Blockade by glibenclamide of the flow-evoked endothelial release of ATP that contributes to vasodilatation in the pulmonary vascular bed of the rat.
1. The effect of step augmentation of flow rate on the level of adenosine -5'-triphosphate (ATP) measured in the Krebs perfusate was investigated, and the effect of glibenclamide on the release of ATP was tested in the rat pulmonary vascular bed. 2. For flow rates between 10.38 +/- 1.18 and 28.88 +/- 2.08 ml min-1 (n = 8) 1 microM suramin, a P2-purinoceptor antagonist, significantly (P < 0.05) increased vascular resistance under conditions of step augmentation of flow rate. This suggests that endogenous ATP released during increases in flow rate dilates pulmonary vessels. 3. In response to a step augmentation in flow rate from 9.13 +/- 0.97 to 18.3 +/- 1.69 ml min-1 (n = 4) ATP levels were up to 23 fold higher (P < 0.05) for 15 s, and gradually dropped to a level of about half the initial rise. Once the ATP levels had stabilized, another step augmentation of flow rate to 27.00 +/- 3.49 ml min-1 was able to evoke a corresponding increase of ATP release. The ability of the vascular bed to respond with increased ATP release after the initial ATP responses had tapered, demonstrates that the drop in ATP levels after the initial rise is not due to depletion of ATP. Furthermore, the maximal ATP response directly precedes the vasodilatation observed following each jump in perfusion pressure produced with each step increase in flow rate. 4. In response to two 3 fold step augmentations of flow rate (8.41-27.29 ml min-1) spaced 30 min apart there were two increases in the level of ATP which were not significantly different from each other.However, perfusion with 1 microM glibenclamide between the first and the second step augmentation of flow rate (8.08-24.67 ml min-1) significantly (P<0.05; n = 6) blocked the increase in ATP release. This suggests that the release of intracellular ATP is mediated by glibenclamide-sensitive K+ channels.5. A concentration of 1 microM glibenclamide perfused for 30 min was without effect on vascular pressure at constant flow. However, under conditions where flow was augmented in a stepwise manner (between 11.50 and 36.45 ml min-1) perfusing with 1 microM glibenclamide increased vascular resistance (P <0.10).6. It is concluded that flow-induced ATP release is mediated by a glibenclamide-sensitive K+ channel,and that the release of ATP from endothelial cells probably functions to vasodilate the pulmonary vascular bed of the rat.
Hasséssian
H
H
Department of Anatomy and Developmental Biology, University College London.
Bodin
P
P
Burnstock
G
G
D000255:Adenosine Triphosphate / Q000378:metabolism*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D004730:Endothelium, Vascular / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D005905:Glyburide / Q000494:pharmacology*; D066298:In Vitro Techniques; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008297:Male; D010477:Perfusion; D015221:Potassium Channels / Q000187:drug effects; D011652:Pulmonary Circulation / Q000187:drug effects / Q000502:physiology*; D051381:Rats; D017208:Rats, Wistar; D013498:Suramin / Q000494:pharmacology; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology*
D015221:Potassium Channels; D013498:Suramin; D000255:Adenosine Triphosphate; D007770:L-Lactate Dehydrogenase; D005905:Glyburide