British journal of pharmacology
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TASK1 (K(2P)3.1) two-pore-domain K(+) channels contribute substantially to the resting membrane potential in human pulmonary artery smooth muscle cells (hPASMC), modulating vascular tone and diameter. The endothelin-1 (ET-1) pathway mediates vasoconstriction and is an established target of pulmonary arterial hypertension (PAH) therapy. ET-1-mediated inhibition of TASK1 currents in hPASMC is implicated in the pathophysiology of PAH. This study was designed to elucidate molecular mechanisms underlying inhibition of TASK1 channels by ET-1. ⋯ ET-1 regulated vascular TASK1 currents through ET(A) and ET(B) receptors mediated by downstream activation of Rho kinase and direct channel phosphorylation. The Rho kinase pathway in PASMC may provide a more specific therapeutic target in pulmonary arterial hypertension treatment.
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Capsiate is produced by 'CH-19 Sweet' (Capsicum annuun L.), a non-pungent cultivar of red pepper. Like capsaicin, capsiate is thought to enhance energy metabolism by activating the sympathetic nervous system and suppressing inflammation, but the underlying mechanisms for this are uncertain. We previously reported that capsiate could activate transient receptor potential vanilloid 1 (TRPV1), a capsaicin receptor. The purpose of the present study is to investigate whether capsinoids activate other TRP channels. ⋯ Taken together, these results indicate that capsinoids activate TRPA1 by an as yet unknown mechanism, and TRPA1 could be involved in physiological phenomena associated with capsinoid treatment.
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Spinal reactive oxygen species (ROS) are critically involved in chronic pain. D-Amino acid oxidase (DAAO) oxidizes D-amino acids such as D-serine to form the byproduct hydrogen peroxide without producing other ROS. DAAO inhibitors are specifically analgesic in tonic pain, neuropathic pain and cancer pain. This study examined the role of spinal hydrogen peroxide in pain and the mechanism of the analgesic effects of DAAO inhibitors. ⋯ Spinal hydrogen peroxide is specifically and largely responsible for formalin-induced pain, and DAAO inhibitors produce analgesia by blocking spinal hydrogen peroxide production rather than interacting with spinal D-serine.
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Randomized Controlled Trial Clinical Trial
Polymorphisms of ADORA2A modulate psychomotor vigilance and the effects of caffeine on neurobehavioural performance and sleep EEG after sleep deprivation.
Prolonged wakefulness impairs sustained vigilant attention, measured with the psychomotor vigilance task (PVT), and induces a compensatory increase in sleep intensity in recovery sleep, quantified by slow-wave activity (SWA) in the sleep electroencephalogram (EEG). These effects of sleep deprivation are counteracted by the adenosine receptor antagonist caffeine, implying involvement of the adenosine neuromodulator/receptor system. To examine a role for adenosine A(2A) receptors, we investigated whether variation of the A(2A) receptor gene (ADORA2A) modified effects of caffeine on PVT and SWA after sleep deprivation. ⋯ Common genetic variation of ADORA2A is an important determinant of psychomotor vigilance in rested and sleep-deprived state. It also modulates individual responses to caffeine after sleep deprivation. These findings demonstrate a role for adenosine A(2A) receptors in the effects of prolonged wakefulness on vigilant attention and the sleep EEG.
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The transactivation of the epidermal growth factor (EGF) receptor appears to be an important central transduction mechanism in mediating diabetes-induced vascular dysfunction. Angiotensin-(1-7) [Ang-(1-7)] via its Mas receptor can prevent the development of hyperglycaemia-induced cardiovascular complications. Here, we investigated whether Ang-(1-7) can inhibit hyperglycaemia-induced EGF receptor transactivation and its classical signalling via ERK1/2 and p38 MAPK in vivo and in vitro. ⋯ These results show for the first time that Ang-(1-7) inhibits EGF receptor transactivation via a Mas receptor/Src-dependent pathway and might represent a novel general mechanism by which Ang-(1-7) exerts its beneficial effects in many disease states including diabetes-induced vascular dysfunction.