It is important to note that among

patients with asymptomatic severe aortic stenosis, the omission of surgical treatment was the most important risk factor for late mortality.”
“The peripheral injection of phorbol myristate acetate (PMA) into the mouse paw induces nociception mediated through activation of protein kinase C (PKC). In the present study, we examine the contribution of kinin B I receptor to PMA-induced nociception. Nociception was assessed Copanlisib after intraplantar injection of PMA or the B-1 receptor agonist des-Arg(9)-bradykinin in mice. Mechanisms of nociception were studied using the combination of knockout mice, selective drugs, and measurement of B-1 receptor mRNA and protein levels. Peripheral injection of PMA (50 pmol/paw) induced a nociceptive behaviour that was abolished by selective B I receptor

antagonist des-Arg9-Leu8-bradykinin or by the B-1 receptor gene deletion. Moreover, PMA treatment did not alter B-1 receptor rnRNA levels, but greatly increased B-1 receptor protein levels in the mouse paw. The injection of des-Arg9-bradykinin did not cause nociception STI571 purchase in naive mice, but produced marked nociception in animals previously treated with a low dose of PMA (0.5 nmol/paw). The co-treatment of PMA with selective PKC or protein synthesis inhibitors, but not with p38 mitogen activated protein kinase (MAPK) or transcription inhibitors significantly reduced des-Arg(9)-bradykinin-induced nociception. On the other hand, the co-administration of selective PKC or p38 MAPK inhibitors, Niclosamide but not of protein synthesis or transcription inhibitors, reduced des-Arg9-bradykinin-induced nociception when evaluated in PMA pre-injected animals. These results suggest that the B 1 receptor exerts a critical role in the nociception caused by PKC activation in peripheral tissues. Since the PKC pathway is

downstream of several pro-inflammatory mediators, B, receptor stimulation appears to contribute to the acute inflammatory pain process. (c) 2007 Elsevier Ltd. All rights reserved.”
“Amphetamine (AMPH) is a potent dopamine (DA) transporter (DAT) inhibitor that markedly increases extracellular DA levels. In addition to its actions as a DAT antagonist, acute AMPH exposure induces DAT losses from the plasma membrane, implicating transporter-specific membrane trafficking in amphetamine’s actions. Despite reports that AMPH modulates DAT surface expression, the trafficking mechanisms leading to this effect are currently not defined. We recently reported that DAT residues 587-596 play an integral role in constitutive and protein kinase C (PKC)-accelerated DAT internalization. In the current study, we tested whether the structural determinants required for PKC-stimulated DAT internalization are necessary for AMPH-induced DAT sequestration.