Basis of pH-Independent Inhibitory Effects of Lactate on Ca Movements and Responses to KCl and PGF2tt in Canine Coronary Arteries

Under ischemic conditions, contractile responses of canine coronary artery smooth muscle are decreased, pH is decreased, and lactate levels are increased. To investigate whether lactate has a pH-independent relaxant action on contractility, inhibitory effects of 1.0 mM lactate on Ca fluxes and increased tension elicited with either 60 mM KCl or 10 ftyi prostaglandin F2o (PGF2o) were measured at physiological pH (7.4) or in the presence of lactic acidosis (pH 6.9-7.0). In addition to isometric tension responses, Ca exchangeability and total Ca uptake and efflux, "Ca retention at nonsuperficial sites or stores was measured after incubation with an isosraotic (80.8 mM) La* solution at 0.5 °C. Pretreatment with lactate specifically depressed PGF2O-induced tension responses more than KC1induced ones, but Ca depletion inhibited the response to KCl more rapidly. The rate of efflux of "Ca from coronary arteries into a calcium-free solution was decreased by lactate; this effect was not prevented by inhibition of "Ca reuptake and rebinding with 0.05 mM EDTA. Exchangeability of "Ca with non-radioactive Ca was decreased by lactate. A Scatchard plot of Ca uptake in coronary arteries shows that Ca is bound at either high or low affinity sites. Lactate increased the rate of "Ca uptake at high affinity sites but did not increase the equilibrated total Ca uptake. However, the retention of Ca (residual Ca uptake) at high affinity sites was increased by lactate and decreased by PGF2,,, whereas low affinity residual Ca 2+ uptake was increased by KCl and unaffected by PGF2<, or lactate (although lactate inhibited the KCl-induced increase in low affinity residual Ca). Thus, lactate acts directly to increase the affinity for Ca at high affinity Ca-binding sites important for the stimulatory action of PGF2l>, which appears to increase tension by mobilizing Ca * from these sites, and only indirectly and to a lesser degree affects that low affinity Ca important for the stimulatory action of KCl. CircRes46: 771-779, 1980