Pharmacological characterization of CGRP1 receptor subtype in the vascular system of the rat: Studies with hCGRP fragments and analogs

Donoso, M. Verónica; Fournier, Alain; St‐Pierre, Serge; Huidobro‐Toro, J. Pablo

doi:10.1016/0196-9781(90)90003-n

Cited by 65 publications

(28 citation statements)

References 26 publications

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“…125 I-hCGRP with ET-1, VIP and ANP, etc. Two kinds of CGRP receptor subtypes have been distinguished in rat tissue, CGRPl and CGRP2 [8,9], and binding site heterogeneity has been demonstrated on the basis of differential antagonist and agonist potencies of the C-terminal hCGRP sequences and linear analogues. We therefore also investigated the effect of competitive inhibition of the C-terminal antagonist a-hCGRP and the linear analogue [acetamidomethyl-Cys 2,7 ]hCGRP ([Cys (ACM) 2,7 ]hCGRP).…”

Section: In Vitro Ligand Bindingmentioning

confidence: 99%

“…These receptors can be identified partly by ligand binding studies and localized quantitatively by using tissue sections for the binding. CGRP binding sites are of two types, termed CGRP1 and CGRP2 [8,9].We hypothesized that changes in the amount of CGRP released will be reflected by an adaptive response shown by changes in its binding sites and, thus, its physiological effects, and have directed our study to investigate the …”

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confidence: 99%

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Decreased endothelium-dependent pulmonary vasodilator effect of calcitonin gene-related peptide in hypoxic rats contrasts with increased binding sites

Mannan

Springall²,

Enard³

et al. 1995

Eur Respir J

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Pulmonary vascular tone is regulated by many vasoactive mediators produced either locally in endothelium, airway epithelium, vascular smooth muscle or nerves, or systemically via the blood. The main effect of alveolar hypoxia is pulmonary hypertension, which is modulated by many counteracting mediators. Amongst the possible candidates is calcitonin gene-related peptide (CGRP) [1], a potent vasodilator that is also present in the sensory innervation and endocrine cells of the rat respiratory tract [1][2][3], which is known to be involved in regulating pulmonary vascular tone [2,4].In previous studies, hypoxia has been shown to cause an increase in whole lung CGRP concentrations [5], particularly in the pulmonary endocrine cells [6,7], and decreased plasma levels of the peptide in rats [5]. Release We conclude that the vasodilator effects of CGRP are endothelium-dependent and, whilst they are reduced in hypoxic lung, this is not due to reduction in receptors, thereby implicating alterations in the nitric oxide guanylyl cyclase system. Furthermore, adaptive responses in some peptide binding sites occur in hypoxia, which may be due to changes in endogenous peptide levels.Eur Respir J., 1995Respir J., , 8, 2029Respir J., -2037 of endogenous CGRP may be of importance in maintaing pulmonary equilibrium, and impaired release may, thus, be relevant to the pulmonary hypertension that is a consequence of hypoxia.Peptides elicit their effect by interacting with specific receptors on the target cell, which in turn will activate various intracellular pathways that lead to a biological response. These receptors can be identified partly by ligand binding studies and localized quantitatively by using tissue sections for the binding. CGRP binding sites are of two types, termed CGRP1 and CGRP2 [8,9].We hypothesized that changes in the amount of CGRP released will be reflected by an adaptive response shown by changes in its binding sites and, thus, its physiological effects, and have directed our study to investigate the

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Section: In Vitro Ligand Bindingmentioning

confidence: 99%

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confidence: 99%

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Decreased endothelium-dependent pulmonary vasodilator effect of calcitonin gene-related peptide in hypoxic rats contrasts with increased binding sites

Mannan

Springall²,

Enard³

et al. 1995

Eur Respir J

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“…CGRP(i837) reversibly antagonizes CGRP-induced vasodilatation in tissues that include the rat mesenteric arterial bed (Han et al, 1990) and porcine coronary arteries (Franco-Cereceda, 1992). In in vivo studies, CGRP(8 37, has been shown to possess selective antagonistic activity in the rat (Donoso et al, 1990;Gardiner et al, 1990) and in rabbit skin (Hughes & Brain, 1991).…”

Section: Introductionmentioning

confidence: 99%

Nitric oxide‐dependent release of vasodilator quantities of calcitonin gene‐related peptide from capsaicin‐sensitive nerves in rabbit skin

Hughes

Brain

1994

British J Pharmacology

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1 Calcitonin gene-related peptide (CGRP) is a potent and long lasting vasodilator in the cutaneous microvasculature of many species including the rabbit. In this study we have investigated the role of nitric oxide in the release of endogenous CGRP, in response to capsaicin, in rabbit skin.2 Cutaneous blood flow was measured in response to intradermally-injected agents by a multiple site '33Xenon clearance technique. 3 The increased blood flow induced by capsaicin (100 nmol/site) and CGRP (3 pmol/site) was totally inhibited by the CGRP antagonist CGRP(837 (1 nmol/site), whilst the increased blood flow induced by sodium nitroprusside (0.3, 1 and 3 nmol/site) was unaffected by CGRP(g-3s,. 4 The nitric oxide synthase inhibitor NG-nitro-L-arginine methyl ester (L-NAME, 30 nmol/site) had no effect the vasodilator response induced by CGRP, but significantly inhibited capsaicin-induced blood flow. The inhibitory effect of L-NAME on capsaicin-induced blood flow was reversed by intradermal L-arginine (300 nmol/site), whilst the inactive enantiomer D-NAME (30 nmol/site) and the a-adrenoceptor agonist phenylephrine (10 pmol/site), at a dose which had a similar effect to L-NAME on basal blood flow, had no effect on capsaicin-induced blood flow. 5These results suggest that CGRP is the important vasodilator which is released from capsaicinsensitive sensory nerves in rabbit skin and that the release of CGRP, but not its mechanism of vasodilator action, is nitric oxide-dependent in the rabbit cutaneous microvasculature.

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“…which has been shown to be effective in inhibiting the hypotensive effects of i.v. CGRP in several studies (Donoso et al, 1990;Gardiner et al, 1990). We have examined the ability of CGRP8-37 to influence the sensory nerve-dependent proinflammatory responses in the rat in response to capsaicin administration and electrical stimulation of the saphenous nerve.…”

Section: Introductionmentioning

confidence: 99%

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

British J Pharmacology

102

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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.

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Pharmacological characterization of CGRP1 receptor subtype in the vascular system of the rat: Studies with hCGRP fragments and analogs

Cited by 65 publications

References 26 publications

Decreased endothelium-dependent pulmonary vasodilator effect of calcitonin gene-related peptide in hypoxic rats contrasts with increased binding sites

Decreased endothelium-dependent pulmonary vasodilator effect of calcitonin gene-related peptide in hypoxic rats contrasts with increased binding sites

Nitric oxide‐dependent release of vasodilator quantities of calcitonin gene‐related peptide from capsaicin‐sensitive nerves in rabbit skin

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

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Pharmacological characterization of CGRP1 receptor subtype in the vascular system of the rat: Studies with hCGRP fragments and analogs

Cited by 65 publications

References 26 publications

Decreased endothelium-dependent pulmonary vasodilator effect of calcitonin gene-related peptide in hypoxic rats contrasts with increased binding sites

Decreased endothelium-dependent pulmonary vasodilator effect of calcitonin gene-related peptide in hypoxic rats contrasts with increased binding sites

Nitric oxide‐dependent release of vasodilator quantities of calcitonin gene‐related peptide from capsaicin‐sensitive nerves in rabbit skin

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

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