European journal of pharmacology
-
Adenosine A2B-receptors mediate the adenosine-evoked renal vasodilations in male rats. Here, we tested whether this finding could be replicated in female renal vasculature and whether K(+) hyperpolarization induced by nitric oxide synthase (NOS) and/or heme oxygenase (HO) accounts for adenosine A2B receptor-sensitive renal vasodilations. In phenylephrine-preconstricted perfused kidneys, vasodilations caused by the adenosine analog 5'-N-ethylcarboxamidoadenosine (NECA, 1.6-50 nmol) were attenuated after blockade of adenosine A2B (alloxazine) but not A2A [8-(3-Chlorostyryl) caffeine, CSC] or A3 receptors (N-(2-methoxyphenyl)-N'-[2-(3-pyridinyl)-4-quinazolinyl]-urea, VUF 5574), confirming the preferential involvement of A2B receptors in NECA responses. ⋯ NECA or minoxidil vasodilations were attenuated by ouabain, Na(+)/K(+)-ATPase inhibitor, and in KCl-preconstricted preparations. Overall, facilitation of adenosine A2B receptor/NOS/K(+) channel/Na(+)/K(+)-ATPase cascade underlies NECA vasodilations in female rats. Enhancing HO activity, albeit not causally related to NECA vasodilations, improves the pharmacologically compromised (alloxazine) NECA response.
-
In rodents, surgery and/or remifentanil induce postoperative pain hypersensitivity together with glial cell activation. The same stimulus also produces long-lasting adaptative changes resulting in latent pain sensitization, substantiated after naloxone administration. Glial contribution to postoperative latent sensitization is unknown. ⋯ A transient microglia/macrophage and astrocyte activation was present between 30 min and 2 days postoperatively, while increased immunoreactivity in satellite glial cells lasted 21 days. At this time point, (-) naloxone, but not (+) naloxone, increased GFAP in satellite glial cells; conversely, both naloxone steroisomers similarly increased GFAP in the spinal cord. The report shows for the first time that surgery induces long-lasting morphological changes in astrocytes and satellite cells, involving opioid and toll-like receptors, that could contribute to the development of latent pain sensitization in mice.
-
Catecholamine neurotransmission in the prefrontal cortex plays a key role in the therapeutic actions of drugs for attention-deficit/hyperactivity disorder (ADHD). Recent clinical studies show that several serotonin-norepinephrine reuptake inhibitors have potential for treating ADHD. In this study, we examined the effects of acute treatment with serotonin-norepinephrine reuptake inhibitors on locomotion and the extracellular levels of monoamines in the prefrontal cortex in spontaneously hypertensive rats (SHR), an animal model of ADHD. ⋯ Citalopram did not affect norepinephrine and dopamine levels in the prefrontal cortex, although it increased the serotonin levels. Neither duloxetine nor venlafaxine increased the dopamine levels in the striatum. These findings suggest that serotonin-norepinephrine reuptake inhibitors, similar to methylphenidate and atomoxetine, have potential for ameliorating motor abnormality in the SHR model.
-
Allergic asthma is a chronic airway disorder characterized by airway hyperresponsiveness to allergens, chronic airway inflammation, airway edema, increased mucus secretion, excess production of Th2 cytokines, and eosinophil accumulation in the lungs. Ursolic acid is known for its pharmacological effects, such as its anti-tumor, anti-inflammatory and antimicrobial activities. To investigate the anti-asthmatic effects and mechanism of ursolic acid, we studied the development of pulmonary eosinophilic inflammation and enhanced pause (Penh) in a mouse model of allergic asthma. ⋯ We investigated the effect of ursolic acid and Cyclosporin A (CsA) on Penh, pulmonary eosinophilic infiltration, various immune cell phenotypes, Th2 cytokines, IL-17 production, and ovalbumin specific IgE production in a mouse model of asthma. In BALB/c mice, ursolic acid had suppressed eosinophil infiltration, allergic airway inflammation, and Penh, which occurred by suppressing the production of IL-5, IL-13, IL-17, and ovalbumin-specific IgE by blocking the GATA-3 and STAT6 pathways. Our data suggest the therapeutic mechanism of ursolic acid in asthma is based on reductions of Th2 cytokines (IL-5 and IL-13), ovalbumin-specific IgE production, and eosinophil infiltration via the Th2-GATA-3, STAT6, and IL-17-NF-κB pathways.
-
Recent studies suggest that endocannabinoid signaling is modulated by 17β-estradiol (17Eβ) however it is unclear if this applies to the cardiovascular actions of anandamide, a major endocannabinoid. This study examined the in vitro effects of 17Eβ on vasorelaxation to anandamide in myograph-mounted small mesenteric arteries obtained from Wistar rats and Spontaneously Hypertensive Rats (SHRs) of both sexes. Treatment with 1μM 17Eβ but not its enantiomer 17Eα significantly enhanced relaxation to anandamide in male Wistar rats. ⋯ Female SHRs displayed a larger maximal relaxation to anandamide; however sex difference was not found in Wistar rats. We conclude that pharmacological levels of 17Eβ potentiate mesenteric relaxation to anandamide through mechanisms dependent on TRPV1 receptors but not FAAH-mediated hydrolysis in male Wistar rats and male SHRs. Sexual dimorphism was observed in the modulatory effects of 17Eβ and URB597, which does not necessarily lead to a greater anandamide response in female rats.