Abstract 822: P2y2 Receptor Stimulation Overrides Sympathetic Vasoconstrictor Activity In Human Skeletal Muscle
Background: Sympathetic vasoconstriction is blunted in the vascular beds of contracting skeletal muscles in humans, due to the release of vaso-active metabolites (functional sympatholysis). Recently we demonstrated that the same phenomenon can occur in resting muscle during the infusion of the nucleotide metabolite ATP, but not during infusion of ATP’s nucleoside derivative, adenosine. We therefore wanted to test whether other nucleotides are capable of producing the same effect to establish a certain receptor specificity for this phenomenon.
Methods: In nine healthy male subjects, we measured leg blood flow (LBF), mean arterial pressure (MAP),and leg a-vO2 difference during:
intrafemoral artery infusion of the vasodilators adenosine ( control) AMP, ADP, ATP or UTP, and,
subsequent combined infusion with the sympathetic vasoconstrictor drug tyramine.
In all five hyperaemic conditions, LBF increased from ~0.5 ± 0.1 l/min at baseline to ~3.6 ± 0.3 l/min without altering plasma ATP or soluble purinergic enzymes. Superimposion of tyramine increased plasma noradrenaline in all hyperaemic conditions, but only caused leg vasoconstriction and augmented O2 extraction during adenosine, AMP and ADP infusion (53 ± 4 %, 56 ± 5, % and 28 ± 3% lower LBF and leg vascular conductance, respectively, P<0.05).Furthermore maximal UTP-induced vasodilatation was investigated at rest and accounted for 56 % of the previously registered peak LBF during maximal bicycling exercise in comparison to the 78% increase in LBF previously registered for ATP.
Conclusion: These findings in humans demonstrate that stimulation of the P2Y2 receptor with ATP/UTP is capable of producing substantial vasodilatation whilst at the same time opposing the effects of increased sympathetic vasoconstrictor activity. Many diseases, such as congestive heart failure, sleep apnoea, obesity and diabetes are associated with elevated sympathetic activity, increased blood pressure and reduced blood flow and drug therapy should be targeted to offset the effect of the elevated sympathetic nerve activity.