Adenosine linking reduced O₂ to arteriolar NO release in intestine is not formed from extracellular ATP

Abstract

We have previously reported that adenosine formed in response to reduced arteriolar and/or tissue PO(2) preserves endothelial nitric oxide (NO) synthesis during sympathetic vasoconstriction in the rat intestine. To more precisely identify the site and mechanism of adenosine formation under these conditions, we tested the hypothesis that ATP released in response to reduced O(2) levels serves as a source of adenosine. Direct application of ATP to the wall of first-order arterioles elicited dose-dependent dilations of 15-33% above resting diameter that were reduced by 71-80% by the 5'-ectonucleotidase inhibitor alpha,beta-methyleneadenosine 5'-diphosphate (AOPCP, 4.5 x 10(-5) M) and completely abolished by N(G)-monomethyl-L-arginine (L-NMMA, 10(-4) M). Under control conditions, sympathetic nerve stimulation at 3 and 8 Hz induced arteriolar constrictions of 11 +/- 1 and 19 +/- 1 microm, respectively. These responses were enhanced by 58-69% in the presence of L-NMMA or when local PO(2) was maintained at resting levels. However, in the presence of AOPCP, the enhancing effects of L-NMMA and the high O(2) superfusate on sympathetic constriction were preserved. These results suggest that, although exogenously applied ATP can stimulate arteriolar NO release in the intestine largely through its sequential extracellular hydrolysis to adenosine, this process does not contribute to adenosine formation and sustained NO release during sympathetic constriction in this vascular bed.

Rabbit erythrocytes release ATP and dilate skeletal muscle arterioles in the presence of reduced oxygen tension

“…Although several mechanisms that could mediate this fundamental physiological response have been proposed, none has been universally accepted. For example, it was suggested that arterioles feeding capillary beds in areas of increased O 2 utilization could respond directly to decreased tissue O 2 levels [2,14,19,26] or that a mediator(s) associated with increased O 2 utilization could be released into the venous circulation and diffuse to feed arterioles producing dilation [11,12,27,28]. Although there is experimental data in support of both mechanisms, the results do not fully explain the tight coupling of O 2 supply with demand observed in skeletal muscle.…”

Effects of hyperoxia on vascular tone in animal models: systematic review and meta-analysis

“…In most studies the animals were anesthetized with pentobarbital ( n = 28, used predominantly in rats and hamsters). Other anesthetics were thiopental [ 33 – 35 ], chloralose [ 36 , 37 ], urethane [ 37 , 38 ], ketamine [ 39 ] or a mixture of droperidol, midazolam and fentanyl [ 40 – 42 ]. In some studies skinfold windows were applied so that the microcirculation could be observed without anesthesia [ 14 , 43 – 45 ].…”

“…According to the effects reported by the original authors (Table 1 ), raising the P (a) O 2 to hyperoxic levels resulted in vasoconstriction in 91% of the studies. In 7% there was no effect on arteriolar diameter [ 35 , 57 , 58 ] and in one study dilation of second order arterioles was observed [ 43 ]. The median diameter change was − 20% with a range of − 64% to + 6%.…”

“…For instance, 20-HETE constricts arteries in the cremaster and gracilis muscle but dilates mesenteric arteries [ 74 ]. Inhibition of nitric oxide in intestinal arteries only temporarily reduces vessel diameter [ 35 ], which suggests that in these vessels the impediment of one vasoactive system is quickly compensated by another. The same might be true for the pathway affected by hyperoxia.…”