title: The role of guanylyl cyclases in the permeability response to inflammatory mediators in pial venular capillaries in the rat.
abstract: Inflammatory mediators have a role in the formation of cerebral oedema and there is evidence that cGMP is an important signal in vascular permeability increase. We have investigated the role and the source of cGMP in mediating the permeability response to acutely applied bradykinin and the histamine H(2) agonist dimaprit on single cerebral venular capillaries, by using the single vessel occlusion technique. We found that 8-bromo-cGMP applied acutely resulted in a small and reversible permeability increase with a log EC(50) -7.2 +/- 0.15 M. KT 5823, the inhibitor of cGMP-dependent protein kinase, abolished the permeability responses to both bradykinin and dimaprit, while zaprinast, an inhibitor of type 5 phosphodiesterase, potentiated the response to bradykinin. On the other hand, L-NMMA blocked the response to dimaprit, but not that to bradykinin. Inhibitors of soluble guanylyl cyclase, LY 85353 and methylene blue, also inhibited the permeability response to dimaprit, but not bradykinin. The permeability responses to the natriuretic peptides ANP and CNP were of similar magnitude to that of bradykinin with log EC(50) -10.0 +/- 0.33 M and -8.7 +/- 0.23 M, respectively. The natriuretic peptide receptor antagonist HS-142-1 blocked permeability responses to bradykinin as well as to ANP, and leukotriene D(4) blocked the responses to CNP and bradykinin, but not to dimaprit. In conclusion, the histamine H(2) receptor appears to signal via cGMP that is generated by a NO and soluble guanylyl cyclase, while bradykinin B(2) receptor also signals via cGMP but through particulate guanylyl cyclase.
authors.affiliation: Centre for Cardiovascular Biology and Medicine, King's College London, New Hunt's House, Guy's Campus, London SE1 1UL, UK.
authors.forename: M H
authors.initials: MH
authors.lastname: Sarker
authors.forename: P A
authors.initials: PA
authors.lastname: Fraser
mesh_terms: D000818:Animals; D009320:Atrial Natriuretic Factor / Q000378:metabolism; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000276:immunology; D001920:Bradykinin / Q000494:pharmacology; D001929:Brain Edema / Q000276:immunology* / Q000378:metabolism*; D002196:Capillaries / Q000201:enzymology; D002199:Capillary Permeability / Q000187:drug effects / Q000276:immunology; D006152:Cyclic GMP / Q000031:analogs & derivatives* / Q000494:pharmacology; D017259:Dimaprit / Q000494:pharmacology; D005260:Female; D006162:Guanylate Cyclase / Q000378:metabolism*; D006632:Histamine / Q000494:pharmacology; D017442:Histamine Agonists / Q000494:pharmacology; D018836:Inflammation Mediators / Q000378:metabolism*; D008297:Male; D009569:Nitric Oxide / Q000378:metabolism; D010841:Pia Mater / Q000098:blood supply*; D051381:Rats; D017208:Rats, Wistar; D043782:Receptor, Bradykinin B2; D018002:Receptors, Bradykinin / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D011970:Receptors, Histamine H2 / Q000378:metabolism; D000071756:Soluble Guanylyl Cyclase; D014699:Venules / Q000201:enzymology
chemical_list: D017442:Histamine Agonists; D018836:Inflammation Mediators; D043782:Receptor, Bradykinin B2; D018002:Receptors, Bradykinin; D018160:Receptors, Cytoplasmic and Nuclear; D011970:Receptors, Histamine H2; C016276:8-bromocyclic GMP; D009569:Nitric Oxide; D006632:Histamine; D009320:Atrial Natriuretic Factor; D006162:Guanylate Cyclase; D000071756:Soluble Guanylyl Cyclase; D006152:Cyclic GMP; D001920:Bradykinin; D017259:Dimaprit