Inhibition of rat paw oedema and pleurisy by the extract from Mandevilla velutina.

This study reports the oral anti-inflammatory profile of the crude extract (CE) of Mandevilla velutina, a plant which has been previously demonstrated to selectively antagonize bradykinin response of the isolated tissues on rat paw oedema and pleurisy caused by different phlogistic agents. The CE (50 to 200 mg/kg), given 60 min before, inhibited in a dose-dependent manner bradykinin (BK) and cellulose sulphate-induced paw oedema, maximal inhibition of 59% and 65%, respectively. In the same range dose the CE also significantly antagonized pleural exudate and cell infiltration caused by these substances, maximal inhibition of 34% and 46%, respectively. In addition, the CE (100 and 200 mg/kg) also inhibited paw oedema induced by serotonin, PAF-acether and zymosan, maximal inhibition of 55%, 38% and 46%, respectively, but enhanced histamine oedema. However, the CE revealed only partial or no inhibition in pleural exudate caused by these agents. The CE (100 and 200 mg/kg) also inhibited in a dose and time-dependent manner carrageenan-induced paw oedema with a maximal inhibition of 44%, but only partially affected carrageenan-induced pleural exudate. The CE also partially inhibited dextran oedema, but even at a higher dose (400 mg/kg) it failed to interfere with Bothrops Jaracaca-induced paw oedema. The CE inhibited BK and to a lesser extent cellulose sulphate-induced cell migration, but failed to interfere with the differential leukocyte migration in the pleural cavity. These findings provide evidence that the CE from M. velutina, besides antagonizing kinin action, exhibit an oral anti-oedematogenic activity against a variety of phologistic agents, but it was more effective in inhibiting those models where kinins are more involved.     

Potassium humate inhibits carrageenan-induced paw oedema and a graft-versus-host reaction in rats

It has been shown in a previous study that brown coal-derived potassium humate is safe and effective in suppressing contact hypersensitivity in rats. In this study the efficacy of potassium humate on other types of inflammation was determined. Preparative TLC followed by mass spectroscopy was used in an attempt to fingerprint the product. The effects of potassium humate, at an oral dose of 60 mg/kg bodyweight, on a delayed type hypersensitivity reaction, a carrageenan-induced inflammation model and an allogeneic graft-versus-host reaction (GVHR) in rats were investigated. Paw oedema was used as a measure of inflammation. It was found that potassium humate had no effect on the delayed type hypersensitivity reaction but significantly inhibited the increase in paw volume of the carrageenan-induced oedema in rats which compared favourably with indomethacin treatment. Furthermore, potassium humate inhibited the GVHR induced in normal and cyclophosphamide-treated immune-incompetent rats. The identification of a naturally occurring compound that is safe and effective in reducing different types of inflammation merits further evaluation in clinical trials.     

Involvement of B1 and B2 receptors in bradykinin-induced rat paw oedema.

1. The mechanisms involved in bradykinin (BK)-induced oedema in the rat paw as well as the interactions between BK and several inflammatory mediators, have been investigated. 2. Intraplantar injection of BK (1 nmol/paw) in rats pretreated with captopril (5 mg kg-1, s.c.) caused a small amount of oedema formation (0.17 +/- 0.05 ml). Des-Arg9-BK (DABK, a selective B1 receptor agonist) up to 300 nmol/paw caused minimal oedema (0.03 +/- 0.01 ml). 3. Co-administration of prostaglandin E2 (PGE2), prostaglandin I2 (PGI2), calcitonin gene-related peptide (CGRP), 5-hydroxytryptamine (5-HT), substance P (SP) or platelet activating factor (PAF) (1 pmol-1 nmol/paw) with BK (1 nmol/paw) dose-dependently potentiated BK-induced paw oedema. The rank order of potency (mean ED50, pmol/paw) for this effect was: SP (8.1) > PAF (13.7) > PGI2 (20.5) > 5-HT (23.8) > CGRP (25.7) > PGE2 (52.0). Co-administration of BK with the various inflammatory mediators resulted in maximal paw oedemas (ml) of: PGE2 (0.71 +/- 0.02); PGI2 (0.66 +/- 0.02); 5-HT (0.65 +/- 0.01); SP (0.63 +/- 0.05); CGRP (0.60 +/- 0.05) and PAF (0.47 +/- 0.02) ml. Histamine (up to 1 nmol/paw) was ineffective in potentiating the response to BK. 4. Hoe 140 or NPC 17731 (two selective B2 receptor antagonists, 0.1-3 nmol/paw) produced dose-dependent inhibition of paw oedema potentiation induced by co-injection of BK with other mediators with the following mean ID50s (nmol/paw): Hoe 140-1.4; 1.3; 1.5 and 1.1 and NPC 17731-1.0; 1.0; 0.9 and 0.7; in the presence of PGE2, PGI2, CGRP and SP, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)     

Modulation of inflammatory paw oedema by cysteamine in the rat.

Cysteamine, a potent somatostatin depletor, was used in the present study to investigate the role of endogenous somatostatin in acute peripheral inflammation. The acute inflammation was induced by intraplantar injection of carrageenan (1%), histamine (5 micromol), or formalin (2.5%) in the rat hind paw. The induced inflammation and the formation of oedema were determined by measurement of the paw thickness. Given subcutaneously (s.c.) 1 h before carrageenan, cysteamine caused significant, dose-dependent and long-lasting inhibition of rat paw oedema induced by carrageenan. At doses of 12.5, 25, 50 or 100 mg kg (-1), cysteamine significantly inhibited the carrageenan-induced paw oedema at 4 h by 52.3, 40, 40.7 or 26.3%. Cysteamine given at 300 mg kg (-1), a dose well known to deplete tissue somatostatin, reduced oedema by only 16.2% vs control values. Significant inhibition of the carrageenan-induced rat paw oedema was still evident 24 h post-injection at cysteamine doses of 12.5, 25, 50 or 100 mg kg (-1). Given s.c. at 300 mg kg (-1), 4 h prior to carrageenan, cysteamine decreased rat paw oedema at 4 h by 14.9%. Cysteamine (300 mg kg (-1)), 4 h beforehand, had little modulatory effect on the oedema induced by formalin (2.5%) but reduced that caused by intraplantar histamine (5 micromol). The anti-oedematogenic effect of indomethacin, but not that of the selective COX-2 inhibitor celecoxib, was less marked in rats pre-treated with cysteamine at 300 mg kg (-1). Cysteamine (0.3 microg- 0.3 mg paw (-1)) co-administered with carrageenan was devoid of anti-inflammatory effect and even promoted inflammation at low concentrations. Cysteamine given locally alone induced slight paw oedema. These data indicate that systemic cysteamine possesses potent and long-lasting anti-inflammatory effects and modulates the anti-inflammatory effect of cyclooxygenase inhibitors in a model of peripheral inflammation in the rat. The effect of cysteamine is likely to be mediated via central action.     

Hydrogen sulphide induces mouse paw oedema through activation of phospholipase A2

BACKGROUND AND PURPOSE

Hydrogen sulphide (H₂S), considered as a novel gas transmitter, is produced endogenously in mammalian tissue from L-cysteine by two enzymes, cystathionine β-synthase and cystathionine γ-lyase. Recently, it has been reported that H₂S contributes to the local and systemic inflammation in several experimental animal models. We conducted this study to investigate on the signalling involved in H₂S-induced inflammation.

EXPERIMENTAL APPROACH

L-cysteine or sodium hydrogen sulphide (NaHS) was injected into the mouse hind paw and oedema formation was evaluated for 60 min. In order to investigate H₂S-induced oedema formation, we used 5-HT and histamine receptor antagonists, and inhibitors of K_ATP channels or arachidonic acid cascade. Prostaglandin levels were determined in hind paw exudates by radioimmunoassay. Paws injected with L-cysteine or NaHS were examined by histological methods.

KEY RESULTS

Both NaHS and L-cysteine caused oedema characterized by a fast onset which peaked at 30 min. This oedematogenic action was not associated with histamine or 5-HT release or K_ATP channel activation. However, oedema formation was significantly inhibited by the inhibition of cyclooxygenases and selective inhibition of phospholipase A₂. Prostaglandin levels were significantly increased in exudates of hind paw injected with NaHS or L-cysteine. The histological examination clearly showed an inflammatory state with a loss of tissue organization following NaHS or L-cysteine injection.

CONCLUSIONS AND IMPLICATIONS

Phospholipase A₂ and prostaglandin production are involved in pro-inflammatory effects of H₂S in mouse hind paws. The present study contributes to the understanding of the role of L-cysteine/H₂S pathway in inflammatory disease.     

Carrageenan-induced oedema in the rat paw - histamine participation

Participation of histamine in the inflammatory reaction produced by carrageenan was studied. Mepyramine did not influence the course of the inflammatory reaction. In contrast to when mepyramine was used, there was a significant inhibition of carrageenan oedema when cimetidine was used. Pretreatment of animals with compound 48/80 significantly reduced the oedema formation. Neither mepyramine nor cimetidine reversed the inhibition of rat paw swelling produced by histamine liberators. It is concluded that histamine participates in carrageenan oedema via its H2-receptors and that the anti-inflammatory effect of compound 48/80 is not connected with the 'anti-inflammatory' action of liberated histamine.     

Involvement of guanylate cyclase and potassium channels on the delayed phase of mouse carrageenan-induced paw oedema

Previous studies from this laboratory have shown that administration of nitric oxide (NO) donors reduces the early phase (which peaks at 4 h) of carrageenan-induced paw oedema. The aim of this study was to investigate the influence of NO donors on the delayed phase of the mouse paw oedema, which peaks 48 h after carrageenan injection. Treatment of animals with sodium nitroprusside (1.5, 5 and 10 micromol/kg, subcutaneously (s.c.)) 8 h after the subplantar carrageenan injection (300 microg/paw), reduced ( approximately 50%) the delayed phase of paw oedema and the delayed increase in plasma leakage, as assessed by Evans Blue extravasation. Two other NO donors, S-nitroso-N-acetyl-dl-penicillamine (SNAP) or glyceril trinitrate (both at 28 micromol/kg) yielded an inhibition in paw oedema similar to that of sodium nitroprusside. NO-induced inhibition of the delayed phase of paw oedema was reversed when animals were treated with 1H-[1,2,4]-oxadiazolo-[4,3-a]quinoxalin-1 (ODQ, a soluble guanylate cyclase inhibitor, 11 micromol/kg, s.c.) or with tetraethylammonium (TEA, a nonselective potassium channel blocker, 300 micromol/kg, s.c.), 30 min before the prophylactic dose of sodium nitroprusside. In conclusion, our results show that a brief exposure to NO donors, even when made several hours after the inflammatory reaction has been triggered, is still able to cause an important reduction on the delayed phase of carrageenan-induced mouse paw oedema and fluid leakage. Moreover, this long-lasting NO antiinflammatory effect appears to be dependent on guanylate cyclase and potassium channels.     

The activity of suprofen on nystatin-induced paw oedema in rats.

Subplantar injection of nystatin into the rat paw induces acute paw oedema of long duration. In this test the anti-inflammatory activity of alpha-methyl-4-(2-thienylcarbonyl)benzeneacetic acid (suprofen) has been studied using doses from 1.25 up to 160 mg/kg. The lowest dose significantly reducing paw diameter increases was 2.5 mg/kg; more intense and longer lasting reductions appeared progressively with increasing doses. The dose producing 50% inhibition of diameter increase was 2.70 mg/kg 1 h and 1.5 h after administration (lowest ED50). Comparative lowest ED50-values for simultaneously tested reference compounds were 6.2 mg/kg for indometacin, 34 mg/kg for phenylbutazone and 38 mg/kg for acetyl-salicylic acid. Within the first 2 h after administration suprofen exhibited anti-inflammatory activity from 2 to 14 times as potent as did the reference compounds.     

Comparative effects of drugs on four paw oedema models in the rat.

The development of novel anti-inflammatory drugs (AID) has been claimed to be dependent on the discovery of models of inflammation that differ from those currently used for drug screening, e.g. carrageenen paw oedema and u.v. erythema. We have thus evaluated the effect of a variety of drugs in a number of novel models of inflammation in the rat produced in the hind paw. We have utilized kaolin, zymosan, anti-rat IgG (anti-IgG) and the Reversed Passive Arthus (RPA) reaction to produce these oedema models. We found that the non-steroidal AID's, e.g. aspirin, flufenamic acid, indomethacin, naproxen, and phenylbutazone, were active in all four tests. Of the nine novel AID examined, levamisole and tetramisole demonstrated considerable activity in all four tests and dapsone was especially active in the anti-IgG and RPA tests. In contrast, the anti-rheumatic d-penicillamine was inactive in all four models. Each of the ten compounds tested which has been claimed to influence complement function, was active in the RPA but not in the kaolin model. These results are discussed in the context of the aetiology of each oedema and the suspected mode of action of the various drugs.     

Bothrops lanceolatus (Fer de lance) venom induces oedema formation and increases vascular permeability in the mouse hind paw.

The ability of snake venoms to increase vascular permeability and to induce oedema through the release of pharmacologically active substances is well known. We have studied the oedema and vascular permeability induced by Bothrops lanceolatus venom in male Swiss white mice. Paw oedema was induced by the subplantar injection of B. lanceolatus venom (125-1000 ng/paw) and was quantified as the increase in paw weight. Changes in vascular permeability were assessed by measuring the amount of Evans blue dye extravasation. The oedema and the increase in vascular permeability were maximal within 2 h and had resolved after 24 h. The administration of the vasodilator iloprost (20 ng/paw) immediately after B. lanceolatus venom potentiated the oedema and the increase in vascular permeability by approximately four-fold. Pretreating the mice with indomethacin, dexamethasone, NDGA or BW A4C inhibited the venom-induced oedema and the increase in vascular permeability. In contrast, histamine, serotonin and PAF-acether antagonists (mepyramine, cyproheptadine and WEB 2086, respectively) were ineffective. Histological examination showed that B. lanceolatus venom (250 ng and 500 ng/paw) caused thickening of the inner dermal layers which was accompanied by extensive intercellular spaces indicative of oedema. In addition, there was a marked infiltration of inflammatory cells, particularly neutrophils, into the underlying muscle layer. The latter, however, remained morphologically unaffected during the 3 h of observation. Venom doses larger than 500 ng/paw produced intense haemorrhage. These results indicate that B. lanceolatus venom induces oedema and increases vascular permeability in the mouse hind paw. The principal mediators of this inflammatory response are cyclooxygenase and lipoxygenase products.     

Pharmacological studies on zymosan inflammation in rats and mice. 1: Zymosan-induced paw oedema in rats and mice

Injections of zymosan in mouse and rat paws provoke inflammatory reactions, the kinetics of which are different. In both models, inflammation occurs at an early stage but oedema is maximal at 30 min in rat paw and 6 h in mouse paw. In this study the two reactions have been studied up to 6 h. The reduction of oedema by anti-H1 compounds, as well as by disodium cromoglycate, proves the active role played by histamine in rat paw oedema. In mouse its role appears to be minor or non-existent. Serotonin seems to be clearly implicated in the early stages of the oedema in mouse, somewhat less in rat. In the two species, non-steroidal anti-inflammatory compounds only reduce the 4-6 h phase. BW755C and phenidone reduce the early and late phase of paw oedema in both species, with the exception of phenidone which is inactive on the 4-6 h phase in the mouse. We can hypothesize that in the two species some leukotrienes seem to be implicated principally in the early phases, while derivatives of cyclooxygenase play a more important role in the late phases. Theophylline reduces inflammation in the two models, hydrocortisone acetate, however, is only active on the late phases. These results indicate that there are important differences in the participation of the various mediators studied in the two models.     

Intracerebroventricularly administered bradykinin augments carrageenan-induced paw oedema in rats

Intracerebroventricular (i.c.v.) administered bradykinin (2.5 and 5.0 micrograms/rat) was found to augment carrageenan-induced acute paw oedema throughout the 4 h post-carrageenan observation period. The effect was statistically significant with the higher dose. The pro-inflammatory effect of i.c.v. bradykinin was antagonized following pretreatment with hemicholinium and atropine ethoiodide administered i.c.v., drugs that reduce central cholinergic activity. Similarly, central administration of drugs that inhibit the synthesis of eicosanoids, hydrocortisone, diclofenac and paracetamol, also attenuated the pro-inflammatory effect of bradykinin. The findings indicate that the inflammation-promoting effect of centrally administered bradykinin involves the central prostaglandin and cholinergic neurotransmitter systems.     

Pharmacological characterization of mouse hind paw oedema induced by Bothrops insularis (jararaca ilhoa) snake venom.

Bothrops snake venoms produce marked local effects, including oedema, haemorrhage and necrosis. The ability of Bothrops insularis venom to induce oedema in mice was investigated. Venom was injected into hind paws and the change in volume over time was measured by plethysmometry. B. insularis venom (0.01-2.5 microg/paw) induced paw oedema which, at high doses (>/=0.5 microg/paw), was accompanied by haemorrhage. The peak oedematogenic response occurred 3 h after venom injection with all doses and decreased gradually thereafter, but was still elevated with high doses after 24 h. Pretreating the mice with cyproheptadine (histamine H(1) and serotonin 5-HT(2) receptor antagonist), mepyramine (histamine H(1) receptor antagonist), L-NAME (inhibitor of nitric oxide synthase), indomethacin and rofecoxib (inhibitors of cyclooxygenases), and dexamethasone (indirect inhibitor of PLA(2)) significantly attenuated venom-induced oedema, whereas methysergide, a serotonin 5-HT(1)/5-HT(2) receptor antagonist, had no effect. The administration of antivenom 30 min before or immediately after venom injection also significantly inhibited venom-induced oedema. These results show that B. insularis venom causes oedema in the mouse hind paw and that this response is mediated by histamine, nitric oxide, and arachidonic acid metabolites formed by cyclooxygenases 1 and 2. The neutralization by commercial antivenom indicates that the venom components responsible for oedema are recognized by the antivenom and share immunological identity with their counterparts in the venoms of mainland Bothrops species.     

Endothelin-1 inhibits pre-stimulated tracheal submucosal gland secretion and epithelial albumin transport.

1. Endothelin-1 potently contracts smooth muscle, including that in the airways. However, its effect on airway mucosal function has not so far been studied. 2. We have used the ferret whole trachea in vitro to examine the effect of endothelin-1 on tracheal smooth muscle tone, transepithelial potential difference (p.d.), submucosal gland secretion (including lysozyme secretion from serous cells) and active epithelial albumin transport. In addition we have examined the effects of endothelin on submucosal gland secretion and albumin transport pre-stimulated with the muscarinic agonist methacholine and the alpha-adrenoceptor agonist phenylephrine. The effects of the Ca2+ channel blocker nifedipine on the responses to endothelin have also been assessed. 3. Endothelin (0.1-100 nM) produced concentration-dependent increases in intraluminal tracheal pressure indicating smooth muscle contraction, and in the negativity of the transepithelial p.d. These effects were partially inhibited by nifedipine (10 microM). 4. Endothelin (0.01-100 nM) had no significant effect on baseline rates of mucus, lysozyme or albumin outputs, but produced concentration-dependent reductions in maintained methacholine- and phenylephrine-induced mucus, lysozyme and albumin outputs. In general endothelin was more potent against methacholine-induced effects. All of the concentration-response curves for endothelin were shallow and some appeared to be biphasic, suggesting the possibility of more than one mechanism of action of endothelin. 5. The effects of endothelin (at concentrations greater than 1 nM) on phenylephrine-induced mucus volume, lysozyme and albumin outputs were significantly inhibited by nifedipine. Similarly the effect of endothelin (greater than 1 nM) on methacholine-induced mucus volume and albumin outputs (but not lysozyme output) was attenuated by nifedipine.(ABSTRACT TRUNCATED AT 250 WORDS)     

On the ability of prostaglandin E1, and arachidonic acid to modulate experimentally induced oedema in the rat paw.

1 Prostaglandins E1 and E2 but not prostaglandin F2alpha, arachidonic acid or linolenic acid, produced slight oedema when injected into the rat hindpaw. 2 Prostaglandin E1 potentiated hindpaw oedema produced by carrageenan, kaolin, bradykinin and trypsin but not that produced by 5-hydroxytryptamine (5-HT), histamine, dextran B or compound 48/80. Carrageenan- and bradykinin-induced paw oedemas were also potentiated by prostaglandin E2. Arachidonic acid potentiated responses to carrageenan and kaolin but not responses to bradykinin, trypsin, 5-HT, histamine, dextran B or compound 48/80. Linolenic acid did not potentiate hindpaw oedema induced by carrageenan. 3 Potentiation of carrageenan-induced oedema by prostaglandin E1 was not diminished by pretreatment with indomethacin, hydrocortisone or cyproheptadine. However, arachidonic acid potentiation of carrageenan oedema was reduced by pretreatment with non-steroidal anti-inflammatory drugs but not by anti-inflammatory steroids or by paracetamol. 4 The enhancement of the response to carrageenan and kaolin by prostaglandins E1, E2 and arachidonic acid is discussed in terms of kinin mediation.     

Carrageenan-induced mouse paw oedema is biphasic, age-weight dependent and displays differential nitric oxide cyclooxygenase-2 expression

Injection of carrageenan 1% (50 microl) in the mouse paw causes a biphasic response: an early inflammatory response that lasts 6 h and a second late response that peaks at 72 h, declining at 96 h. Only mice 7- or 8-week old, weighing 32-34 g, displayed a consistent response in both phases. In 8-week-old mice, myeloperoxidase (MPO) levels are significantly elevated in the early phase at 6 h and reach their maximum at 24 h to decline to basal value at 48 h. Nitrate+nitrite (NO(x)) levels in the paw are maximal after 2 h and slowly decline thereafter in contrast to prostaglandin E(2) levels that peak in the second phase at the 72 h point. Western blot analysis showed that inducible nitric oxide synthase (iNOS) is detectable at 6 h and cyclooxygenase 2 (COX-2) at 24 h point, respectively. Analysis of endothelial nitric oxide synthase (eNOS), iNOS and COX-2 expression at 6 and 24 h in 3-8-week-old mice demonstrated that both eNOS and iNOS expressions are dependent upon the age-weight of mice, as opposite to COX-2 that is present only in the second phase of the oedema and is not linked to mouse age-weight. Subplantar injection of carrageenan to C57BL/6J causes a biphasic oedema that is significantly reduced by about 20% when compared to CD1 mice. Interestingly, in these mice, iNOS expression is absent up to 6 h, as opposite to CD1, and becomes detectable at the 24 h point. Cyclooxygenase (COX-1) expression is upregulated between 4 and 24 h after carrageenan injection, whereas in CD1 mice COX-1 remains unchanged after irritant agent injection. MPO levels are maximal at the 24 h point and they are significantly lower, at 6 h point, than MPO levels detected in CD1 mice. In conclusion, mouse paw oedema is biphasic and age-weight dependent. The present results are the first report on the differential expressions of eNOS, iNOS, COX-1 and COX-2 in response to carrageenan injection in the two phases of the mouse paw oedema.     

Effects of prolactin on rat paw oedema induced by different irritants.

Evidence suggests that prolactin (PRL) may have a role in immune function, but no data exist on the possible interference between PRL and inflammatory processes, in spite of the known correlation between inflammatory and immune reactions. In the present study the activity of prolactin on rat paw oedema was investigated. Repeated administrations of ovine PRL or a hyperprolactinaemia induced by pituitary gland graft provoked an evident increase of the inflammatory response induced by carrageenan. This effect was also present when adrenalectomised animals were used. Indomethacin completely suppressed the pro-inflammatory effect of ovine PRL; bromocriptine reduced the paw oedema, but when both bromocriptine and PRL were administered the two opposite effects seem to annual each other. Also phospholipase A2-induced paw oedema was potentiated by PRL pretreatment and inhibited by bromocriptine, whereas in dextran or serotonin-induced paw oedema both PRL and bromocriptine were ineffective. A possible involvement of prostaglandins and/or of phospholipase A2 in the pro-oedemigenic activity of PRL is suggested.     

The effect of kinins on paw oedema and uterus in rats

Summary Bradykinin (BK) produced a dose-related increase in the paw volume of the rat. Responses to BK at all doses used were not affected by pretreating the rats with diphenhydramine, 1 mg kg^–1, or indomethacin, 2.5 and 5 mg kg^–1. Indomethacin, 10 mg kg^–1 produced a small but significant reduction in the responses to BK. Captopril 1 mg kg^–1 enhanced responses to low but not to high doses of BK.The rank order of potency of various kinin analogues to increase paw volume was found to be methionyl-lysyl-BK (met-lys-BK) > BK > kysyl-BK (Kallidin) des-Arg⁹-BK. The B₁-receptor antagonist des-Arg⁹-Leu⁸-BK did not affect responses to BK on paw volume.Two modified kinin fragments S2302 (H-D-Pro-Phe-Arg-p-Nitroaniline) and S2441 (H-D-Pro-Phe-Arg-NH-heptyl) produced dose-related increases in paw volume both having approximately half the potency of BK. These responses were not anagonised by diphenhydramine, 1 mg kg^–1 which reduced significantly the response to histamine.On the isolated rat uterus the rank order of potency of various kinins was BK > Kallidin > met-lys-BK > des-Arg⁹-BK. The two modified kinin fragments S2302 and S2441 (but not des-Arg⁹-Leu⁸-BK) antagonised BK induced contractions of the rat uterus.From the rank order of potency studies the receptor mediating contraction of the rat uterus in vitro and increase in rat paw volume to BK appear to be of the same type. Whether the differences in the action of S2302 and S2441 in the rat paw and rat uterus reflect a real difference in receptor type requires further study.