Abdominal aortic aneurysm repair results in aortic stiffening

Long-term follow-up studies show that all-cause mortality remains unchanged after repair of abdominal aortic aneurysm (AAA), possibly because of an increased cardiovascular risk in this high risk group. Repair of the AAA introduces a semirigid conduit into the circulation with unknown effects on the central aortic haemodynamics, such as pulse-wave velocity (PWV). One recent study revealed that a 1 m/s increase in PWV confers a 15% increased risk of cardiovascular events. We investigated whether central aortic haemodynamic changes resulting from AAA repair could be contributing to this excess cardiovascular risk.In nine patients undergoing endovascular aneurysm repair of infrarenal AAA who were assessed for changes in carotid-femoral PWV (cfPWV), mean cfPWV (n=9) was 10·3 m/s (SD 1·0) preoperatively. 1 week and 6 weeks postoperatively, mean cfPWV was 10·2 m/s and 11·2m/s, respectively (mean difference at 6 weeks 0·9m/s [95% CI 0·1–1·8], p=0·03).AAA repair appears to result in a functional stiffening of the aorta. A larger powered study is in progress to confirm this finding and also investigate whether this phenomenon is sustained in the long term. Intensive cardiovascular risk monitoring and pharmacomodulation may be indicated in this high-risk population.FundingBritish Heart Foundation.     

Inhibition of CXCR3-mediated chemotaxis by the human chemokine receptor-like protein CCX-CKR

Background and Purpose

Induction of cellular migration is the primary effect of chemokine receptor activation. However, several chemokine receptor-like proteins bind chemokines without subsequent induction of intracellular signalling and chemotaxis. It has been suggested that they act as chemokine scavengers, which may control local chemokine levels and contribute to the function of chemokines during inflammation. This has been verified for the chemokine-like receptor proteins D6 and DARC as well as CCX-CKR. Here, we provide evidence for an additional biological function of human (h)CCX-CKR.

Experimental Approach

We used transfection strategies in HEK293 and human T cells.

Key Results

Co-expression of hCCX-CKR completely inhibits hCXCR3-induced chemotaxis. We found that hCCX-CKR forms complexes with hCXCR3, suggesting a relationship between CCX-CKR heteromerization and inhibition of chemotaxis. Moreover, negative binding cooperativity induced by ligands both for hCXCR3 and hCCX-CKR was observed in cells expressing both receptors. This negative cooperativity may also explain the hCCX-CKR-induced inhibition of chemotaxis.

Conclusions and Implications

These findings suggest that hCCX-CKR prevents hCXCR3-induced chemotaxis by heteromerization thus representing a novel mechanism of regulation of immune cell migration.     

Activation of PAC1 and VPAC receptor subtypes elicits differential physiological responses from sympathetic preganglionic neurons in the anaesthetized rat

BACKGROUND AND PURPOSE

Pituitary adenylate cyclase-activating polypeptide (PACAP) is an excitatory neuropeptide with central and peripheral cardiovascular actions. Intrathecal PACAP increases splanchnic sympathetic nerve activity and heart rate, but not mean arterial pressure (MAP). We hypothesize that the three PACAP receptors (PAC₁, VPAC₁ and VPAC₂) have different actions in central cardiovascular control, and that their summed effect results in the lack of MAP response observed following intrathecal PACAP injection.

EXPERIMENTAL APPROACH

The effects of the PACAP receptors on baseline cardiovascular parameters were investigated using selective agonists and antagonists administered into the intrathecal space of urethane-anaesthetized, vagotomized and artificially ventilated male Sprague-Dawley rats.

KEY RESULTS

Selective activation of the PACAP receptors had different effects on MAP. When activated by maxadilan, PAC₁ receptors increased MAP. The VPAC receptors decreased MAP when both were activated with vasoactive intestinal polypeptide or when only VPAC₁ receptors were activated. The PAC₁ and VPAC₂ receptor antagonist PACAP(6–38) had no cardiovascular effects, suggesting that PACAP is not tonically released.

CONCLUSIONS AND IMPLICATIONS

PACAP neurotransmission was not responsible for the moment-to-moment tonic regulation of central cardiovascular control mechanisms. Nevertheless, PACAP release within the spinal cord may have pleiotropic effects on sympathetic outflow depending on the postsynaptic receptor type. PAC₁ and VPAC receptor subtypes produced opposing changes in blood pressure when activated by intrathecal PACAP-38 in the anaesthetized Sprague-Dawley rat, resulting in no net change in MAP.     

Mephedrone (4-methylmethcathinone) and d-methamphetamine improve visuospatial associative memory,but not spatial working memory,in rhesus macaques

BACKGROUND AND PURPOSE

The novel cathinone derivative 4-methylmethcathinone (4-MMC; mephedrone) is increasingly popular with recreational users. Little scientific information is available but users report both entactogen-like and classic stimulant-like subjective properties. A recent study in humans reported psychomotor speed improvement after intranasal 4-MMC suggesting classic stimulant properties. Limitations of the user group (which was impaired on some tasks) prompt controlled laboratory investigation.

EXPERIMENTAL APPROACH

Adult male rhesus monkeys were trained to perform tasks from the non-human primate Cambridge Neuropsychological Test Automated Battery, which assess spatial working memory, visuospatial associative memory, learning and motivation for food reward. Test of bimanual motor coordination and manual tracking were also included. The subjects were challenged with 0.178–0.56 mg·kg⁻¹ 4-MMC and 0.056–0.56 mg·kg⁻¹ d-methamphetamine (MA), i.m., in randomized order for behavioural evaluation.

KEY RESULTS

A pronounced improvement in visuospatial memory and learning was observed after the 0.32 mg·kg⁻¹ dose of each compound, this effect was confirmed with subsequent repetition of these conditions. Spatial working memory was not improved by either drug, and the progressive ratio, bimanual motor and rotating turntable tasks were all disrupted in a dose-dependent manner.

CONCLUSIONS AND IMPLICATIONS

These studies show that 4-MMC produces behavioural effects, including improvements in complex spatial memory and learning that are in large part similar to those of MA in non-human primates. Thus, the data suggest that the effects of 4-MMC in monkeys can be classified with classical psychomotor stimulants.     

化学修饰小干扰RNA作为治疗药物的研究进展

化学修饰为小干扰RNA（siRNA）治疗面临的诸多挑战提供了解决方法。此综述考察现有的各种siRNA修饰方法,包括RNA和双链siRNA结构的各个方面。然后考察化学修饰siRNA的应用,重点关注其作用的专一性（消除免疫反应和杂交依赖性的脱靶作用）和转运方法,同时对酶稳定性和效价也进行了讨论。     

Dual modulation of urinary bladder activity and urine flow by prostanoid EP3 receptors in the conscious rat

Background and purpose:

Cyclooxygenase inhibitors function to reduce levels of prostaglandin E₂ (PGE₂) and are broadly efficacious in models of bladder overactivity. We therefore investigated a regulation of urinary bladder function in conscious rats by modulation of the EP₃ receptor for PGE₂.

Experimental approach:

The activity of the EP₃ receptor agonist GR63799X, and EP₃ receptor antagonists, CM9 and DG041, at recombinant EP₃ receptors was evaluated in vitro. In vivo, intraduodenal dosing during conscious, continuous-filling cystometry of spontaneously hypertensive rats was utilized to determine the urodynamic effect of EP₃ receptor modulation.

Key results:

GR63799X dose-dependently (0.001–1 mg·kg⁻¹) reduced bladder capacity, as indicated by a reduction in both the micturition interval and volume of urine per void. In contrast, CM9 (10 and 30 mg·kg⁻¹) and DG041 (30 mg·kg⁻¹) enhanced bladder capacity, as indicated by significantly longer micturition intervals and larger void volumes. CM9 and DG041 inhibited the responses to GR63799X supporting the in vivo activity of these pharmacological agents at the EP₃ receptor. In addition to its effect on bladder capacity, GR63799X increased endogenous urine production. Intra-arterial infusion of saline mimicked the enhancement of urine flow observed with GR63799X, and the response was inhibited by CM9.

Conclusions and implications:

These data support the EP₃ receptor as a modulator of urinary bladder activity in the conscious rat, and in addition, indicate a role for EP₃ receptor activity in regulating urine flow.     

Peripheral and central sites of action for the non-selective cannabinoid agonist WIN 55,212-2 in a rat model of post-operative pain

Background and purpose:

Activation of cannabinoid (CB) receptors decreases nociceptive transmission in inflammatory or neuropathic pain states. However, the effects of CB receptor agonists in post-operative pain remain to be investigated. Here, we characterized the anti-allodynic effects of WIN 55,212-2 (WIN) in a rat model of post-operative pain.

Experimental approach:

WIN 55,212-2 was characterized in radioligand binding and in vitro functional assays at rat and human CB₁ and CB₂ receptors. Analgesic activity and site(s) of action of WIN were assessed in the skin incision-induced post-operative pain model in rats; receptor specificity was investigated using selective CB₁ and CB₂ receptor antagonists.

Key results:

WIN 55,212-2 exhibited non-selective affinity and agonist efficacy at human and rat CB₁ versus CB₂ receptors. Systemic administration of WIN decreased injury-induced mechanical allodynia and these effects were reversed by pretreatment with a CB₁ receptor antagonist, but not with a CB₂ receptor antagonist, given by systemic, intrathecal and supraspinal routes. In addition, peripheral administration of both CB₁ and CB₂ antagonists blocked systemic WIN-induced analgesic activity.

Conclusions and implications:

Both CB₁ and CB₂ receptors were involved in the peripheral anti-allodynic effect of systemic WIN in a pre-clinical model of post-operative pain. In contrast, the centrally mediated anti-allodynic activity of systemic WIN is mostly due to the activation of CB₁ but not CB₂ receptors at both the spinal cord and brain levels. However, the increased potency of WIN following i.c.v. administration suggests that its main site of action is at CB₁ receptors in the brain.British Journal of Pharmacology (2009) 157, 645–655; doi:10.1111/j.1476-5381.2009.00184.x; published online 3 April 2009