MODULATION OF VASODILATATION TO LEVCROMAKALIM BY ADENOSINE-ANALOGS IN THE RABBIT EAR - AN EXPLANATION FOR HYPOXIC AUGMENTATION

1 We have used a rabbit isolated ear, buffered-perfused preparation to investigate the effects of adenosine analogues on the vasodilatation to the potassium channel opener, levcromakalim (the active (-)-enantiomer of cromakalim). We have examined the effects of 8-cyclopentyl-1,3-dipropylxanthine (DPCPX), a selective adenosine A(1) antagonist, on vasodilatation to levcromakalim under hypoxic conditions and also following inhibition of nitric oxide synthesis. 2 Levcromakalim relaxed preconstricted preparations with an EC(50) = 369 +/- 48 nM and maximum relaxation of tone (R(max)) = 81.0 +/- 3.2%. In the presence of 1 mu M N-6-cyclohexyladenosine (CHA) a selective adenosine A(1) agonist, there was a significant (P<0.01) leftward shift in the concentration-response curve with an EC(50) = 194 +/- 54 nM and R(max) = 93.2 +/- 2.0%. Conversely, the presence of CHA did not influence vasodilatation to either pinacidil or sodium nitroprusside. 3 Hypoxia also significantly (P<0.001) increased the vasodilator potency of levcromakalim (EC(50) = 134 +/- 22 nM), and this enhancement was completely reversed (EC(50) = 380 +/- 107 nM, P<0.01) by pretreatment of the preparations with 5 mu M DPCPX, a selective A(1) adenosine antagonist. However, under normoxic conditions DPCPX did not influence vasodilatation to levcromakalin. 4 Inhibition of nitric oxide synthesis with 100 mu M N-G-nitro-L-arginine methyl ester (L-NAME) caused a significant (P<0.001) leftward shift in the concentration-response curve to levcromakalim (EC(50) = 73.0 +/- 7.6 nM). Pretreatment of preparations with DPCPX partially reversed the increase in potency found in the absence of nitric oxide synthesis (EC(50) = 153 +/- 18 nM, P<0.001). 5 We have shown that an adenosine A(1) agonist may increase the potency of levcromakalim indicating that adenosine receptor activation may augment the vasodilator activity of levcromakalim. That responses to levcromakalim but not those to pinacidil were affected by CHA points to further differences in the pharmacology of these potassium channel openers. The reversal by the adenosine A(1) antagonist of the hypoxic-potentiation of vasodilatation to levcromakalim, and also augmentation following inhibition of nitric oxide synthesis, suggests that under these conditions there is an endogenous release of adenosine which may enhance responses to levcromakalim. The findings of this study suggest that levcromakalim may selectively dilate vessels where there is elevated adenosine release.