Sodium channel blockers and uridine triphosphate: effects on nasal potential difference in cystic fibrosis mice.
Sodium channel inhibitors block the enhanced Na+ reabsorption in cystic fibrosis (CF). Extracellular nucleotides facilitate Cl- secretion via Ca2+ gated Cl- channels. A combination of these effects may produce less viscid secretions in CF which are easier to expectorate. This study examined the effects of combining sodium channel blockers with uridine triphosphate (UTP) on nasal membrane potential difference (PD) in CF insertional null mutant mice (cftr(tm1HGU)), deltaF508 homozygous mice (cftr(tm1Cam)) and matched control animals. Median basal PD in the insertional CF mice and deltaF508 CF mice were -28 and -34 mV respectively. These values were significantly different to the control animals (-20 mV). Amiloride and loperamide reduced the PD in cftr(tm1HGU) CF mice (deltaPD 13 mV & 15 mV respectively) suggesting Na+ blockade. The subsequent addition of UTP in a chloride-free vehicle increased the PD (deltaPD -8- -12.5 mV). DeltaF508 mice showed significantly greater responses compared with CF insertional null mutant mice (p<0.05). The action of UTP was brief and not prolonged by the addition alpha-beta-methylene-adenosine 5' diphosphate. Suramin, a competitive antagonist of P2 purinoceptors blocked the action of UTP. In conclusion, this study demonstrated dose dependant nasal membrane potential changes in differences mice with uridine triphosphate in the presence of sodium channel blockers suggestive of chloride secretion. More stable analogues of uridine triphosphate in combination with long acting sodium channel blockers such as loperamide may have therapeutic potential in cystic fibrosis.
Ghosal
S
S
Division of Child Health, University of Sheffield, UK.
Taylor
C J
CJ
Colledge
W H
WH
Ratcliff
R
R
Evans
M J
MJ
D000584:Amiloride / Q000494:pharmacology*; D000818:Animals; D002712:Chlorides / Q000378:metabolism; D003550:Cystic Fibrosis / Q000188:drug therapy* / Q000503:physiopathology; D004359:Drug Therapy, Combination; D008139:Loperamide / Q000494:pharmacology*; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D051379:Mice; D018181:Mice, Inbred CFTR; D009297:Nasal Mucosa / Q000187:drug effects* / Q000503:physiopathology; D015222:Sodium Channels / Q000187:drug effects* / Q000502:physiology; D014544:Uridine Triphosphate / Q000494:pharmacology*
D002712:Chlorides; D015222:Sodium Channels; D008139:Loperamide; D000584:Amiloride; D014544:Uridine Triphosphate