10, 2012, Pages: 1375-1389

BACKGROUND AND PURPOSE Depression is the most common psychiatric disorder in Huntington's disease (HD) patients. Women are more prone to develop depression and such susceptibility might be related to 5‐hydroxytryptaminergic (serotonergic) dysregulation. EXPERIMENTAL APPROACH We performed tests of depression‐related behaviours on female R6/1 HD mice that had been chronically treated with sertraline or provided with...