Increase in interstitial ATP of rat soleus muscle during lactic acid infusion

Abstract

We investigated the effect of acidosis on ATP efflux from muscle. Lactic acid (LA) was infused into the arterial supply of the buffer-perfused rat hindlimb muscle; ATP concentrations were measured by HPLC in interstitial microdialysate from soleus muscle. Inhibitors of several ATP transporters were used to explore the mechanism. LA (10 mM) reduced venous pH from 7.14±0.02 to 7.00±0.03 (P<0.01) and increased interstitial ATP from 31±6 nM to 62±10 nM (P<0.01, n=13). Infusion of alpha-cyano-4-hydroxycinnamic acid, a lactate-transporter-inhibitor, prevented the LA-infusion-induced increase in interstitial ATP, suggesting that cellular uptake of the LA is necessary for the stimulation of ATP efflux. LA-induced elevation of interstitial ATP was reduced to 48±5 nM by nifedipine, an inhibitor of electrodiffusional transport, and abolished by the nonspecific blockers of CFTR, 4-acetamido-4′-isothiocyanatostilbene-2, 2′-disulfonic acid (SITS, 100 μM) or glibenclamide (200 μM). Atractyloside, an inhibitor of mitochondrial ATP transporter, could not prevent LA-infusion-stimulated ATP efflux. These results suggested that pH depression could stimulate the efflux of ATP from rat soleus muscle, thereby elevating the interstitial ATP concentration. This ATP release had the nature of electrodiffusional movement, and may be conducted through CFTR. This study is supported by the University of Hong Kong and the Hong Kong Research Grants Council.