1. The
vasorelaxant effect of the
sodium salt of the
short chain fatty acid,
butyrate, on preconstricted rat small mesenteric arteries (mean inner diameter approximately 300 microns) was characterized. Isometric force development was measured with a myograph, and intracellular pH (pHi) was simultaneously monitored, in arteries loaded with the
fluorescent dye BCECF in its acetomethoxy form.
Sodium butyrate (substituted isosmotically for NaCl) was applied to arteries after
noradrenaline (NA) or high K+
contractures were established. 2. Arteries preconstricted with a concentration of NA inducing an approximately half maximal contraction were relaxed by 91.5 +/- 6.3% by 50 mmol l-1
butyrate. This concentration of
butyrate did not, however, cause a significant relaxation of
contractures to a maximal (5 mumol l-1) NA concentration, and also failed to relax significantly
contractures stimulated by high (45 and 90 mmol l-1) K+ solutions.
Contractures elicited with a combination of NA (at a submaximal concentration) and 45 mmol l-1 K+ were, however, markedly relaxed by
butyrate. 3. Investigation of the concentration-dependency of the
butyrate-induced relaxation of the half maximal NA response revealed an EC50 for
butyrate of approximately 22 mmol l-1. 4.
Sodium butyrate (50 mmol l-1) caused pHi to decrease from 7.25 +/- 0.02 to 6.89 +/- 0.08 (n = 4, P < 0.001). However, the
vasorelaxant effect of
butyrate on the submaximal NA
contracture was not significantly modified when this fall in intracellular pH was prevented by the simultaneous application of NH4Cl. 5.
Butyrate-induced relaxation was also unaffected by endothelial denudation and inhibition of
NO synthase with
N omega-nitro-L-arginine methyl ester (100 mumol l-1). 6. The relaxation of the NA
contracture by 50 mmol l-1
sodium butyrate was abolished in arteries pretreated with the
cyclic AMP antagonist
Rp-cAMPS (25 mumol l-1). 7. We conclude that the
butyrate-induced relaxation of the NA
contracture is independent of intracellular acidification. The ability of
Rp-cAMPS to abolish the
butyrate relaxation indicates that stimulation of the
cyclic AMP second messenger system may play an important role in mediating this effect.