1. The effects of the
sodium salt of the weak
acid lactate on tension and intracellular pH (pH1) were studied in rat mesenteric small arteries mounted on a wire myograph.
Sodium lactate was substituted iso-osmotically for
sodium chloride. 2. At a concentration of 50 mM, both L- and D-stereoisomers of
lactate markedly relaxed arteries preconstricted with
noradrenaline (NA) within 10 min. The concentration-response relationship for L-
lactate showed that the NA
contracture was relaxed by 50% at approximately 26 mM. L-
Lactate did not, however, relax arteries preconstricted with high-K+(45 mM)
solution. 3. L-
Lactate did not alter extracellular pH (pHo) but caused a small but significant decrease in pH1, measured using the pH-sensitive
fluorochrome, 2',7'-bis(carboxyethyl)-5-(6)-carboxyfluorescein (
BCECF). Relaxation to L-
lactate was unaffected when this change in pHi was offset by the simultaneous addition of NH4Cl to the
solution. 4.
Sodium pyruvate (50 mM) caused a significant intracellular
acidosis but did not relax arteries preconstricted with NA. 5. L-
Lactate-induced relaxations were unaffected by removal of the endothelium or when the synthesis of
nitric oxide (NO) was inhibited by 10(-4) M
N omega-nitro-L-arginine methyl ester (
L-NAME). 6. The
potassium channel blockers glibenclamide (10 microM),
4-aminopyridine (3 mM) and
tetraethylammonium chloride (10 mM) did not affect L-
lactate-induced relaxation in arteries preconstricted with NA. Inhibition of
guanylate cyclase with
Methylene Blue, or cyclooxgenase with
indomethacin, also did not affect relaxation to L-
lactate. 7. The Rp stereoisomer of adenosine-3',5'-cyclic monophosphothioate (
Rp-cAMPS), an analogue of cAMP which inhibits competitively stimulation of
protein kinase A, reduced significantly L-
lactate-induced relaxation at a concentration of 25 microM.
Rp-cAMPS also significantly reduced
forskolin-induced relaxation of the NA
contracture. 8. It is concluded that L-
lactate-induced relaxation in this vascular bed is
pHi-1 endothelium-, and
nitric oxide-independent. It is not mediated by inhibition of voltage-gated Ca2+ channels, opening of K+ channels, prostacylin or
cyclic GMP. cAMP may however play a role in L-
lactate-induced relaxation.