Serotonin inhibition of 1‐methylxanthine metabolism parallels its vasoconstrictor activity and inhibition of oxygen uptake in perfused rat hindlimb

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Abstract
The effect of serotonin (5‐HT) on the metabolism of infused 1‐methylxanthine (1‐MX), a putative substrate of capillary endothelial xanthine oxidase (XO), and on the distribution of infused fluorescent microspheres (15 μm) by the artificially constant‐flow perfused rat hindlimb preparation was investigated. 1‐MX (5–100 μM) caused a slight inhibition of oxygen uptake (V˙O2) but was not vasoactive, either alone or with 5‐HT. 1‐MX was converted to 1‐methylurate (1‐MU) and this conversion was inhibited by allopurinol and xanthine. 5‐HT (0.35 μM), which caused vasoconstriction and decreased V˙O2, also inhibited the conversion of 1‐MX, indicated by a lowered venous perfusate steady‐state 1‐MU:1‐MX ratio from 1.14 ± 0.02 to 0.71 ± 0.02 (P < 0.001), which is equivalent to the rate of conversion decreasing from 0.83 ± 0.03 to 0.63 ± 0.05 nmol min−1 g−1. This change closely followed the time course for changes in V˙O2 and perfusion pressure and all three changes reversed in parallel when 5‐HT was removed. Recoveries of 1‐MU plus 1‐MX at all times were high (100 ± 5%). 5‐HT did not act to inhibit XO. When compared with vehicle alone, 5‐HT had either no effect (plantaris, gastrocnemius white, tibialis, extensor digitorum longus, vastus and thigh), or increased microsphere content (soleus and gastrocnemius red, P < 0.05) of muscles with only bone showing a significant decrease (P < 0.05). Since 5‐HT did not inhibit XO or alter the net flow to individual muscles in this constant‐flow model, the inhibition of conversion of 1‐MX to 1‐MU is concluded to be the result of a 5‐HT‐mediated decrease in the access of 1‐MX to capillary XO within individual muscles. Possibilities include the redirection of flow to capillaries either in muscle or in connective tissue closely associated with muscle, where resistance is low and effective surface area is less. 1‐MX has potential as a marker for muscle nutritive flow.

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