Effect of reproductive ageing on pregnant mouse uterus and cervix.

Key Points: Older pregnant women have a greater risk of operative delivery, still birth and post-term induction. This suggests that maternal age can influence the timing of birth and processes of parturition. We have found that increasing maternal age in C57BL/6J mice is associated with prolongation of gestation and length of labour.

The effects of benzofury (5-APB) on the dopamine transporter and 5-HT2-dependent vasoconstriction in the rat.

5-APB, commonly marketed as 'benzofury' is a new psychoactive substance and erstwhile 'legal high' which has been implicated in 10 recent drug-related deaths in the UK. This drug was available on the internet and in 'head shops' and was one of the most commonly sold legal highs up until its recent UK temporary ban (UK Home Office). Despite its prominence, very little is known about its pharmacology.

Proteinase-activated receptor-1, CCL2, and CCL7 regulate acute neutrophilic lung inflammation.

PAR1 plays a central role in mediating the interplay between coagulation and inflammation, but its role in regulating acute neutrophilic inflammation is unknown. We report that antagonism of PAR1 was highly effective at reducing acute neutrophil accumulation in a mouse model of LPS-induced lung inflammation. PAR1 antagonism also reduced alveolar-capillary barrier disruption in these mice.

Proinflammatory mediators disrupt glucose homeostasis in airway surface liquid.

The glucose concentration of the airway surface liquid (ASL) is much lower than that in blood and is tightly regulated by the airway epithelium. ASL glucose is elevated in patients with viral colds, cystic fibrosis, chronic obstructive pulmonary disease, and asthma. Elevated ASL glucose is also associated with increased incidence of respiratory infection.

Cardiovascular toxicity of novel psychoactive drugs: lessons from the past.

The long use of ephedrine, amphetamines, cocaine, LSD and more recently 3,4-methylenedioxy-N-methylamphetamine (MDMA; "Ecstasy") allows us to predict with some confidence what cardiovascular risks are likely to be associated with novel psychoactive substances (NPS). Once the probably multiple biological activities of a compound are known it is possible to define the likely risks of cardiovascular toxicity. Agonists of 5-HT(2A) receptors or alpha-adrenoceptors may cause vasoconstriction and tissue ischemia.

Reduced KCNQ4-encoded voltage-dependent potassium channel activity underlies impaired β-adrenoceptor-mediated relaxation of renal arteries in hypertension.

KCNQ4-encoded voltage-dependent potassium (Kv7.4) channels are important regulators of vascular tone that are severely compromised in models of hypertension. However, there is no information as to the role of these channels in responses to endogenous vasodilators.

Participation of KCNQ (Kv7) potassium channels in myogenic control of cerebral arterial diameter.

KCNQ gene expression was previously shown in various rodent blood vessels, where the products of KCNQ4 and KCNQ5, Kv7.4 and Kv7.5 potassium channel subunits, respectively, have an influence on vascular reactivity.

Increased local expression of coagulation factor X contributes to the fibrotic response in human and murine lung injury.

Uncontrolled activation of the coagulation cascade contributes to the pathophysiology of several conditions, including acute and chronic lung diseases. Coagulation zymogens are considered to be largely derived from the circulation and locally activated in response to tissue injury and microvascular leak. Here we report that expression of coagulation factor X (FX) is locally increased in human and murine fibrotic lung tissue, with marked immunostaining associated with bronchial and alveolar epithelia.

Molecular and functional characterization of Kv7 K+ channel in murine gastrointestinal smooth muscles.

Members of the K(v)7 voltage-gated K(+) channel family are important determinants of cardiac and neuronal membrane excitability. Recently, we and others have shown that K(v)7 channels are also crucial regulators of smooth muscle activity. The aim of the present study was to assess the K(v)7 expression in different parts of the murine gastrointestinal (GI) tract and to assess their functional roles by use of pharmacological agents.

Proteinase-activated receptors in the lower urinary tract.

Proteinase-activated receptors (PARs) are G-protein-coupled receptors that convert specific extracellular proteolytic activity into intracellular signals, and have been suggested to play diverse roles in the body. In this review, evidence for the roles of PARs in bladder contractility and inflammation are presented. The role of PARs in prostate cancer is also reviewed.

Activation of corticotropin-releasing factor receptor-2 causes bronchorelaxation and inhibits pulmonary inflammation in mice.

Urocortins are members of the corticotropin-releasing factor (CRF) family of peptides that bind to two receptors, CRF(1) and CRF(2). While CRF(1) is a high-affinity receptor for CRF, urocortin III binds with much greater affinity to CRF(2). In the present study we investigated the effect of CRF(2) receptor activation with urocortin III on airway smooth muscle tone in vitro and in an acute model of airway inflammation in mice.

Protease-activated receptor-2 peptides activate neurokinin-1 receptors in the mouse isolated trachea.

Protective roles for protease-activated receptor-2 (PAR(2)) in the airways including activation of epithelial chloride (Cl(-)) secretion are based on the use of presumably PAR(2)-selective peptide agonists. To determine whether PAR(2) peptide-activated Cl(-) secretion from mouse tracheal epithelium is dependent on PAR(2), changes in ion conductance across the epithelium [short-circuit current (I(SC))] to PAR(2) peptides were measured in Ussing chambers under voltage clamp. In addition, epithelium- and endothelium-dependent relaxations to these peptides were measured in two established PAR(2) bioassays, isolated ring segments of mouse trachea and rat thoracic aorta, respectively.

What targets have knockouts revealed in asthma?

There have been numerous studies of mice rendered genetically deficient of various genes in the context of allergic inflammatory airway disease. These studies have provided invaluable information about basic immune processes, but have also been considered to be useful in predicting novel pharmacological targets. In this review, the effect of a wide range of individual knockouts (KO) on the development of asthma-like pathologies in mice is compiled and considered.

Pharmacological characterisation of the adenosine receptor mediating increased ion transport in the mouse isolated trachea and the effect of allergen challenge.

The effect of adenosine on transepithelial ion transport was investigated in isolated preparations of murine trachea mounted in Ussing chambers. The possible regulation of adenosine receptors in an established model of allergic airway inflammation was also investigated. Mucosally applied adenosine caused increases in short-circuit current (I(SC)) that corresponded to approximately 50% of the response to the most efficacious secretogogue, ATP (delta I(SC) 69.

Proteinase-activated receptor pharmacology: trickier and trickier.

Proteinase-activated receptors (PARs) are G-protein-coupled receptors for serine and other proteinases. Peptide agonists of these receptors are frequently used to characterise the presence and role of PARs in cells and organ systems. However, the specificity of these peptides is questionable in some assay systems.

Effects of inhaled thrombin receptor agonists in mice.

Active thrombin is found in the airways of patients with a variety of inflammatory lung diseases. However, whether thrombin contributes to the pathologies of these diseases is unknown, although thrombin is a potent inflammatory mediator in other organ systems. In the present study we have assessed the acute inflammatory effect of inhaled thrombin and investigated the possible receptors mediating any effects in mice.

Shooting for PARs in lung diseases.

Proteinase-activated receptors (PARs) are novel G-protein-coupled receptors activated by serine and other proteinases to induce changes in cellular function. There is extensive evidence that PARs are expressed in the airways in a variety of cell types that are relevant to inflammatory lung diseases, and that activation of these receptors might be linked to significant pathological changes. Thus, PARs are exciting new targets in lung disease research.

Role of the epithelium and acetylcholine in mediating the contraction to 5-hydroxytryptamine in the mouse isolated trachea.

1. The 5-HT receptor subtype that mediates bronchocontraction and the involvement of neuronal and non-neuronal acetylcholine was assessed in murine isolated tracheae. 2.

Pharmacologically distinct intracellular calcium pools regulate tonic and oscillatory responses in porcine thoracic duct.

The present study investigated the mechanisms by which the thromboxane A2 mimetic U46619 can elicit phasic and tonic contractions in the pig thoracic duct, whereas other agonists like 5-hydroxytryptamine (5-HT) produce tonic contractions only. Tonic contractions in response to either agonist were abolished by the l-type voltage-operated calcium channel (VOCC) inhibitor nifedipine, the store-operated calcium channel inhibitor SKF 96365, the calcium-sensitive chloride channel (ClCa) inhibitor niflumic acid, and by removal of extracellular Cl-. Superimposed phasic responses to U46619 were abolished by only nifedipine.

Enzymatic activation of endothelial protease-activated receptors is dependent on artery diameter in human and porcine isolated coronary arteries.

Protease-activated receptor (PAR)-mediated vascular relaxations have been compared in coronary arteries of different diameters isolated from both humans and pigs. Thrombin, trypsin, and the PAR1-activating peptide, TFLLR, all caused concentration-dependent relaxation of both large (epicardial; approximately 2 mm internal diameter) and small (intramyocardial; approximately 200 microm internal diameter) human coronary arteries. EC(50) values for thrombin (0.

Protease-activated receptor-2 activating peptide SLIGRL inhibits bacterial lipopolysaccharide-induced recruitment of polymorphonuclear leukocytes into the airways of mice.

Protease-activated receptor-2 (PAR2) acts as a receptor for trypsin and trypsin-like enzymes. The role of this receptor in airway inflammation is uncertain. In this study we assessed the effect of activation of PAR2 following intranasal administration of the peptide activator of PAR2, SLIGRL, over 72 h in mice.