Modulation of vasodilatation to levcromakalim by adenosine analogues 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 A1 antagonist, on vasodilatation to levcromakalim under hypoxic conditions and also following inhibition of nitric oxide synthesis. 2. Levcromakalim relaxed preconstricted preparations with an EC50 = 369 +/- 48 nM and maximum relaxation of tone (Rmax) = 81.0 +/- 3.2%. In the presence of 1 microM N6-cyclohexyladenosine (CHA) a selective adenosine A1 agonist, there was a significant (P < 0.01) leftward shift in the concentration-response curve with an EC50 = 194 +/- 54 nM and Rmax = 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 (EC50 = 134 +/- 22 nM), and this enhancement was completely reversed (EC50 = 380 +/- 107 nM, P < 0.01) by pretreatment of the preparations with 5 microM DPCPX, a selective A1 adenosine antagonist. However, under normoxic conditions DPCPX did not influence vasodilatation to levcromakalim. 4. Inhibition of nitric oxide synthesis with 100 microM NG-nitro-L-arginine methyl ester (L-NAME) caused a significant (P < 0.001) leftward shift in the concentration-response curve to levcromakalim (EC50 = 73.0 +/- 7.6 nM). Pretreatment of preparations with DPCPX partially reversed the increase in potency found in the absence of nitric oxide synthesis (EC50 = 153 +/- 18 nM, P < 0.001). 5. We have shown that an adenosine Al 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 Al 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.
Department of Diagnostic Radiology, University of Wales College of Medicine, Heath Park, Cardiff.
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Randall
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Ujiie
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Griffith
D000241:Adenosine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives / Q000494:pharmacology; D001578:Benzopyrans / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects; D019806:Cromakalim; D004357:Drug Synergism; D004431:Ear, External / Q000098:blood supply* / Q000187:drug effects; D006146:Guanidines / Q000494:pharmacology; D000860:Hypoxia / Q000503:physiopathology*; D066298:In Vitro Techniques; D008297:Male; D019331:NG-Nitroarginine Methyl Ester; D009569:Nitric Oxide / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D009599:Nitroprusside / Q000494:pharmacology; D020110:Pinacidil; D011758:Pyrroles / Q000494:pharmacology*; D011817:Rabbits; D012039:Regional Blood Flow / Q000187:drug effects; D014664:Vasodilation / Q000187:drug effects*; D014665:Vasodilator Agents / Q000494:pharmacology*; D014970:Xanthines / Q000494:pharmacology
D001578:Benzopyrans; D006146:Guanidines; D011758:Pyrroles; D014665:Vasodilator Agents; D014970:Xanthines; D019806:Cromakalim; D009599:Nitroprusside; D009569:Nitric Oxide; C027513:N(6)-cyclohexyladenosine; D020110:Pinacidil; D001120:Arginine; C051360:1,3-dipropyl-8-cyclopentylxanthine; D000241:Adenosine; D019331:NG-Nitroarginine Methyl Ester