Cutaneous permeability responses to bradykinin and histamine in the guinea-pig: possible differences in their mechanism of action.
1. Plasma protein extravasation (PPE) responses in guinea-pig skin have been measured using accumulation of intravenously injected 125I-labelled human serum albumin (125I-HSA). 2. The nitric oxide (NO) synthase inhibitor, NG-nitro-L-arginine methyl ester (L-NAME; 0.1 mumol/site) significantly reduced responses to bradykinin (BK; 0.5 nmol/site) or histamine (4.5 nmol/site) when co-injected with the inflammatory mediators. D-NAME (0.1 mumol/site) had no significant effect. 3. L-NAME (0.01-0.1 mumol/site) appeared to produce greater shifts of the dose-response curve to BK (0.1-3 nmol/site) than of that to histamine (2.3-27 nmol/site). Both 0.01 and 0.1 mumol L-NAME/site significantly reduced the response to BK (0.5 nmol/site) whereas only the higher dose of L-NAME produced a significant reduction in the response to histamine (4.5 nmol/site). 4. The inhibitory effect of L-NAME (0.1 mumol/site) on the response to BK but not on that to histamine was significantly reversed by L-arginine (L-Arg; 10 mumol/site). D-arginine (D-Arg; 10 mumol/site) had no significant effect in either case. 5. L-Arg (10 mumol/site) significantly enhanced the response to BK but inhibited that to histamine. D-Arg (10 mumol/site) had no significant effect on BK but significantly inhibited histamine. L-Lysine (L-Lys: 10 mumol/site) had no significant effect on the response to either BK or histamine. 6. L-Arg (100 mM) had a significant inhibitory effect on isometric contractions to histamine, but not BK in guinea-pig ileum in vitro. D-Arg (100 mM) also significantly inhibited histamine responses whereas L-Lys (100 mM) had no effect. 7. The alpha-adrenoceptor agonist, phenylephrine (0.3 or 6 nmol/site) inhibited matched responses to BK (0.5 nmol/site) or histamine (5.4 nmol/site) to comparable degrees, but gave significant inhibition only at the higher dose. 8. The Beta-adrenoceptor agonist, isoprenaline (0.5 or 10 nmol/site) had a significant inhibitory effect on the response to histamine (5.4 nmol/site) whereas a comparable response to BK (0.5 nmol/site) was significantly reduced by the higher dose only.9. Our results with L-NAME suggest that local production of NO is involved in the modulation of mediator-induced vascular permeability. It is possible that NO may play a greater role in the extravasation response to BK than to that induced by histamine.10. The differential effects of L-NAME and isoprenaline on BK- and histamine-induced PPE raise the possibility that BK and histamine may induce vascular permeability via different mechanisms in guinea-pig skin.
Department of Pharmacology, King's College, London.
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W
Paul
G J
GJ
Douglas
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Lawrence
A M
AM
Khawaja
A C
AC
Perez
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Schachter
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CP
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D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives / Q000494:pharmacology; D001920:Bradykinin / Q000378:metabolism / Q000494:pharmacology*; D002199:Capillary Permeability / Q000187:drug effects*; D006168:Guinea Pigs; D006632:Histamine / Q000378:metabolism / Q000494:pharmacology*; D007082:Ileum / Q000187:drug effects; D066298:In Vitro Techniques; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects*; D019331:NG-Nitroarginine Methyl Ester; D009569:Nitric Oxide / Q000037:antagonists & inhibitors; D010656:Phenylephrine / Q000494:pharmacology; D012867:Skin / Q000098:blood supply*; D013237:Stereoisomerism
D010656:Phenylephrine; D009569:Nitric Oxide; D006632:Histamine; D001120:Arginine; D007545:Isoproterenol; D001920:Bradykinin; D019331:NG-Nitroarginine Methyl Ester