Actions of Locally Administered Adrenoceptor Agonists on Increased Plasma Protein Extravasation and Blood Flow in Guinea‐pig Skin

Prostaglandins possess both pro‐ and anti‐inflammatory actions depending on their route of administration and the experimental model used. In this study, we have investigated the effect of locally injected prostaglandins on oedema formation, neutrophil accumulation and eosinophil accumulation in inflammatory responses in guinea‐pig skin. Prostaglandin E1 (PGE1) significantly enhanced local oedema formation induced by zymosan‐activated plasma (ZAP), bradykinin and in a passive cutaneous anaphylatic (PCA) reaction. The accumulation of ZAP‐induced 111In‐labelled neutrophils was also significantly enhanced by PGE1. In addition, the prostacyclin analogue, iloprost, enhanced ZAP‐induced responses. In contrast PGE1 decreased the accumulation of 111In‐labelled eosinophils in skin sites. This was demonstrated on eosinophil accumulation and local eodema formation induced by PAF, compound 48/80 and in the PCA reaction. PGE2 also suppressed eosinophil accumulation while iloprost had no detectable effect. Isoprenaline inhibited eosinophil accumulation in a dose‐dependent manner with no effect on local oedema formation, except in the case of responses to ZAP where suppression was observed. The vasodilator neuropeptide, calcitonin gene‐related peptide (CGRP), enhanced local oedema formation but had no detectable effect on eosinophil accumulation. In conclusion, the magnitude of a given response to an inflammatory mediator in vivo depends on the net effect of stimulation of several cell types e.g. arteriolar smooth muscle cells, microvascular endothelial cells, mast cells and accumulating leukocytes. In this study, we have demonstrated that different components of the inflammatory response in guinea‐pig skin can be differentially modulated by E‐type prostaglandins and isoprenaline, suggesting that cyclic AMP has an important regulatory role.

Section: Effect Of Calcitonin Gene-related Peptide (Cgrp) On Eosinophmentioning

confidence: 99%

E‐type prostaglandins enhance local oedema formation and neutrophil accumulation but suppress eosinophil accumulation in guinea‐pig skin

Teixeira

Williams

Hellewell

1993

“…range of a-adrenoceptor agonists which reduce cutaneous blood flow inhibit BK-induced exudation responses (Beets & Paul, 1980). Thus, the magnitude of an acute inflammatory response may be modulated by changes in local blood flow interacting with alterations in microvessel permeability.…”

Section: Introductionmentioning

confidence: 99%

Cutaneous permeability responses to bradykinin and histamine in the guinea‐pig: possible differences in their mechanism of action

Paul

Douglas

Lawrence

et al. 1994

Self Cite

1 Plasma protein extravasation (PPE) responses in guinea-pig skin have been measured using accumulation of intravenously injected '25I-labelled human serum albumin ('25I-HSA).2 The nitric oxide (NO) synthase inhibitor, N0-nitro-L-arginine methyl ester (L-NAME; 0.1 mol/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 pmol/site) had no significant effect.3 L-NAME (0.01-0.1 gmol/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 fmol 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 tmol/site) on the response to BK but not on that to histamine was significantly reversed by L-arginine (L-Arg; 10 pmol/site). D-arginine (D-Arg; 10 gpmol/site) had no significant effect in either case. D-Arg (10 l mol/site) had no significant effect on BK but significantly inhibited histamine. L-Lysine (L-Lys: limol/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 a-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 P-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.

“…Increased plasma protein extravasation (IPPE) IPPE was measured by means of isotopically labelled albumin (Beets & Paul, 1980). Each animal was injected intravenously with 0.5 ml Evans blue dye containing 1.5 plCi 251I-human serum albumin ([125T]-HSA; Amersham International); 40min after the intradermal injections, animals were killed by a blow to the head, bled (1 ml blood was collected) and skinned.…”

Section: Intradermal Injectionsmentioning

confidence: 99%

Inflammatory actions of platelet activating factor (Paf‐acether) in guinea‐pig skin

Morley¹,

Page²,

Paul³

1983

Self Cite

1Cutaneous responses to synthetic platelet activating factor (Paf-acether) have been studied in guinea-pigs by means of radioisotopic marker techniques. 2 Intradermal injection of Paf-acether elicited increased plasma protein extravasation (IPPE) (0.2-200 pmol/site), platelet accumulation (PA) (20-200 pmol/site) and red blood cell accumulation (RBCA) (200 pmol/site), whereas lyso-Paf (up to 2 nmol/site) was inactive in all these respects. 3 Following intradermal injection, the IPPE responses to Paf-acether (2 and 20 pmol/site) were complete within 15 and 30 min respectively, although in response to 200 pmol/site, IPPE was detectable up to 1.5 h. The PA and RBCA responses to Paf-acether (200 pmol/site) were complete within 1 h. 4 IPPE induced by Paf-acether (3 pmol/site) was potentiated by concomitant intradermal injection of a cutaneous vasodilator prostaglandin E2 (PGE2, lnmol/site) and inhibited by the Padrenoceptor agonist, isoprenaline (4.5 nmol/site) or the cx-adrenoceptor agonist, phenylephrine (6 nmol/site). Such observations are consistent with Paf-acether effecting increased vessel wall permeability. 5 Intradermal injection of PGE1 (3 nmol/site) significantly reduced PA in response to Paf-acether (200 pmol/site), whilst significantly enhancing IPPE. This dissociation of increased vascular permeability from PA is consistent with Paf-acether eliciting IPPE via a platelet-independent mechanism. 6 These results indicate that a direct effect on vessel wall permeability contributes to the inflammatory response to Paf-acether in guinea-pig skin. It is suggested that Paf-acether is a potential mediator of allergy and inflammation.