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IDENTIFICATION OF A NOVEL SYMPATHETIC VASOCONSTRICTOR IN MOUSE COLONIC SUBMUCOSAL ARTERIOLES AND ITS ROLE IN COLITIS

AE Lomax, MT O'Reilly, SJ Vanner
Gastrointestinal Diseases Research Unit, Hotel Dieu Hospital, Kingston, Ontario

Maintenance of tissue oxygenation is vital to repairing inflammatory damage and maintaining normal function in the gastrointestinal (GI) tract. The GI microvasculature delivers oxygen to GI tissues and is subject to complex neural control mechanisms. Recent studies have suggested that altered neural control of the microvasculature may contribute to the pathogenesis of inflammatory bowel disease. Therefore, we wished to determine the effects of nerve stimulation on the submucosal microvasculature in the mouse colon and to examine the effect of colitis.
Videomicroscopy techniques were employed to measure submucosal arteriolar diameter changes in response to nerve stimulation at 5 Hz, 10 Hz and 20 Hz. In arterioles that were preconstricted by superfusion of prostaglandin F2_a, nerve stimulation resulted in frequency dependent vasoconstrictor responses that had a biphasic time course comprising a transient and sustained component. The neurally mediated constrictions were abolished by tetrodotoxin (1 µM; n = 4) and guanethidine (10 µM; n = 6), indicating that the constrictions were due to action potentials in sympathetic nerve terminals. ATP or a related purine is the neurotransmitter at sympathetic neuroeffector junctions in submucosal arterioles in guinea-pig ileum, as sympathetic vasoconstrictions can be abolished by a P2 purinoceptor antagonist. In contrast, superfusion of mouse colon submucosa with two potent P2 receptor antagonists (Suramin at 100 µM and PPADs at 30 µM; n = 18 combined) reduced but did not abolish the vasoconstriction. The residual vasoconstriction was not sensitive to adrenergic receptor antagonists propranolol or phentolamine (both 1 µM; n = 8). In preliminary experiments, we examined the effect of TNBS colitis on arteriolar responses to nerve stimulation. Constrictions no longer had a biphasic time course and blockade of P2 or adrenergic receptors had no effect. These data support the conclusion that sympathetic vasoconstrictor neurons in mouse colon release ATP and an as yet unidentified vasoconstrictor substance. Moreover, during colitis sympathetic purinergic neurotransmission is disrupted such that the novel sympathetic vasoconstrictor is the only vasoconstrictor substance released.

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