Modulation of polymyxin B effects on mammalian urinary bladder

Area of Science:

• Pharmacology
• Membrane Biophysics
• Renal Physiology

Background:

• Polymyxin B (PX) is a cationic antibiotic clinically used for its bactericidal properties.
• PX increases apical membrane conductance, a key factor in bladder function.
• Understanding the modulators of PX activity is crucial for optimizing its therapeutic use.

Purpose of the Study:

• To investigate the effects of Ca2+, Mg2+, and protons on PX-induced apical membrane conductance in the rabbit urinary bladder.
• To elucidate the mechanisms by which these ions modulate PX activity.
• To develop a model for PX-induced membrane conductance.

Main Methods:

• Electrophysiological techniques were employed to measure membrane conductance.
• Varying concentrations of Ca2+, Mg2+, and protons were used to assess their impact on PX activity.
• Binding site competition assays were performed.

Main Results:

• Ca2+, Mg2+, and protons significantly altered PX-induced apical membrane conductance.
• These ions acted via rapid, reversible blockade and competition for PX binding sites.
• High pH (>8.8) inhibited PX activity by reducing its positive charge; Ca2+ affected the reversal rate of conductance.
• The fatty acid tail of PX was essential for its maximal activity.

Conclusions:

• Ca2+, Mg2+, and protons modulate polymyxin B's ability to increase rabbit urinary bladder apical membrane conductance through competitive binding and blockade.
• The activity of PX is dependent on its charge and fatty acid tail, with specific ions influencing its efficacy.
• A model was proposed to explain the mechanism of PX-induced conductance, aiding in understanding its clinical application.