Acute effects of bradykinin on cerebral microvascular permeability in the anaesthetized rat.
1. The permeability response to acutely applied bradykinin and [des-Arg9]-bradykinin on single cerebral venular capillaries has been investigated using the low molecular mass fluorescent dyes Lucifer Yellow and Sulforhodamine B with the single vessel occlusion technique. 2. When bradykinin was applied repeatedly for up to 2 h, the permeability increase was small and reversible for concentrations that ranged from 5 nM to 50 microM. 3. The logEC50 of the permeability response to bradykinin was -5.3 +/- 0.15 (logM; mean +/- s.e.m.). This was reduced to -6.37 +/- 0.24 with the angiotensin-converting enzyme inhibitor captopril, to -6.33 +/- 0.19 with the neutral endopeptidase inhibitor phosphoramidon and to -7.3 +/- 0.20 with captopril and phosphoramidon combined. 4. The permeability response to bradykinin was blocked by the bradykinin B2 receptor antagonist HOE 140, by inhibition of the Ca2+-independent phospholipase A2, by the scavenging of free radicals, or by inhibition of both cyclo-oxygenase and lipoxygenase in combination. Block of Ca2+ entry channels with SKF 96365 had no effect on the response. 5. Application of [des-Arg9]-bradykinin also increased permeability over the concentration range 5 nM to 50 microM, with a logEC50 of -5.6 +/- 0. 37. This response was not affected by free radical scavenging, but was completely blocked by the histamine H2 receptor blocker cimetidine. 6. These results imply that the acute permeability response to bradykinin is mediated via the release of arachidonic acid, which is acted on by cyclo-oxygenase and lipoxygenase resulting in the formation of free radicals, and that the response to [des-Arg9]-bradykinin is mediated via histamine.
Sarker
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Centre for Cardiovascular Biology and Medicine, King's College London, New Hunt's House, Guy's Campus, London SE1 1UL, UK.
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Fraser
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D000758:Anesthesia; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology; D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism; D001920:Bradykinin / Q000031:analogs & derivatives* / Q000378:metabolism* / Q000494:pharmacology; D065168:Bradykinin Receptor Antagonists; D002196:Capillaries / Q000187:drug effects / Q000378:metabolism; D002199:Capillary Permeability / Q000187:drug effects / Q000502:physiology*; D002560:Cerebrovascular Circulation / Q000187:drug effects / Q000502:physiology*; D004305:Dose-Response Relationship, Drug; D005260:Female; D016166:Free Radical Scavengers / Q000494:pharmacology; D005609:Free Radicals / Q000037:antagonists & inhibitors / Q000378:metabolism; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D015290:Second Messenger Systems / Q000187:drug effects / Q000502:physiology
D000806:Angiotensin-Converting Enzyme Inhibitors; D065168:Bradykinin Receptor Antagonists; D016166:Free Radical Scavengers; D005609:Free Radicals; C024626:bradykinin, des-Arg(9)-; D016718:Arachidonic Acid; D001920:Bradykinin