THEOPHYLLINE AND MAGNESIUM INHIBIT THE CONTRACTION ELICITED WITH CICLOSPORIN AND ANGIOTENSIN-II IN MESANGIAL CELL-CULTURES

One serious side effect of ciclosporin (CS) therapy is its acute nephrotoxicity characterized by a marked decrease in glomerular filtration rate (GFR). A main determinant of GFR is the ultrafiltration coefficient which is thought to be regulated by the contractile state of the cells of the mesangium. CS enhances contractions of mesangial cells elicited with angiotensin II. By way of a lowered ultrafiltration coefficient this effect of CS may be partly responsible for its acute nephrotoxicity. We have therefore examined the effect of compounds that may attenuate the enhanced contractile response of the smooth-muscle-like mesangial cells. Prostaglandin E2 (10-8-10-5 mol/l) and dibutyryl cyclic AMP (10-4 mol/l) reduced the number of contracting cells from more than 50% to about 10%. The clinically used agent theophylline (10-5 g/ml) decreased the number of contractions of CS-pretreated mesangial cells from 80.0 to 28.4% (p < 0.001). Additionally, a marked decrease in the percentage of contractions (83.3 to 33.3%; p < 0.001) was observed when the concentration of magnesium chloride was elevated from 0 to 2 mmol/l. The finding that the enhanced contractile response of CS-pretreated mesangial cells can be overcome by theophylline and/or high magnesium levels may be of clinical interest with a view to acute CS nephrotoxicity.