Basis of pH-independent inhibitory effects of lactate on 45Ca movements and responses to KCl and PGF2 alpha in canine coronary arteries.

Abstract

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 45Ca fluxes and increased tension elicited with 60 mM KCl or 10 .mu.M prostaglandin F2.alpha. (PGF2.alpha.) were measured at physiological pH (7.4) or in the presence of lactic acidosis (pH 6.9-7.0). Isometric tension responses, 45Ca exchangeability, total 45Ca uptake and efflux and 45Ca retention at nonsuperficial sites or stores were measured after incubation with an isosmotic (80.8 mM) La3+ solution at 0.5.degree. C. Pretreatment with lactate specifically depressed PGF2.alpha.-induced tension responses more than KCl-induced ones, but Ca2+ depletion inhibited the response to KCl more rapidly. The rate of efflux of 45Ca from coronary arteries into a Ca-free solution was decreased by lactate; this effect was not prevented by inhibition of 45Ca reuptake and rebinding with 0.05 mM EDTA. Exchangeability of 45Ca with non-radioactive Ca2+ was decreased by lactate. A Scatchard plot of Ca2+ uptake in coronary arteries shows that Ca2+ is bound at high or low affinity sites. Lactate increased the rate of 45Ca uptake at high affinity sites but did not increase the equilibrated total 45Ca uptake. The retention of 45Ca (residual Ca2+ uptake) at high affinity sites was increased by lactate and decreased by PGF2.alpha.; low affinity residual Ca2+ uptake was increased by KCl and unaffected by PGF2.alpha. or lactate (although lactate inhibited the KCl-induced increase in low affinity residual Ca2+). Lactate acts directly to increase the affinity for Ca2+ at high affinity Ca2+-binding sites important for the stimulatory action of PGF2.alpha., which appears to increase tension by mobilizing Ca2+ from these sites, and only indirectly and to a lesser degree affects that low affinity Ca2+ important for the stimulatory action of KCl.