Bone cells constitutively release ATP into the extracellular environment where it acts locally via P2 receptors to regulate bone cell function. Whilst P2Y receptor stimulation regulates bone mineralisation, the functional effects of this receptor in osteoclasts remain unknown. This investigation used the P2Y receptor knockout ( ) mouse model to investigate the role of this receptor in bone. MicroCT analysis of mice demonstrated age-related increases in trabecular bone volume (≤48%), number (≤30%) and thickness (≤17%). osteoblasts displayed a 3-fold increase in bone formation and alkaline phosphatase activity, whilst osteoclasts exhibited a 65% reduction in resorptive activity. Serum cross-linked C-telopeptide levels (CTX, resorption marker) were also decreased (≤35%). The resorption defect in osteoclasts was rescued by the addition of exogenous ATP, suggesting that an ATP deficit could be a key factor in the reduced function of these cells. In agreement, we found that basal ATP release was reduced up to 53% in osteoclasts. The P2Y receptor agonists, UTP and 2-thioUTP, increased osteoclast activity and ATP release in wild-type but not in cells. This indicates that the P2Y receptor may regulate osteoclast function indirectly by promoting ATP release. UTP and 2-thioUTP also stimulate ATP release from osteoblasts suggesting that the P2Y receptor exerts a similar function in these cells. Taken together, our findings are consistent with the notion that the primary action of P2Y receptor signalling in bone is to regulate extracellular ATP levels.
I Experiments have been done to study the gastric vascular response to histamine given intraarterially in the cat. 2 In experiments utilising pump perfusion of the stomach at constant flow rates, rapid intra-arterial injections of histamine elicited dose-dependent vasodilatation. The dose-response curve to histamine was displaced to the right by mepyramine and further to the right by mepyramine plus cimetidine. Cimetidine alone did not displace the histamine dose-response curve. This interaction between histamine and histamine antagonists is very similar to the interaction observed in other vascular beds. 3 Intra-arterial infusions of histamine also caused vasodilatation with increased gastric blood flow, measured with an electromagnetic flow probe. Mepyramine reduced the immediate increase in blood flow during each infusion, although responses in the later stages of the infusions were unaltered. Cimetidine had no effect on the immediate response but reduced sustained responses to histamine. Treatment with mepyramine and cimetidine was required to abolish histamine responses. 4 Infusions of 2-(2-aminoethyl) pyridine and dimaprit also increased gastric blood flow. 5 These results indicate the involvement of both H1-and H2-receptors in histamine-induced gastric vasodilatation. There appears to be a time-base in the interaction between histamine and vascular histamine receptors; HI-receptor responses preceding H2-receptor responses.
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