Mast cell degranulation and de novo histamine formation contribute to sustained postexercise vasodilation in humans

Abstract

In humans, acute aerobic exercise elicits a sustained postexercise vasodilation within previously active skeletal muscle. This response is dependent on activation of histamine H₁ and H₂ receptors, but the source of intramuscular histamine remains unclear. We tested the hypothesis that interstitial histamine in skeletal muscle would be increased with exercise and would be dependent on de novo formation via the inducible enzyme histidine decarboxylase and/or mast cell degranulation. Subjects performed 1 h of unilateral dynamic knee-extension exercise or sham (seated rest). We measured the interstitial histamine concentration and local blood flow (ethanol washout) via skeletal muscle microdialysis of the vastus lateralis. In some probes, we infused either α-fluoromethylhistidine hydrochloride (α-FMH), a potent inhibitor of histidine decarboxylase, or histamine H₁/H₂-receptor blockers. We also measured interstitial tryptase concentrations, a biomarker of mast cell degranulation. Compared with preexercise, histamine was increased after exercise by a change (Δ) of 4.2 ± 1.8 ng/ml (P < 0.05), but not when α-FMH was administered (Δ-0.3 ± 1.3 ng/ml, P = 0.9). Likewise, local blood flow after exercise was reduced to preexercise levels by both α-FMH and H₁/H₂ blockade. In addition, tryptase was elevated during exercise by Δ6.8 ± 1.1 ng/ml (P < 0.05). Taken together, these data suggest that interstitial histamine in skeletal muscle increases with exercise and results from both de novo formation and mast cell degranulation. This suggests that exercise produces an anaphylactoid signal, which affects recovery, and may influence skeletal muscle blood flow during exercise.NEW & NOTEWORTHY Blood flow to previously active skeletal muscle remains elevated following an acute bout of aerobic exercise and is dependent on activation of histamine H₁ and H₂ receptors. The intramuscular source of histamine that drives this response to exercise has not been identified. Using intramuscular microdialysis in exercising humans, we show both mast cell degranulation and formation of histamine by histidine decarboxylase contributes to the histamine-mediated vasodilation that occurs following a bout of aerobic exercise.

Keywords: extracellular fluid; histamine; microdialysis; postexercise hypotension; regional blood flow.

Fig. 1.

Effect of mast cell degranulation on dialysate histamine and tryptase concentrations ([Histamine]_Dialysate and [Tryptase]_Dialysate, respectively) collected via intramuscular microdialysis in the biceps brachii. Samples were obtained before degranulation (control; open bars) and after administration of compound 48/80, a mast cell degranulator (compound 48/80; solid bars). Samples represent absolute histamine and tryptase concentrations in the dialysate and were not corrected for probe recovery. Values are means ± SE.

Fig. 2.

Effect of exercise on dialysate histamine concentrations ([Histamine]_Dialysate) collected via intramuscular microdialysis in the biceps brachii. Samples were obtained before, during, and after moderate-intensity leg cycle exercise with the arm resting. Samples represent absolute histamine concentration in the dialysate and were not corrected for probe recovery. Values are means ± SE.

Fig. 3.

Effect of exercise and inhibition of histidine decarboxylase on interstitial histamine concentrations ([Histamine]_interstitial) collected via intramuscular microdialysis in the vastus lateralis. Samples were obtained before, during, and after sham (seated rest; top) and before, during, and after exercise (bottom). Open bars denote control (no drug or combined histamine H₁/H₂-receptor blockade, which does not affect histamine concentrations); solid bars denote inhibition of histidine decarboxylase with α-FMH. Samples represent interstitial histamine concentration after correcting for probe recovery. Values are means ± SE. *P < 0.05 vs. preexercise. †P < 0.05 vs. control during exercise and P = 0.06 vs. control during postexercise.

Fig. 4.

Effect of exercise, inhibition of histidine decarboxylase, and combined histamine H₁/H₂-receptor blockade on ethanol washout in the vastus lateralis. A larger (more negative) reduction is reflective of a larger rise in local blood flow. Top: sham. Bottom: exercise. Open bars denote control (no drug); shaded bars denote combined histamine H₁/H₂-receptor blockade; and solid bars denote inhibition of histidine decarboxylase with α-FMH. Values are means ± SE. *P < 0.05 vs. preexercise. †P < 0.05 vs. control.

Fig. 5.

Effect of exercise on dialysate tryptase concentrations ([Tryptase]_Dialysate) collected via intramuscular microdialysis in the vastus lateralis. Samples were obtained before, during, and after sham (seated rest; top) and before, during, and after exercise (bottom). Values are means ± SE. *P < 0.05 vs. preexercise.