Article date: May 1994
By: Michael D. Randall, Hiroshi Ujiie, Tudor M. Griffith, in Volume 112, Issue 1, pages 49-54
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.
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 μm 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.
Hypoxia also significantly (P < 0.001) increased the vasodilator potency of levcromakalim (EC50 = 134 ± 22 nm), and this enhancement was completely reversed (EC50 = 380 ± 107nm, P<0.01) by pretreatment of the preparations with 5 μm DPCPX, a selective A1 adenosine antagonist. However, under normoxic conditions DPCPX did not influence vasodilatation to levcromakalin.
Inhibition of nitric oxide synthesis with 100 μm 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).
We have shown that an adenosine A1 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 A1 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.
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.
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 μm 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.
Hypoxia also significantly (P < 0.001) increased the vasodilator potency of levcromakalim (EC50 = 134 ± 22 nm), and this enhancement was completely reversed (EC50 = 380 ± 107nm, P<0.01) by pretreatment of the preparations with 5 μm DPCPX, a selective A1 adenosine antagonist. However, under normoxic conditions DPCPX did not influence vasodilatation to levcromakalin.
Inhibition of nitric oxide synthesis with 100 μm 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).
We have shown that an adenosine A1 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 A1 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.
DOI: 10.1111/j.1476-5381.1994.tb13027.x
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