Coinfusion of ATP with l-NMMA, indomethacin, or both reduced ATP-induced leg blood flow increases by 14%, 15%, and 39% respectively (all P<0.05), indicating roles for NO and prostaglandins.
What are the roles of nitric oxide, prostaglandins, and adenosine in ATP-induced limb vasodilation in healthy male subjects?
Nitric oxide and prostaglandins, but not adenosine, partially mediate ATP-induced vasodilation in human skeletal muscle, potentially via P2Y2 and P2X1 receptors.
Effect estimate: 39% reduction with l-NMMA + INDO
p-value: p=<0.05
Plasma ATP is thought to contribute to the local regulation of skeletal muscle blood flow. Intravascular ATP infusion can induce profound limb muscle vasodilatation, but the purinergic receptors and downstream signals involved in this response remain unclear. This study investigated: 1) the role of nitric oxide (NO), prostaglandins, and adenosine as mediators of ATP-induced limb vasodilation and 2) the expression and distribution of purinergic P(2) receptors in human skeletal muscle. Systemic and leg hemodynamics were measured before and during 5-7 min of femoral intra-arterial infusion of ATP 0.45-2.45 micromol/min in 19 healthy male subjects with and without coinfusion of N(G)-monomethyl-l-arginine (l-NMMA; NO formation inhibitor; 12.3 +/- 0.3 (SE) mg/min), indomethacin (INDO; prostaglandin formation blocker; 613 +/- 12 microg/min), and/or theophylline (adenosine receptor blocker; 400 +/- 26 mg). During control conditions, ATP infusion increased leg blood flow (LBF) from baseline conditions by 1.82 +/- 0.14 l/min. When ATP was coinfused with either l-NMMA, INDO, or l-NMMA + INDO combined, the increase in LBF was reduced by 14 +/- 6, 15 +/- 9, and 39 +/- 8%, respectively (all P < 0.05), and was associated with a parallel lowering in leg vascular conductance and cardiac output and a compensatory increase in leg O(2) extraction. Infusion of theophylline did not alter the ATP-induced leg hyperemia or systemic variables. Real-time PCR analysis of the mRNA content from the vastus lateralis muscle of eight subjects showed the highest expression of P(2Y2) receptors of the 10 investigated P(2) receptor subtypes. Immunohistochemistry showed that P(2Y2) receptors were located in the endothelium of microvessels and smooth muscle cells, whereas P(2X1) receptors were located in the endothelium and the sacrolemma. Collectively, these results indicate that NO and prostaglandins, but not adenosine, play a role in ATP-induced vasodilation in human skeletal muscle. The expression and localization of the nucleotide selective P(2Y2) and P(2X1) receptors suggest that these receptors may mediate ATP-induced vasodilation in skeletal muscle.
Mortensen et al. (Thu,) conducted a other in Healthy (n=19). ATP coinfused with l-NMMA, indomethacin, and/or theophylline vs. ATP infusion alone was evaluated on Increase in leg blood flow (LBF) from baseline (39% reduction with l-NMMA + INDO, p=<0.05). Coinfusion of ATP with l-NMMA, indomethacin, or both reduced ATP-induced leg blood flow increases by 14%, 15%, and 39% respectively (all P<0.05), indicating roles for NO and prostaglandins.
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