Modulation by propranolol of the uptake of ethidium bromide by rat submandibular acinar cells exposed to a P2X(7) agonist or to maitotoxin

We have compared the formation of pores in rat submandibular acinar cells i n response to 2 ' ,3 ' -O-(4-benzoylbenzoyl) adenosine 5 ' -triphosphate (B z-ATP) and maitotoxin. Bz-ATP (100 muM) permeabilized the cells to ethidium bromide. The uptake of ethidium increased to 29 +/- 1% of maximal uptake i n 10 min. DL-Propranolol (300 muM) inhibited the Bz-ATP-induced uptake of e thidium bromide by 40% without affecting the P2X(7)-gated cation channel. T he inhibitory effect of DL-propranolol on the formation of ports by Bz-ATP was reproduced by D-propranolol. an optical isomer with very poor beta -blo cking activity. Tenidap. an antiinflammatory drug, enhanced the permeabiliz ation in response to Bz-ATP. Propanolol inhibited the response to tenidap p lus Bz-ATP. The effect of propranolol was reproduced by labetolol, a beta - adrenergic antagonist with membrane-stabilizing properties. but not by aten olol, which blocks beta -adrenergic receptors but has no effect on the stab ility of the membrane. In the presence of extracellular calcium, maitotoxin also increased the uptake of ethidium bromide. Tenidap had no effect on th is response. which was delayed by propranolol. In conclusion, we have shown that propranolol. in a range of 10-300 muM, inhibits the pore-forming acti vity of the P2X(7) receptor without affecting the opening of the cation cha nnel coupled to this receptor. This inhibition is not related to its beta - adrenergic blocking activity bur rather to its membrane-stabilizing: proper ties. Propranolol also delays the uptake of ethidium bromide in response to maitotoxin. This is in agreement with the current view that P2X(7) agonist s and maitotoxin share a common pore. (C) 2001 Elsevier Science Inc. All ri ghts reserved.