Absorption of high levels of acetate, butyrate and propionate following a meal may elicit localised increases in intestinal blood flow. We have previously shown that lactate (McKinnon et al. 1996) and butyrate (Aaronson et al. 1996) relax the rat mesenteric artery independently of intracellular pH or the endothelium. In the present study, the mechanisms of propionate-induced relaxation were investigated.
Rats were killed by cervical dislocation and small mesenteric arteries (internal diameter 200-300 µm) were mounted on a myograph, preconstricted with 2.5 µM noradrenaline for 5 min and challenged with 10 mM propionate (iso-osmotically substituted for NaCl) for 15 min, in the continued presence of noradrenaline.
After an initial transient contraction, propionate produced 60-70 % relaxation (when corrected for spontaneous decay of control contractions in the same arteries), peaking after 6-8 min. Relaxation responses to propionate were abolished in endothelium-denuded arteries (performed by rubbing with a human hair and assessed functionally by absence of relaxation to 1 µM acetylcholine, n = 6, data not shown). Relaxation was not significantly inhibited by pre-incubation with 100 µM L-NAME (mean ± S.E.M.: 66 ± 4 % vs. control 70 ± 3 %, n = 35, n.s.).
In the continued presence of L-NAME, the effects of potassium channel blockers on propionate-induced relaxation were assessed. Relaxation was significantly inhibited by 50 µM barium (an inhibitor of inward rectifier K+ channels (KIR: 57 ± 13 % inhibition, n = 12, P < 0.01 by Student’s paired t test), by 100 µM ouabain (blocker of the Na+,K+-ATPase, 82 ± 3 % inhibition, n = 6, P < 0.01, paired t test) and the combination of 100 nM charybdotoxin and apamin (inhibitors of intermediate and small-conductance calcium-activated potassium channels (IKCa and SKCa, respectively, 52 ± 4 % inhibition, n = 9, P < 0.001, paired t test), but was unaffected by 100 nM iberiotoxin (inhibitor of large-conductance calcium-activated potassium channels, BKCa: 20 ± 11 % inhibition, n = 9, n.s., paired t test).
Propionate-induced relaxation was prevented by raising extracellular potassium from 4.7 to 25 mM (97 ± 8 % inhibition, n = 5, P < 0.01, paired t test), a concentration that, in the absence of noradrenaline, itself caused little or no sustained contraction (data not shown).
Propionate-induced relaxation was also inhibited by 100 nM thapsigargin (SERCA pump inhibitor, 72 ± 4 % inhibition, n = 8, P < 0.001, paired t test).
Our results show that propionate relaxes rat mesenteric arteries in an endothelium-dependent manner, via activation of IKCa, SKCa and KIR potassium channels and the Na+,K+-ATPase, as part of the EDHF response (Edwards et al. 1998), and that propionate may trigger EDHF release via release of Ca2+ from intracellular stores in the endothelium (Fukao et al. 1997).
- Aaronson, P.I., McKinnon, W. & Poston, L. (1996). Br. J. Pharmacol. 117, 365-371.
Edwards, G., Dora, K.A., Gardener, M.J., Garland, C.J. & Weston, A.H. (1998). Nature 396, 269-272.
Fukao, M., Hattori, Y., Kanno, M., Sakuma, I. & Kitabatake, A. (1997). Br. J. Pharmacol. 120, 1328-1334.
McKinnon, W., Aaronson, P.I., Knock, G., Graves, J. & Poston, L. (1996). J. Physiol. 490, 783-792. abstract