Modulation of the vasoconstrictor response to adrenergic stimulation by nucleosides and nucleotides

The ability of nucleosides and nucleotides to modulate adrenergic neuromuscular transmission was examined in the isolated, perfused rat mesentery. The nucleosides adenosine and cytidine and the stable nucleotide of ATP, beta, gamma-methylene ATP (APPCP), and GTP depressed in a concentration-dependent manner the vasoconstrictor response to nerve stimulation (NS). APPCP and cytidine required concentrations less than those of adenosine or GTP to cause inhibition of the constriction to NS. Guanosine had no apparent effect on the constriction to NS, whereas cytidine 5'-triphosphate enhanced this response. In contrast to the inhibitory effect of several nucleotides and nucleosides on the response to NS, only adenosine depressed the vasoconstriction to exogenous norepinephrine (NE). APPCP, GTP, cytidine 5'-triphosphate and guanosine were essentially equipotent in potentiating the vasoconstriction to NE; cytidine had no apparent effect. The ability of these agents to enhance vasoconstriction is not specific for alpha adrenergic receptor-mediated effects inasmuch as APPCP also potentiated the vasopressor response to KCl. Theophylline abolished the depressant effects of adenosine, cytidine, APPCP and GTP on the vasoconstriction to NS and the ability of adenosine to inhibit the constrictor response to NE. Theophylline did not inhibit the ability of APPCP to potentiate the vasoconstriction to NE. These results indicate that the nucleosides adenosine, guanosine and cytidine and the nucleotides APPCP and GTP act prejunctionally, possibly at a common receptor, to inhibit the neuronal release of NE. In addition, the data suggest the existence of two postjunctional sites, one that is inhibitory and selective for adenosine and another that enhances vasoconstrictor responses and is activated by nucleotides and guanosine.