Evidence for a P2-purinoceptor mediating vasoconstriction by UTP, ATP and related nucleotides in the isolated pulmonary vascular bed of the rat

Abstract

1. The vasoconstrictor effects of uridine 5'-triphosphate (UTP), uridine 5'-diphosphate (UDP), uridine 5'-monophosphate (UMP) and uridine were tested in the isolated pulmonary vascular bed of the rat. Comparison was made with the effects of adenine nucleotides, adenosine 5'-triphosphate (ATP), adenosine 5'-diphosphate (ADP), adenosine 5'-monophosphate (AMP) and with adenosine. The effect of P(2x)-purinoceptor desensitization and blockade was compared on the vascular responses to uracil and adenine nucleotides. 2. At doses ranging from 10-8 to 10-5 mol, UTP elicited dose-dependent vasoconstriction. UDP was equiactive to UTP, while UMP and uridine did not show vasomotor activity. Similarly, ATP showed dose-related vasoconstrictor activity. ADP was less potent than ATP in eliciting vasoconstriction, while AMP was active only at the higher doses tested and adenosine was ineffective. 3. Vasoconstriction was produced by ATP analogues with the following order of potency: α,β-methylene ATP > ATPγS > β,γ-methylene ATP > 2-methylthio ATP ≤ ATP. 4. Desensitization of P(2x)-purinoceptors by the selective agonist α,β-methylene ATP did not modify the vasoconstrictor activity of UTP and UDP and only partially reduced vasoconstrictor responses to ATP, while it abolished vascular responses to α,β-methylene ATP itself. 5. The antagonists of P2-purinoceptors, suramin and pyridoxalphosphate-6-azophenyl-2',4'-disulphonic acid (PPADS), did not affect vascular responses to UTP and UDP, but reduced vasoconstriction evoked by β,γ-methylene ATP and ATP by about 70 and 30%, respectively. 6. This study demonstrates that uracil nucleotides, UTP and UDP, elicit vasoconstriction in the rat pulmonary vascular bed. In addition to confirming the presence of classical P(2x)-purinoceptors, these results also suggest the presence of a distinct purinoceptor subtype which mediates UTP- and ATP-evoked vasoconstriction in the rat pulmonary circulation.