Vardenafil corrects transrectal chloride transport in CF mice

We have previously shown that characteristic transepithelial ion transport defects in cystic fibrosis (CF), namely increased sodium absorption and reduced or abolished chloride transport, can be assessed at the intestinal level, a clinically relevant CF target organ, by means of the rectal potential difference test (RPD). The aim of this work is to test the efficacy of vardenafil, an inhibitor of phosphodiesterase type 5, to correct CFTR-dependent transrectal ion transport in CF mice homozygous for the F508del mutation as compared to heterozygous (HTZ) and wild-type homozygous (WT) animals from the same 129/FVB genetic background. RPD was performed 1 h after a single ip injection of vardenafil (0.14 mg/kg). Total chloride secretion across the rectal mucosa (TCS) was monitored under perfusion of a Ringer’s solution without chloride (replaced by gluconate) and with 10- 5 M forskolin, and containing 10-4 M amiloride and 5 x 10-3 M barium, to block sodium and potassium movement. Vardenafil significantly stimulated TCS in CF mice when values obtained in the absence of vardenafil (-4.2 0.5 mV; mean SEM; n:5) reached -9.3 1.1mV (n:7; p:0.0054) after vardenafil treatment. Intermediately reduced TCS values in the HTZ group were also significantly increased by vardenafil treatment. The corrector effect of vardenafil was mainly due to the contribution of forskolin sensitivity that was increased by 4-fold in the HTZ group and by 5-fold in the CF group. These data indicate that RPD is a powerful tool to assess efficacy of therapeutic strategies in CF. Our findings confirm that vardenafil corrects CFTR-dependent chloride transport in CF intestinal tissue

Effects of Insulin Secretagogues On B-cell Ph in Intact Mouse Islets

Abstract of the Belgian Society of Fundamental and Clinical Physiology and Pharmacology (Autumn Meeting), 20 November 1993, Brussels, Belgiu