NK‐1 receptor mediation of neurogenic plasma extravasation in rat skin

102

1 The effect of the calcitonin gene-related peptide antagonist (CGRP837, 400 nmol kg-', 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-', i.v.) on the increased blood flow (measured by laser Doppler flowmetry) and oedema formation (measured by the extravascular accumulation of ['25f]-albumin) was investigated in the rat hind paw.3 CGRP8-37 (400 nmol kg-', 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. CGRP837 (400 nmol kg-', 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. CGRP837 (400 nmol kg-', 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. The oedema formation was significantly inhibited by CGRP8-37 (400 nmol kg-', i.v., P<0.05). 7 The results suggest that the potent microvascular vasodilator neuropeptide, CGRP, is responsible for the increased blood flow observed after short stimulation of the saphenous nerve and that endogenous CGRP contributes in a pro-inflammatory manner to neurogenic oedema formation in the rat hind paw.

Section: Discussionsupporting

confidence: 80%

Effect of a calcitonin gene‐related peptide antagonist (CGRP_8–37) on skin vasodilatation and oedema induced by stimulation of the rat saphenous nerve

Escott

Brain

1993

102

“…An N-terminal analogue of SP as verified in human skin (Foreman et al, 1983) failed to induce plasma extravasation. The common C-terminal of the tachykinins suggest that they should all induce plasma extravasation as was found to be the case in studies on rat skin (Brain & Williams, 1989;Andrews et al, 1989). The present studies on the rat knee have shown that this is not always the case, as among the neuropeptides tested, only SP and to a lesser extent NKB, were effective in producing plasma extravasation in the rat knee but not NKA or CGRP.…”

Section: Discussionmentioning

confidence: 56%

Specific neurokinin receptors mediate plasma extravasation in the rat knee joint

Lam

Ferrell

1991

1 Plasma extravasation in the rat knee joint was induced by intra-articular injection of neurokinins and specific neurokinin receptor agonists.2 Pronounced plasma extravasation was produced by substance P (SP, 4-185,gM) 4 Injections of SP or NKA into the synovial cavity of the rat knee were equally effective in producing marked plasma extravasation in remote sites such as the forelimb and hindlimb paws. 5 Co-administration experiments showed that the effects of SP were synergistic with NKA or the NK1 receptor agonist, but not with CGRP or the NK2 receptor agonist. 6 The rank order of potency was NK1 agonist > SP > NKB > NK2 agonist suggesting that NK1 receptors mediate plasma extravasation in the rat knee joint.

“…Our results with morphine, which reduced or abolished the effects of bradykinin on microvascular permeability but did not modify those of histamine, clearly support this hypothesis. Substance P and neurokinins A and B released by the NANC system have proved to be potent stimulants of microvascular leakage Andrews et al, 1989).…”

Section: Discussionmentioning

confidence: 99%

Formoterol and salbutamol inhibit bradykinin‐ and histamine‐induced airway microvascular leakage in guinea‐pig

Advenier¹,

Qian²,

Koune³

et al. 1992

1 The effects of the #2-adrenoceptor agonists, salbutamol and formoterol, on the increase of microvascular permeability induced by histamine or bradykinin in guinea-pig airways have been studied in vivo. Extravasation of intravenously injected Evans blue dye was used as an index of permeability. The effects of salbutamol and formoterol on the increase in pulmonary airway resistance induced by histamine or bradykinin have also been studied. 2 The increase in pulmonary airway resistance induced by histamine or bradykinin was totally inhibited by salbutamol and formoterol. The ED50 of the two mediators were 0.59 + 0.21 (n = 5) and 0.20 + 0.14 (n = 5) pg kg'-respectively for salbutamol, and 0.13 + 0.12 (n = 6) and 0.02 + 0.01 (n = 6) pg kgrespectively for formoterol.3 Salbutamol (10 and 30pgkg-1) and formoterol (1 and lOpgkg-1) inhibited the increase of microvascular permeability induced by histamine (30pgkg-') in the guinea-pig airways. The inhibitory effect was predominant in the trachea and the main bronchi, with a maximum inhibition of 20 to 50%. The two drugs had little or no inhibitory effect on the other structures studied, viz. nasal mucosa, larynx, proximal and distal intrapulmonary airways.4 Salbutamol and formoterol (1 and 10pgkg-1) abolished the increase in microvascular permeability induced by bradykinin (0.3 Mg kg'-). This inhibitory effect of two f-adrenoceptor stimulants was predominant in the trachea and the nasal mucosa where it was observed with 1 pg kg-1 of the f-adrenoceptor agonists. In the main bronchi, and in the proximal and distal intrapulmonary airways, the effects of bradykinin were abolished by 10 pg kg -of formoterol and salbutamol. 5 The effects of bradykinin, but not those of histamine, were significantly reduced (nasal mucosa, main bronchi and distal intrapulmonary airways) or abolished (trachea, proximal intrapulmonary airways) by morphine 10mgkg-1, i.v. These results suggest that an indirect effect, through non-adrenergic noncholinergic (NANC) nerves is involved in the action of bradykinin on the microvascular permeability. 6 In conclusion, intravenously injected f-adrenoceptor stimulants can inhibit, partially or totally, the increase of airways microvascular permeability induced by intravenous histamine or bradykinin. However, these effects require doses that are higher than those that inhibit the increase in pulmonary airway resistance induced by these mediators. As suggested by the results obtained with morphine, the higher efficacy of fi2-adrenoceptor agonists versus bradykinin may occur through activation of presynaptic receptors of the non-adrenergic non-cholinergic (NANC) nerves preventing release of inflammatory neuropeptides such as substance P and neurokinin A.