Biomedical subjects

S D Brain

Publications and source records attributed to S D Brain.

At least 91 records · Page 5Linked to original sources

PubMed1992

The partial inhibition of inflammatory responses induced by capsaicin using the Fab fragment of a selective calcitonin gene-related peptide antiserum in rabbit skin.

The effect of an anti-calcitonin gene-related peptide (CGRP) antibody on responses induced by the sensory C-fibre neuropeptide, CGRP, and capsaicin, which selectively activates C-fibre nerves, was investigated in rabbit skin. Test agents and antibody were injected intradermally. Local blood flow changes were measured by 133Xenon clearance and oedema formation by [125I]albumin accumulation. Preinjection intradermally with the Fab fragment of a goat anti-human alpha CGRP antibody selectively inhibited increased blood flow induced by CGRP (3 x 10(-12) mol/site) and caused a partial, but significant inhibition of increased blood flow induced by capsaicin (3 x 10(-7) mol/site). Oedema induced by histamine and bradykinin was potentiated by vasodilator doses of CGRP and capsaicin. These potentiating effects were significantly inhibited by pretreatment with anti-CGRP Fab. The Fab fragment was more potent in inhibiting capsaicin-induced responses than the parent IgG. These results suggest that capsaicin releases vasodilator quantities of CGRP in rabbit skin.

Animals↗

PubMed1992

Endothelin-1 induces a histamine-dependent flare in vivo, but does not activate human skin mast cells in vitro.

The role of the mast cell in endothelin-1 induced flare has been investigated by in vivo and in vitro experiments. The intradermal injection of endothelin-1 (10 pmol) into human skin induced a pallor with surrounding axon-reflex flare which is similar to the flare response to histamine (1 nmol). At these doses, chosen to give identical flare areas, blood flow was increased in the area of the endothelin-induced flare over a longer period. A systemic H1-receptor antagonist significantly inhibited the area of both flares, although blood flow in the remaining portion of the endothelin-induced flare remained raised. Endothelin-1 at concentrations up to 3 x 10(-5) M failed to release histamine from human dispersed skin mast cells. We suggest from these results that a major component of endothelin-1 induced flare results from mast cell activation that is secondary to direct stimulation of sensory nerves by the peptide.

Adult↗

PubMed1992

Responses to endothelins in the rat cutaneous microvasculature: a modulatory role of locally-produced nitric oxide.

1. The response of the cutaneous microvasculature to intradermal injection of the endothelins (ET-1, ET-2 and ET-3) and the modulatory effect of endogenously produced nitric oxide (NO) have been determined in the rat. 2. Intradermal injection of endothelins (0.1- 10 pmol/site) induced dose-dependent local reductions in blood flow, measured by 133xenon clearance, with the following potency order; ET-1 = ET-2 greater than ET-3. 3. Laser Doppler blood flowmetry established that ET-1 (10 pmol/site) significantly (P less than 0.05) reduced microvascular blood flow for 3 h after injection. Over a wide dose-range, the response to the endothelins did not include any vasodilatation or visible flare. 4. A possible modulatory role of locally-produced NO was investigated by the intradermal injection of the potent inhibitor of NO generation NG-nitro-L-arginine methyl ester (L-NAME). L-NAME (100 nmol/site) injected alone induced a significant decrease in blood flow. The vasoconstriction induced by L-NAME was partially reversed by L-arginine (P less than 0.05) but not observed with NG-nitro-D-arginine methyl ester (D-NAME). 5. L-NAME significantly (P less than 0.05) enhanced the decrease in blood flow induced by submaximal doses of ET-1, ET-2 and ET-3 and vasopressin, although the results do not suggest that any of the vasoconstrictors stimulate NO release. The response to L-NAME was still observed 3.5 h after inducing a prolonged constriction with ET-1 (10 pmol/site).6. These results indicate that locally produced NO maintains a dilator tone in the cutaneous microvasculature of the rat and acts to modulate the effect of vasoconstrictors such as endothelins. Hence, it is suggested that in conditions where endogenous NO release is reduced, vasoconstrictor agents such as the endothelins could induce a dangerous decrease in blood flow possibly leading to ischaemia and tissue necrosis.

Animals↗

PubMed1992

Calcitonin gene-related peptide increases blood flow and potentiates plasma protein extravasation in the rat knee joint.

1. The effects of calcitonin gene-related peptide (CGRP) and other vasoactive mediators of inflammation on blood flow in the synovial vessels and plasma protein extravasation into the knee (femoro-tibial) joint of the pentobarbitone-anaesthetized rat were measured. 2. Changes in synovial blood flow were estimated by 133xenon clearance from the synovial cavity. CGRP (0.1 pmol and 10 pmol) and prostaglandin E1 (PGE1; 3 pmol and 300 pmol) significantly increased clearance from the knee joint measured 5 min after intra-articular injection. Substance P (10 pmol) had no effect on synovial blood flow. 3. Intra-articular perfusion of the rat knee with CGRP at concentrations up to 0.1 mM, or PGE1 at concentrations up to 10 microM, did not increase plasma extravasation into the synovial cavity measured by accumulation of intravenously injected 125I-albumin in the perfusate. 4. Plasma extravasation into the knee was significantly increased by infusion of bradykinin (0.1 microM), 5-hydroxytryptamine (1 microM) and histamine (0.1 mM), compared with the contralateral joints in the same animals which were perfused with Tyrode solution. 5. Perfusion of the knee joint with substance P did not specifically induce 125I-labelled albumin accumulation in the synovial cavity even at doses that had systemic effects as observed by marked plasma extravasation into other tissues. 6. The increase in plasma extravasation induced by histamine (0.1 mM) was potentiated by co-infusion with CGRP (0.1 microM) and PGE1 (3 microM). However the response to a submaximal dose (0.1 microM) of bradykinin, which induced similar plasma extravasation to histamine (0.1 mM), was not increased by co-infusion with CGRP or PGE1.7. These results show that CGRP is a potent vasodilator in the rat knee. CGRP released from sensory nerves may act synergistically with mediators of increased vascular permeability to modify the inflammatory response in this site.

Alprostadil↗

PubMed1992

Altered microvascular reactivity to endothelin-1, endothelin-3 and NG-nitro-L-arginine methyl ester in streptozotocin-induced diabetes mellitus.

1 We have determined the dermal microvascular effects of the nitric oxide (NO) synthase inhibitor, NG-nitro-L-arginine methyl ester (L-NAME, 100 nmol/site), endothelin-1 (ET-1, 0.1-10 pmol/site) and ET-3 (0.1-30 pmol/site) in rats with streptozotocin (STZ)-induced diabetes mellitus. Cutaneous blood flow changes as measured by a 133xenon (133Xe) clearance technique, were determined in diabetic rats four weeks after treatment with streptozotocin (STZ) and compared with responses measured in normal rats four weeks after treatment with saline. 2 Resting skin blood flow was similar in diabetic and in normal rats, as measured by 133Xe clearance and laser Doppler flowmetry. 3 Intradermal NG-nitro-L-arginine methyl ester (L-NAME) reduced skin blood flow in normal rats by 55.2 +/- 2.6% as measured by 133Xe clearance, (n = 9). L-NAME was significantly less effective in diabetic rats, inducing a 40.9 +/- 7.7% decrease in blood flow (n = 9, P less than 0.05). The enantiomer D-NAME had no effect in either group of rats. 4 Low doses of ET-1 and ET-3 injected intradermally induced dose-dependent decreases in blood flow, measured by 133Xe clearance, which were similar in both groups of rats. However, the responses to the highest doses of ET-1 (10 pmol/site) and ET-3 (10 and 30 pmol/site) were significantly reduced in the diabetic compared with the normal rats (P less than 0.05).In addition vasoconstriction to the highest doses of vasopressin (0.3 and 3 pmol/site) and vasodilatation to the neuropeptide calcitonin gene-related peptide (CGRP, 1O pmol/site) were similarly reduced in the diabetic rats (P <0.05).5. The decrease in blood flow induced by submaximal doses of ET-1 was enhanced by co-injection with L-NAME (100 nmol/site) in both diabetic and normal rats. However, this enhanced response was significantly reduced in the diabetic rats (P<0.05). A similar pattern of responses were observed to ET-3 in the presence and absence of L-NAME.6. These results indicate that the cutaneous microvasculature of rats with STZ-induced diabetes responds differently to intradermal ET-1 and ET-3 compared with normal rats; a similarly altered vascular reactivity was observed with vasopressin and CGRP. Hence, the diabetic microcirculation has impaired responses to several vasoconstrictors and a vasodilator. The effect of the nitric oxide synthase inhibitor L-NAME is also suppressed in the diabetics, suggesting that there may be decreased local production of, or response, to nitric oxide.

Animals↗

PubMed1991

Inflammatory edema induced by interactions between IL-1 and the neuropeptide calcitonin gene-related peptide.

The neuropeptide calcitonin gene-related peptide (CGRP) is a potent vasodilator with a long duration of action. CGRP is widely distributed and is present in perivascular nerves of tissues that include skin and the synovium. In this study we have investigated the possibility that CGRP can modulate the inflammatory actions of the cytokine IL-1 by using an inflammatory model in rabbit skin. The intradermal injection of IL-1 (1.4 x 10(-14) mol/site) alone stimulated little edema formation. However, when IL-1 was injected with CGRP (10(-11) mol/site), a highly significant edema was observed, and neutrophil accumulation induced by IL-1 was potentiated. These results suggest that the action of IL-1 as a potent mediator of increased microvascular permeability is only observed when skin blood flow is increased in this model. This was confirmed by experiments in which PGE2 (3 x 10(-9) mol/site) at a dose with a similar duration of vasodilator action as CGRP (10(-11) mol/site) also potentiated edema induced by IL-1. Further experiments investigated the mechanism by which IL-1 increased microvascular permeability. Edema induced by IL-1 was dependent on de novo protein synthesis and the presence of circulating neutrophils. However, selective platelet-activating factor and histamine H1 antagonists had no inhibitory effect on this response. Thus it appears that when a microvascular bed is dilated by the long-lasting vasodilator CGRP, edema induced by IL-1 is clearly observed. These results highlight a potentially important synergistic interaction between cytokines and neuropeptides in inflammation.

Animals↗

PubMed1991

Time-dependent synergistic interactions between the vasodilator neuropeptide, calcitonin gene-related peptide (CGRP) and mediators of inflammation.

1. The action of the long lasting neuropeptide vasodilator, calcitonin gene-related peptide (CGRP), in potentiating oedema formation and neutrophil accumulation was investigated in the dorsal skin of the rabbit, in vivo. Combinations of agents under test were administered by intradermal (i.d.) injection. Oedema formation and neutrophil accumulation were then measured by quantitative radiolabel techniques. 2. CGRP (1 x 10(-11) mol per site) potentiated neutrophil accumulation induced by zymosan activated plasma, (used as a source of C5a des Arg), N-formyl-methionyl-leucyl-phenylalanine (FMLP) and leukotriene B4 (LTB4). In contrast CGRP did not induce neutrophil accumulation when injected alone. 3. Oedema formation induced by a series of chemically distinct mediators of increased microvascular permeability; bradykinin, platelet activating factor (PAF), FMLP and zymosan-activated plasma; measured 0-30 min after i.d. injection was potentiated by CGRP (1 x 10(-11) mol per site). 4. Oedema formation induced by zymosan activated plasma and FMLP but not bradykinin and PAF, was also significantly potentiated by CGRP when oedema was measured 30-60 min after i.d. injection. The potentiation of oedema induced by zymosan activated plasma measured 30-60 min after i.d. injection was not observed in the presence of the shorter acting prostanoid vasodilator prostacyclin (PGI2, 3 x 10(-10) mol per site). 5. These results suggest that CGRP, as a consequence of its sustained vasodilator activity could have prolonged potentiating effects on neutrophil accumulation and oedema formation in inflammatory conditions.

Animals↗

PubMed1991

A calcitonin gene-related peptide (CGRP) antagonist (CGRP8-37) inhibits microvascular responses induced by CGRP and capsaicin in skin.

1. The effect of the calcitonin gene-related peptide (CGRP) antagonist CGRP8-37 on responses to CGRP and other mediators was investigated in rabbit dorsal skin. 2. Blood flow changes at intradermally-injected sites were measured by a multiple site 133xenon clearance technique. CGRP8-37 had little effect on blood flow at doses up to 0.3 nmol/site, when injected alone, although a significant increase in blood flow was observed at the highest dose tested (1 nmol/site). 3. CGRP8-37 dose-dependently inhibited the increased blood flow induced by human alpha CGRP and human beta CGRP, but had no effect on equivalent vasodilator responses induced by vasoactive intestinal peptide (VIP) and prostaglandin E1 (PGE1). CGRP8-37 showed a preferential ability to inhibit alpha CGRP (IC50 0.04 nmol), when compared with beta CGRP (IC50 greater than or equal to 0.3 nmol). 4. Capsaicin, which selectively activates sensory nerves, caused a dose-dependent increase in blood flow when injected intradermally into rabbit skin. The effects of capsaicin (0.01-0.1 mumol/site) were inhibited by CGRP8-37 (0.3 nmol/site), with a partial but significant attenuation of blood flow induced by the highest dose of capsaicin. 5. Oedema formation, induced by intradermal histamine injection (3 nmol/site), was measured in rabbit skin by the local accumulation of intravenously-injected 125I-labelled albumin. Vasodilator doses of CGRP, PGE1 and capsaicin potentiated, in a synergistic manner, oedema formation induced by histamine. GRP8-37 totally inhibited the potentiating effect of CGRP, partially inhibited the synergistic effect of capsaicin, but did not affect PGE1-induced responses.6. The results suggest that capsaicin acts to release a rabbit form of CGRP in skin and that CGRP8 37 is a useful antagonist for investigating the potential of CGRP as a neurogenic mediator of inflammation.

Alprostadil↗

PubMed1991

Potent vasoactive properties of endothelin 1 in human skin.

The effect of the endothelial cell-derived peptide endothelin 1 was investigated in human skin. Intradermal injection of endothelin 1 (1-100 pmol) caused a dose-dependent area of pallor that was associated with a significant reduction in basal skin blood flow, measured by laser-Doppler blood flowmeter (with 1 pmol endothelin, P = 0.012, analysis of variance). The coadministration of endothelin 1 (1-100 pmol) with the neuropeptide vasodilator calcitonin gene-related peptide (CGRP) inhibited the vasodilator response to CGRP (10 pmol) by up to 82.7 +/- 9.2% (with 100 pmol endothelin, P less than 0.001). The response of the prostanoid vasodilator prostaglandin E2 (10 pmol) was inhibited by endothelin in a similar manner. In addition to the vasoconstrictor effects, endothelin 1 produced a dose-dependent flare that surrounded the area of pallor, and this was associated with a significant increase in blood flow (P less than 0.05) within the flare area. The H1 antagonist terfenadine (120 mg po) significantly reduced the flare area associated with endothelin 1: flare 5 min after intradermal endothelin (10 pmol, placebo treated), 668 +/- 405 mm2; terfenadine treated, 201 +/- 257 mm2 (P less than 0.05). The flare was also significantly attenuated when endothelin (10 pmol) was injected into local anesthetic-treated skin. Thus intradermal injection of endothelin in humans causes long-lasting vasoconstriction at the site of injection and a surrounding flare. Results suggest that the flare component is partially histamine dependent and the result of an axon reflex. This study demonstrates the potent activity of endothelin in human skin. It is possible that endothelin could be relevant to the local response of skin to injury.

Adult↗

PubMed1990

Evidence that endogenous nitric oxide modulates oedema formation induced by substance P.

The possibility that nitric oxide (NO) could have a role in the modulation of inflammatory oedema formation was investigated in rat skin using selective inhibitors of NO synthesis. Intradermally injected substance P (0.03-1 nmol) induced oedema which was inhibited by concurrent administration of the inhibitor of NO synthesis L-NG-nitro arginine methyl ester (L-NAME), but not by the enantiomer D-NAME. L-Arginine reversed the inhibitory effect of L-NAME. A second inhibitor of NO formation, L-NG-monomethyl arginine (L-NMMA), had a similar inhibitory effect on substance P-induced oedema. The results suggest that endogenous NO has a modulatory role in oedema formation induced by mediators of increased microvascular permeability.

Animals↗

PubMed1990

Structure-activity relationship of human calcitonin-gene-related peptide.

The calcitonin-calcitonin-gene-related peptide (CGRP) gene complex encodes a small family of peptides: calcitonin, CGRP and katacalcin. Calcitonin is a circulating hormone that prevents skeletal breakdown by inhibiting the resorption of bone by osteoclasts. CGRP, a potent vasodilator, is involved in normal regulation of blood flow. The calcitonins structurally resemble the CGRP peptides, and both are known to cross-react at each others' receptors. The present study was undertaken to examine the structural prerequisites for biological activity of the intact CGRP molecule. We therefore prepared eight chymotryptic and tryptic fragments of CGRP and synthesized its acetylated and S-carboxyamidomethylcysteinyl analogues. The analogues were purified by h.p.l.c. and their structures were confirmed by fast-atom bombardment mass spectrometry. We have examined the effects of structurally modified analogues and fragments of human CGRP in a calcitonin-receptor-mediated assay, the osteoclast bone resorption assay, and in one or two CGRP-receptor-mediated assays, the rabbit skin blood flow assay and the oedema formation assay. The results showed that (1) in the osteoclast bone resorption assay, both CGRP peptides, alpha and beta, were equipotent, and were both at least 1000-fold were both approx. 1000-fold more potent than salmon calcitonin; human calcitonin had no effect; (3) the bis- and N-acetylated CGRP analogues retained reduced levels of biological activity in all assays, whereas S-carboxyamidomethylcysteinyl-human CGRP was without activity; and (4) all tryptic and chymotryptic fragments of CGRP were without biological activity, with the exception of hCGRP-(Ala1-Lys35): this fragment had much reduced activity compared with the intact peptide in inhibiting osteoclastic bone resorption and increasing blood flow in the rabbit skin. The results suggest that: (1) calcitonin and CGRP act at distinct receptors to mediate different physiological effects; (2) minor amino acid substitutions, as between the alpha and beta forms of CGRP (these two forms have 94% structural similarity) do not result in differences in biological activity; (3) the intact peptide is required for full biological activity of the CGRP molecule, and even the loss of two amino acids at the C-terminus of the molecule results in a marked decrease in activity; (4) the disulphide bridge appears to play an important role in the interaction of the intact CGRP molecule with its receptor; and (5) the C-terminal region is probably necessary for the peptide to assume the right conformation in the interaction with the receptor.

Amino Acid Sequence↗

PubMed1990

Leukotrienes and inflammation.

The leukotrienes are synthesized from essential fatty acids via a 5-lipoxygenase enzyme. Most is known about the four-series leukotrienes derived from arachidonic acid. Leukotriene B4 is a potent chemotactic agent for leukocytes and it induces neutrophil-dependent increased microvascular permeability. Leukotrienes C4, D4 and E4 are bronchoconstrictors; and potent mediators of microvascular tone and permeability. The leukotrienes have been suggested to have a role in many inflammatory conditions in man in the skin (e.g. psoriasis), the lung (e.g. allergic asthma), joints (e.g. rheumatoid arthritis) and in the heart (e.g. myocardial infarction). Drugs which inhibit the generation and the actions of leukotrienes are under development and are being tested clinically as potential anti-inflammatory agents.

Animals↗

PubMed1990

Cutaneous blood flow responses in the forearms of Raynaud's patients induced by local cooling and intradermal injections of CGRP and histamine.

1. The cutaneous responses of the forearm to local cold exposure and intradermal injection of CGRP and other vasoactive mediators were compared in primary Raynaud's sufferers and normal volunteers. 2. Skin responses in the forearm were measured in terms of erythema reddening and skin blood flow. Visual responses were recorded by tracing and then area calculated by computerised planimetry. Skin blood flow was measured using a laser Doppler blood flow meter. 3. Cooling (5-6 degrees C for 2 min) of a 1 cm2 area of the forearm caused a localised reactive hyperaemia response in normal volunteers, measured using the last Doppler blood flow meter. The peak response in Raynaud's patients was significantly smaller than that of normal volunteers. 4. The cutaneous responses of Raynaud's patients and normal volunteers to intradermal injections of CGRP, histamine and PGE2 were not significantly different. 5. The results suggest that Raynaud's sufferers do not exhibit a diminished response to CGRP in the cutaneous microvasculature and can respond normally to histamine with an axon reflex mediated flare.

Adult↗

PubMed1990

Ruthenium red selectively inhibits oedema formation and increased blood flow induced by capsaicin in rabbit skin.

It has been suggested that ruthenium red has a selective inhibitory effect on capsaicin-induced nociceptor stimulation. We have investigated the effect of ruthenium red on oedema formation and vasodilatation induced by intradermal (i.d.) injection of capsaicin in the rabbit in vivo. Responses induced by capsaicin were inhibited by ruthenium red, but responses induced by bradykinin, N-formyl-methionyl-leucyl-phenylalanine (FMLP), platelet activating factor (PAF), histamine and calcitonin gene-related peptide (CGRP) were not affected. These results suggest that ruthenium red selectively inhibits capsaicin-induced local plasma protein leakage and vasodilatation in the rabbit skin microvasculature.

Animals↗

PubMed1990

Action of calcitonin gene-related peptide upon bovine vascular endothelial and smooth muscle cells grown in isolation and co-culture.

1. Bovine aortic endothelial cells (BAE) and smooth muscle cells (BASM) were grown separately and in co-culture. 2. Calcitonin gene-related peptide (CGRP) caused dose-dependent activation of adenylate cyclase in each cell type when grown in isolation. The concentration of CGRP causing half-maximal activation in BAE and BASM was 200 nM and 310 nM, respectively. 3. In cells grown in co-culture exposure to bradykinin produced dose-dependent elevations in cyclic GMP content which were maximal 1 min after application of the agonist. 4. CGRP (1 nM-1 microM) did not stimulate a rise in cyclic GMP in co-cultures. 5. Displaceable CGRP binding was identified throughout the wall of the bovine aorta. 6. We conclude that CGRP receptors coupled to adenylate cyclase are present on BAE and BASM, but there is no coupling of these receptors to the release of any agent (such as endothelium-derived relaxing factor) that activates guanylate cyclase.

Adenylyl Cyclases↗

PubMed1990

The demonstration of vasodilator activity of pancreatic amylin amide in the rabbit.

Amylin amide, a 37-amino acid peptide that is a major component of amyloid deposits in the diabetic pancreas, possesses vasodilator activity. Human synthetic amylin amide (30 to 300 pmol/site) stimulated a dose-dependent increase in blood flow after intradermal injection in rabbit skin. Amylin amide was 100 times less active than the structurally related potent vasodilator neuropeptide calcitonin gene-related peptide. Amylin amide did not induce edema formation; however, as a consequence of its vasodilator activity, amylin amide potentiated edema formation induced in rabbit skin by bradykinin. The intravenous injection of amylin amide (10 nmol) caused a systemic drop in blood pressure. This study demonstrates that amylin amide elicits vasodilator responses in vivo. It is possible that the release of amylin amide from the pancreas in type II diabetes could lead to changes in vascular tone.

Amyloid↗

PubMed1989

The direct observation of arteriolar constriction induced by endothelin in vivo.

The effect of endothelin on the microvasculature of the hamster cheek pouch was observed directly using intravital microscopy. Endothelin caused a dose-dependent arteriolar constriction without affecting adjacent venules. Endothelin was less potent than vasopressin, but responses to endothelin were longer lasting (48.9 +/- 11.1% reduction in arteriolar diameter was still observed 30 min after topical application of 3 pmol endothelin). The results demonstrate that endothelin induces a prolonged increase in local arteriolar tone after a single application in vivo.

Animals↗

PubMed1989

Interactions between the tachykinins and calcitonin gene-related peptide lead to the modulation of oedema formation and blood flow in rat skin.

1. The mechanisms involved in tachykinin-induced oedema were investigated in rat skin and interactions between the tachykinins and calcitonin gene-related peptide (CGRP) were studied. 2. Intradermal injections of the tachykinins, substance P, neurokinin A and neurokinin B, stimulated local oedema formation which was in each case potentiated by co-injection of the vasodilator CGRP. Oedema induced by substance P, in the presence and absence of CGRP, was significantly inhibited by pretreatment of rats with a combination of the histamine H1 antagonist, mepyramine, and the 5-hydroxytryptamine antagonist, methysergide. Oedema induced by neurokinin A or B was not inhibited by this pretreatment. 3. Intradermally-injected CGRP induced a long lasting increase in local blood flow, which was measured with a laser Doppler blood flow meter. The simultaneous injection of substance P, but not of the structurally-related neurokinins, caused a loss of the prolonged vasodilator activity of CGRP. 4. These results show that oedema induced by substance P is partially dependent on mast cell amines and that only substance P causes a loss of the prolonged vasodilator activity of CGRP. 5. We suggest that the ability of substance P to prevent the persistent vasodilator activity of CGRP may be a direct consequence of substance P-induced activation of mast cells.

Animals↗