Antiadhesive properties of glycoclusters against Pseudomonas aeruginosa lung infection.

Pseudomonas aeruginosa lung infections are a major cause of death in cystic fibrosis and hospitalized patients. Treating these infections is becoming difficult due to the emergence of conventional antimicrobial multiresistance. While monosaccharides have proved beneficial against such bacterial lung infection, the design of several multivalent glycosylated macromolecules has been shown to be also beneficial on biofilm dispersion. In this study, calix[4]arene-based glycoclusters functionalized with galactosides or fucosides have been synthesized. The characterization of their inhibitory properties on Pseudomonas aeruginosa aggregation, biofilm formation, adhesion on epithelial cells, and destruction of alveolar tissues were performed. The antiadhesive properties of the designed glycoclusters were demonstrated through several in vitro bioassays. An in vivo mouse model of lung infection provided an almost complete protection against Pseudomonas aeruginosa with the designed glycoclusters.

Effects of potassium channel modulators on human detrusor smooth muscle myogenic phasic contractile activity: potential therapeutic targets for overactive bladder.

OBJECTIVES: Increased urinary bladder detrusor smooth muscle phasic contractility has been suggested to be associated with idiopathic bladder overactivity (OAB). We examined the role of voltage-dependent L-type calcium channels, adenosine triphosphate-sensitive potassium (K(ATP)) channels, and calcium-activated potassium (BK(Ca) and SK(Ca)) channels in the regulation of human detrusor phasic contractile activity. METHODS: Isolated human bladder strip phasic contractions were measured and quantified as the mean area under the force-time curve, amplitude, and frequency of phasic contractions in 22 bladder samples. RESULTS: Human detrusor strips displayed myogenic phasic contractions in the presence of atropine (10(-6) M), phentolamine (10(-6) M), propranolol (10(-6) M), suramin (10(-5) M), and tetrodotoxin (10(-6) M). The L-type calcium channel inhibitor nifedipine (300 nM) abolished the contractile activity. Blockade of K(ATP) channels by glibenclamide (1 and 10 microM) did not alter myogenic contractions. In contrast, the K(ATP) channel opener pinacidil (10 microM) markedly inhibited phasic contractility. Iberiotoxin (100 nM) and apamin (100 nM), potent and selective inhibitors of BK(Ca) and SK(Ca) channels, respectively, significantly increased the area under the force-time curve and the amplitude of contractions. CONCLUSIONS: Phasic contractions of human detrusor are dependent on calcium entry through L-type calcium channels. BK(Ca) and SK(Ca) channels play a key role in the modulation of human detrusor smooth muscle phasic contractility. Furthermore, these observations support the concept that increasing conductance through K(ATP), BK(Ca), and SK(Ca) channels may represent attractive pharmacologic targets for decreasing phasic contractions of detrusor smooth muscle in OAB.