Physiological increases in lactate inhibit intracellular calcium transients, acidify myocytes and decrease force in term pregnant rat myometrium

Abstract

Lactate is increased in myometrial capillary blood from women in slow or non-progressive labour (dystocia), suggesting that it is detrimental to uterine contractions. There are no studies of the effect of lactate on the myometrium. In the present study, we have investigated its effects and mechanism of action on myometrial strips from term pregnant rats. We show that lactate significantly decreased spontaneous contractility. Lactatedecreased pHi and inhibited Ca2+ transients. Nulling the decrease in pHi abolished the effects of lactate effects. If Ca2+ entry was enhanced, the effects of lactate were abolished. The present study suggests that the accumulation of extracellular lactate could contribute to labour dystocia. Lactate is increased in myometrial capillary blood from women in slow or non-progressive labour (dystocia), suggesting that it is detrimental to uterine contractions. There are, however, no studies of the effect of lactate on the myometrium. We therefore investigated its effects and mechanism of action on myometrial strips from term pregnant rats. The effects on spontaneous and oxytocin-induced contractility in response to sodium lactate and other weak acids (1-20 mM) were studied. In some experiments, simultaneous force and intracellular Ca2+ or pH (pHi) were measured with Indo-1 or Carboxy-SNARF, respectively. Statistical differences were tested using non-parametric tests. Lactate significantly decreased spontaneous contractility with an EC50 of 3.9 mM. Propionate, butyrate and pyruvate also reduced contractions with similar potency. The effects of lactate were reduced in the presence of oxytocin but remained significant. Lactate decreased pHi and nulling the decrease in pHi abolished its effects. We also show that lactate inhibited Ca2+ transients, with these changes mirroring those produced on force. If Ca2+ entry was enhanced by depolarization (high KCl) or applying the Ca2+ channel agonist, Bay K 4644, the effects of lactate were abolished. Taken together, these data show that lactate in the physiological range potently decreases myometrial contractility as a result of its inhibition of Ca2+ transients, which can be attributed to the induced acidification. The present study suggests that the accumulation of extracellular lactate will reduce myometrial contractions and could therefore contribute to labour dystocia.