The modulation of inflammatory oedema by calcitonin gene-related peptide.

1. The effect of calcitonin gene-related peptide (CGRP) when given with or as a pretreatment to oedema inducing agents was investigated in the skin and paws of male Wistar and Sprague Dawley rats. 2. Oedema formation at intradermally-injected sites in the skin was measured by a 125I-labelled human serum albumin accumulation technique and paw oedema was measured by a weight displacement technique. 3. CGRP (30 pmol) when given with, or as a 20 min pretreatment, markedly potentiated oedema formation induced by substance P (100 pmol) in rat skin. In comparison, CGRP had little effect on 5-hydroxytryptamine (5-HT, 0.1-3 nmol)-induced oedema when given as a co-injection but significantly potentiated 5-HT-induced oedema when given as a 20 min pretreatment in the skin. Similar results were obtained in both Wistar and Sprague Dawley rats. 4. Pretreatment with CGRP (30 pmol) had little modulatory effect on oedema induced by substance P (100 pmol) in the presence of the vasodilator prostanoid, prostaglandin E1 (PGE1, 850 pmol) in the skin of Wistar rats. 5. Pretreatment with CGRP (30 pmol) caused a non-significant increase in carrageenin (300 micrograms)-induced oedema in the hind paw of Wistar rats. Capsaicin (100 nmol) given as a pretreatment had little effect on carrageenin-induced oedema. 6. CGRP (30 pmol), given as a pretreatment, had little modulatory effect on 5-HT (3 nmol)-induced oedema in the paw of Wistar rats but a non-significant decrease in paw oedema was observed in Sprague Dawley rats.(ABSTRACT TRUNCATED AT 250 WORDS)     

The effects of calcitonin gene-related peptide on formation of intra-articular oedema by inflammatory mediators.

1. The temporal and quantitative effects of inflammatory mediators on plasma extravasation in the rat knee were investigated by use of a perfusion technique. 2. Intra-articular perfusion of substance P (SP), bradykinin or histamine over a 5 min test period produced rapid-onset and prolonged plasma extravasation in a dose-dependent fashion. The rank order of potency was bradykinin greater than SP greater than histamine. 3. Calcitonin gene-related peptide (CGRP) did not induce plasma extravasation but enhanced substance P-induced plasma extravasation in a dose-dependent fashion. A 5 min co-perfusion of the two agents produced short-term enhancement lasting 10 min while continuous co-perfusion produced enhancement for the duration of the perfusion. 4. A 5 min perfusion of CGRP enhanced plasma extravasation when co-perfused with bradykinin but not histamine. However, when CGRP and histamine were continuously co-perfused over a 20 min test period, an enhanced response was apparent. 5. The results indicate that intra-articular perfusion of CGRP enhances synovial plasma extravasation induced by agents that increase vascular permeability, but suggest that the response is not uniform and is critically dependent on the duration of perfusion within the joint.     

Effect of calcitonin on different inflammatory models.

The effect of synthetic salmon calcitonin was studied on adjuvant arthritis, pertussis vaccine edema, tuberculin skin reaction, passive direct Arthus reaction and nystatin edema. The results show that calcitonin inhibits these inflammatory processes.     

Evidence for a direct anti-inflammatory action of calcitonin: inhibition of histamine-induced mouse pinnal oedema by porcine calcitonin

Porcine calcitonin (PCT) caused a potent inhibition of histamine-induced vascular leakage in the mouse pinna. These effects were observed at doses of PCT lower than those required to affect plasma calcium concentrations. In contrast PCT did not inhibit responses of the mouse pinna to 5-hydroxytryptamine despite observed falls in plasma calcium concentrations. It would appear that PCT inhibits histamine-induced oedema in the mouse by a direct action which may partially or fully explain the anti-inflammatory action of PCT, observed by other workers, in some acute inflammatory conditions.     

Evidence for a direct anti-inflammatory action of calcitonin: inhibition of histamine-induced mouse pinnal oedema by porcine calcitonin

Porcine calcitonin (PCT) caused a potent inhibition of histamine-induced vascular leakage in the mouse pinna. These effects were observed at doses of PCT lower than those required to affect plasma calcium concentrations. In contrast PCT did not inhibit responses of the mouse pinna to 5-hydroxytryptamine despite observed falls in plasma calcium concentrations. It would appear that PCT inhibits histamine-induced oedema in the mouse by a direct action which may partially or fully explain the anti-inflammatory action of PCT, observed by other workers, in some acute inflammatory conditions.     

Effect of calcitonin on ACTH secretion

We have investigated the effects of salmon calcitonin injected intracerebroventricularly on adrenocorticotropic (ACTH) secretion in rats. Salmon calcitonin was able to increase significantly (p less than 0.05) ACTH secretion at the dose of 5 ng/rat and (p less than 0.01) at the doses of 12.5, 25 and 50 ng/rat; the effect (50 ng/rat) was maximal at 30 min and still present after 60 and 120 min. The maximal dose of calcitonin produced a significant (p less than 0.05) increase in serum ACTH concentration also in stressed animals. It is suggested that calcitonin may increase serum ACTH secretion by central norepinephrine and/or 5-hydroxytryptamine pathways that regulate corticotropic releasing factor activity.     

Effect of a calcitonin gene-related peptide antagonist (CGRP8-37) on skin vasodilatation and oedema induced by stimulation of the rat saphenous nerve.

1. The effect of the calcitonin gene-related peptide antagonist (CGRP8-37, 400 nmol kg-1, i.v.) on the increased blood flow induced by calcitonin gene related peptide (CGRP), vasodilator prostaglandins, and topical capsaicin was measured with a laser Doppler blood flow meter in rat abdominal skin. 2. The saphenous nerve was electrically stimulated and the effect of CGRP8-37 (400 nmol kg-1, i.v.) on the increased blood flow (measured by laser Doppler flowmetry) and oedema formation (measured by the extravascular accumulation of [125I]-albumin) was investigated in the rat hind paw. 3. CGRP8-37 (400 nmol kg-1, i.v.) had no effect on basal cutaneous blood flow at uninjected sites and sites injected with Tyrode buffer, but acted selectively to inhibit the increased blood flow induced by intradermal CGRP (10 pmol/site, P < 0.05), but not that induced by prostaglandin E2 (PGE2, 300 pmol/site) or carba-prostacyclin (cPGI2, 100 pmol/site). 4. Capsaicin (0.1-33 mM), applied topically, acted in a dose-related manner to increase blood flow. CGRP8-37 (400 nmol kg-1, i.v.) almost totally inhibited blood flow induced by capsaicin (10 mM; P < 0.05) but did not significantly inhibit blood flow induced by a higher dose of capsaicin (33 mM). 5. The increased blood flow induced by short stimulation of the saphenous nerve (10 V, 1 ms, 2 Hz for 30 s) was inhibited by 76%, 5 min after i.v. CGRP8-37 (400 nmol kg-1, i.v., P < 0.05). 6. A longer (5 min) electrical stimulation of the saphenous nerve caused oedema formation, in addition to increased blood flow.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of catecholamines on oedema induced by inflammatory agents in the rat.

The effect of intracutaneous adrenaline and noradrenaline (5 X 10(-12) and 5 X 10(-11) mol) was examined on the oedema (Evans blue dye leakage) response of rats to several inflammatory agents. The catecholamines reduced the oedema response to all agents tested except prostaglandin E1 (PGE1) which was significantly potentiated by noradrenaline (5 X 10(-11) mol), and a combination of bradykinin 5 X 10(-11) mol with PGE1 5 X 10(-10) mol which was not significantly affected by any dose of catecholamine. Adrenaline was more effective than noradrenaline in reducing oedema produced by 5-hydroxytryptamine (5HT) and histamine and by agents which release these amines (compound 48/80, dextran and antigen challenge with egg albumin in sensitized rats), but noradrenaline was more potent against bradykinin-induced oedema. The inhibitory effect of catecholamines against oedema produced by histamine and 5HT was abolished by a combination of phentolamine and propranolol. It was concluded that the oedema-inhibiting effect of catecholamines is due to alpha- and beta-adrenoreceptor mediated actions.     

Enhancement of carrageenin foot oedema by 1,10 -phenanthroline and evidence for the bradykinin as endogenous mediator.

Carrageenin oedema in enhanced by the simultaneous injection in the rat paw of 1,10-phenanthroline, a kininase inhibitor. The analysis of the time-course of this enhancement showed that the maximal effect was observed about 3 hours after the injection. This enhancement was also present when the oedema-producing agent was cellulose sulphate, a kinin-releasing compound. On the contrary, oedema induced by eggwhite as well as by dextran, which are mainly mediated by histamine and 5-hydroxytryptamine, were unaffected by 1,10-phenanthroline. These results further support the role of kinins in the pathogenesis of carrageenin oedema.     

Inflammatory oedema induced by synergism between calcitonin gene-related peptide (CGRP) and mediators of increased vascular permeability.

The potent vasodilator calcitonin gene-related peptide (CGRP, human synthetic), when mixed with histamine and injected intradermally in the rabbit, induced a marked potentiation of local oedema. CGRP also potentiated oedema induced by other mediators of increased microvascular permeability in the rabbit; bradykinin, platelet-activating factor (Paf), C5a des Arg, N-formylmethionyl-leucyl-phenylalanine (FMLP) and leukotriene B4 (LTB4). Substance P alone, or mixtures of substance P and CGRP, failed to induce oedema in rabbit skin. In rat skin, however, substance P induced oedema and this was potentiated by CGRP. CGRP had a protracted potentiating action following intradermal injection in the rabbit. The time for half loss of activity for CGRP was 40.1 +/- 7.5 min compared to 18 +/- 1 min for prostaglandin E2 (PGE2). No loss of potentiating activity was detected after incubation of CGRP in rabbit plasma or blood for 60 min. We postulate that endogenous CGRP, if released locally from nerve endings, could have a marked enhancing effect on oedema induced by other mediators in an inflammatory reaction.     

降钙素基因相关肽对人皮肤成纤维细胞增殖的影响

目的探讨降钙素基因相关肽(CGRP)在不同浓度下对人皮肤成纤维细胞(Fb)增殖的影响。方法以含不同浓度的降钙素基因相关肽(CGRP)培养基培养成纤维细胞,在不同时间用细胞计数板进行细胞计数,四甲基偶氮唑盐比色法(MTT)法检测细胞的活性,选择最适浓度生长因子干预的细胞,用流式细胞仪检测细胞的DNA倍体情况及细胞周期,对所得数据进行统计学处理。结果降钙素基因相关肽(CGRP)促皮肤成纤维细胞(Fb)增殖作用的强度与CGRP的浓度和作用时间有关,在一定范围内随降钙素基因相关肽浓度递增作用增强,时间是在48 h促增殖作用最强。结论降钙素基因相关肽能够促进人皮肤成纤维细胞的增殖。     

The kinin antagonist hoe 140 reduces acute paw oedema in rats caused by carrageenan, bradykinin and kaolin

The present study aimed to evaluate the effect of Hoe 140, a BK receptor B₂ antagonist, on acute oedema induced by carrageenan, BK and kaolin in male Wistar Kyoto rats. Hoe 140 (0.2 mg/kg and 20 mg/kg) given ip caused significant (p<0.05 and p<0.01) inhibition of carrageenan and BK-induced paw oedema. This suggests that BK is the prime inflammatory mediator of carrageenan oedema, and that it is also a specific blocker of oedema caused by BK. Furthermore, Hoe 140 was found to be less effective in reducing kaolin-induced oedema in rats. This might reflect that BK is not a prime inflammatory mediator of kaolin-induced oedema. The possible significance of these findings is discussed.     

Water-logged women--idiopathic oedema.

The clinical details of ten women with idiopathic oedema are presented and one is discussed in detail. The condition is characterised by an excessive diurnal weight gain with the development of peripheral oedema when the patient is in the upright position. Treatment is frequently unsatisfactory but should include, a full explanation, weight reduction, moderate sodium restriction, psychiatric assessment, no smoking and avoidance of prolonged standing. If this approach fails the smallest effective dose of a mild diuretic agent may be prescribed during an episode of fluid retention.     

Effect of drugs on rat paw oedema induced by mercury

1 Metallic mercury (0.04 ml) injected into the foot pad of rats induced a consistent inflammatory reaction, which at 4 h showed oedema but no cellular infiltration or vascular changes. The lesions exhibited lymphocytic infiltration, vasodilatation and haemorrhages at 24 and 48 h, and often became cystic after 2-3 weeks, before healing. The oedema volume at 4 h was used to test anti-inflammatory activity of drugs.2 Cortisone, phenylbutazone, indomethacin, acetylsalicylic acid, flufenamic acid and propranolol exhibited potent, dose-related anti-inflammatory activity. Aminopyrine, chloroquine and chlorpromazine were only moderately effective. Dimercaprol, adrenaline, and to some extent, mepyramine also inhibited mercury-induced oedema.3 This simple model of acute inflammation may be useful for preliminary tests of anti-inflammatory activity.