title: Mechanism of lactate-induced relaxation of isolated rat mesenteric resistance arteries.
abstract: 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.
authors.affiliation: Department of Physiology, United Medical School, Guy's Hospital, London, UK.
authors.forename: W
authors.initials: W
authors.lastname: McKinnon
authors.forename: P I
authors.initials: PI
authors.lastname: Aaronson
authors.forename: G
authors.initials: G
authors.lastname: Knock
authors.forename: J
authors.initials: J
authors.lastname: Graves
authors.forename: L
authors.initials: L
authors.lastname: Poston
mesh_terms: D000818:Animals; D004305:Dose-Response Relationship, Drug; D006863:Hydrogen-Ion Concentration; D007773:Lactates / Q000494:pharmacology*; D008297:Male; D008638:Mesenteric Arteries / Q000187:drug effects*; D009126:Muscle Relaxation / Q000187:drug effects*; D011188:Potassium / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D013997:Time Factors
chemical_list: D007773:Lactates; D011188:Potassium