5‐Carboxamidotryptamine is a selective agonist at 5‐hydroxytryptamine receptors mediating vasodilatation and tachycardia in anaesthetized cats

Connor, Helen E.; Feniuk, W.; Humphrey, P. P. A.; Perren, M.J.

doi:10.1111/j.1476-5381.1986.tb10832.x

Cited by 71 publications

(36 citation statements)

References 17 publications

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“…This 5-HT receptor, apparently not much dependent on extracellular calcium as indicated by the ineffectiveness of verapamil, may resemble the one that mediates either the positive inotropic effect of 5-HT in the kitten isolated papillary muscle (Kaumann, 1985;1986) or the slow depolarization of myenteric type II/AH neurones in the guinea-pig small intestine (Mawe et al, 1986). In the kitten isolated papillary muscle the responses to 5-HT, unlike that in the kitten isolated atria (Kaumann, 1985;1986) or the cat heart in vivo (Saxena et al, 1985a;Connor et al, 1986), are neither mimicked by 5-CT nor antagonized by methysergide or phenoxybenzamine. Similarly, the above 5-HT receptor in the gut is insensitive to ICS 205-930 or lysergide, but is antagonized by dipeptides of 5-hydroxytryptophan and excited by hydroxylated indalpines (Mawe et al, 1986).…”

Section: Consideration Of Non-s-ht Mechanismsmentioning

confidence: 99%

“…It is to be noted that while the antagonists for 5-HT2 and 5-HT3 are selective, the drugs antagonizing '5-HT1-like' receptors, being even more effective against the responses mediated via 5-HT2 receptors, are not. The above agonistantagonist criteria are clearly fulfilled with respect to 5-HT-induced tachycardia in the cat (5-CT in doses of 0.1 to 1pgkg-1 mimics, and methiothepin and methysergide, but not ketanserin and cyproheptadine, antagonize) (Saxena et al, 1985a;Connor et al, 1986), the rat (5-CT does not mimic and, ketanserin and cyproheptadine antagonize) (Saxena & Lawang, 1985) and the rabbit (2-methyl-5-HT mimics, and MDL 72222 and ICS 205-930 antagonize) (Fozard, 1984;Richardson et al, 1985). However, in the present investigation in the anaesthetized pig, it was noticed that the above drugs neither mimicked nor antagonized the tachycardiac responses to 5-HT.…”

Section: Consideration Of Known 5-ht Receptorsmentioning

confidence: 99%

“…The tachycardiac action of 5-HT has been analysed in some species and it involves several different mechanisms (Trendelenburg, 1960;Saxena, 1986). In the cat 5-HT-induced tachycardia is mediated by myocardial '5-HT1-like' receptors (Saxena et al, 1985a;Connor et al, 1986), and in the rat (Saxena & Lawang, 1985;Gothert et al, 1986) and the dog (Feniuk et al, 1981) 5-HT2 receptors, present on the myocardium and adrenal medulla, respectively, seem to be involved. The third 5-HT receptor type characterized so far (5-HT3 receptor), located on the postganglionic cardiac sympathetic fibres, mediates the effects of 5-HT in the rabbit (Fozard, 1984) while, in the guinea-pig, tachycardia has been attributed to P-adrenoceptors (Eglen et al, 1985), probably activated by catecholamines released via a tyramine-like action (De Boer et al, 1986;Dhasmana et al, 1988).…”

Section: Introductionmentioning

confidence: 99%

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5‐Hydroxytryptamine‐induced tachycardia in the pig: possible involvement of a new type of 5‐hydroxytryptamine receptor

Bom

Duncker

Saxena

et al. 1988

British J Pharmacology

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1 The mechanism of 5-hydroxytryptamine (5-HT)-induced tachycardia is species-dependent and is mediated directly or indirectly either by '5-HT1-like' (cat), 5-HT2 (rat, dog) or 5-HT3 (rabbit) receptors, or by an action similar to tyramine (guinea-pig). The present investigation is devoted to the analysis of the positive chronotropic effect of 5-HT in the pentobarbitone-anaesthetized pig.2 Intravenous bolus injections of 5-HT (3, 10 and 30pgkg-1) in pigs resulted in dose-dependent increases in heart rate of 24 + 2, 38 + 3 and 51 + 3beatsmin-1, respectively (n = 39). Topical application of a high concentration of 5-HT (150pgkg-' in 5ml) on the right atrium was also followed by tachycardia (38 + 6 beats min-1, n = 4). The 5-HT-induced tachycardia was also not affected by antagonists at a-and f-adrenoceptors, muscarinic, nicotinic, histamine and dopamine receptors, and calcium channels. 5 Selective inhibitors of 5-HT-uptake, indalpine and fluvoxamine, themselves increased porcine heart rate and facilitated 5-HT-induced tachycardia both in magnitude and in duration. 6 A number of putative selective agonists at '5-HT1-like' receptors or their possible subtypes (5-carboxamidotryptamine (5-CT), 8-hydroxy-24di-N,N-n-propylamino) tetralin (8-OH-DPAT), BEA 1654 and RU 24969), or at 5-HT3 receptors (2-methyl-5-HT), elicited no or only a weak tachycardiac response in the pig. RU 24969, but not 8-OH-DPAT, seemed to potentiate the responses to 5-HT, whereas 5-CT slightly inhibited these responses. 7 It was concluded that the tachycardia induced by 5-HT in the pig does not involve the receptors for some common neurotransmitter substances but may be mediated by a new 5-HT receptor type that is clearly different from '5-HT1-like', 5-HT2 or 5-HT3 receptors.

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Section: Consideration Of Non-s-ht Mechanismsmentioning

confidence: 99%

Section: Consideration Of Known 5-ht Receptorsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

5‐Hydroxytryptamine‐induced tachycardia in the pig: possible involvement of a new type of 5‐hydroxytryptamine receptor

Bom

Duncker

Saxena

et al. 1988

British J Pharmacology

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“…In the carotid vasculature, systemic bolus injections of sumatriptan produced well-sustained vasoconstrictor responses, reflecting its constrictor action at the extensive arteriovenous anastomoses which characterize this vascular bed (see also Humphrey et al, 1988;Feniuk et al, 1989). In this vascular bed 5-carboxamidotryptamine produced long-lasting vasodilator responses (see also Saxena & Verdouw, 1985;Connor et al, 1986), although this agonist is also know to constrict arteriovenous anastomoses (Saxena & Verdouw, 1985).…”

Section: Introductionmentioning

confidence: 99%

“…The vasoconstrictor 5-HTI-like receptors are selectively stimulated by the 5-HT,-like agonist, sumatriptan (Humphrey et al, 1988;Feniuk et al, 1989;Cambridge et al, 1995), whilst the tryptamine analogue, 5-carboxamidotryptamine, is a potent agonist at the vasodilator 5-HT,-like receptors (Saxena & Verdouw, 1985;Connor et al, 1986;Leff et al, 1987;Martin et al, 1987;Cambridge et al, 1995).…”

Section: Introductionmentioning

confidence: 99%

Canine renovascular responses to sumatriptan and 5‐carboxamidotryptamine: modulation through endothelial 5‐HT₁‐like receptors by endogenous nitric oxide

Whiting

Cambridge

1995

British J Pharmacology

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1 In anaesthetized dogs, intra-left atrial (i.l.a.) administration of the 5-HTI-like receptor agonists, sumatriptan (1-10 gkg-') and 5-carboxamidotryptamine (0.03-0.3plgkg-') produced dose-related reductions in renal blood flow and vascular conductance, which were characterized by their rapid onset and recovery. 2 In these animals, i.v. administration of the inhibitor of nitric oxide (NO) synthase, N0-nitro-Larginine methyl ester (L-NAME; 10 mg kg-') significantly augmented the renal vasoconstrictor responses to i.l.a. sumatriptan and 5-carboxamidotryptamine. 3 The effects of L-NAME upon these responses to sumatriptan and 5-carboxamidotryptamine were significantly reversed by subsequent i.v. administration of L-arginine (1000mgkg-'). 4 L-NAME-significantly attenuated the systemic hypotensive responses to i.v. acetylcholine (0.3-3 ,tg kg-') and this effect was also reversed by L-arginine. 5 L-NAME had no effect upon the renal vasoconstrictor response to i.l.a. administration of angiotensin II, nor did it affect the renal vascular conductance recovery response to brief mechanical occlusion of the renal artery. 6 These data suggest that sumatriptan and 5-carboxamidotryptamine stimulate the release of NO through the activation of a 5-HTI-like receptor located on the endothelial cells.7 It is concluded that in canine renal vasculature, 5-HT,-like agonists (and presumably endogenous 5-hydroxytryptamine) can cause simultaneous activation of a 5-HT,-like receptor on both vascular smooth muscle and endothelial cells. The net renal vascular response to these agonists is therefore a function of both the vascular smooth muscle vasoconstriction and the concurrent vasodilator influence of NO released from the endothelium.

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Further characterization of 5‐hydroxytryptamine₁‐like receptors mediating tachycardia in the cat: No apparent relationship to known subtypes of the 5‐hydroxytryptamine₁ binding site

Saxena

1988

Drug Development Research

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Saxena, P.R.:Further characterization of 5-hydroxytryptamine,-like receptors mediating tachycardia in the cat: No apparent relationship to known subtypes of the 5-hydroxytryptamine, binding site. Drug Dev. Res. 13:245-258, 1988 5-Hydroxytryptamine (5-HT) increases heart rate in the spinal-transected cat by acting on 5-HTl-like receptors, since this effect is not modified by ketanserin or MDL 72222 but is blocked by methysergide [Saxena et al., 19851. These 5-HTl-like receptors in the cat heart have been further characterized in this investigation using compounds that have high affinities for 5-HT1 binding site subtypes. Like 5-HT, the putative 5-HT1-like receptor agonists 5-carboxamidotryptamine (5-CT; nanomolar affinities for 5-HTlA, 5-HT1 B, and 5-HT1 subtypes) and N-(3-acetylaminophenyl) piperazine (BEA 1654; preferential and nanomolar affinity for 5-HTIA site) elicited dose-dependent tachycardia. The doses needed to increase heart rate by 50 beats.min-' were calculated to be 84 6, 4 & 1 and 21,720 5,200 nmol. kg-I for 5-HT, 5-CT, and BEA 1654, respectively. 8-Hydroxy-2-(di-N,N-npropy1amino)tetralin (8-OH DPAT; selective nanomolar affinity for 5-HTIA site) and 5-methoxy9-(1,2,3,6-tetrahydro-4-pyridinyl)-l H-indole (RU 24969; preferential nanomolar affinity for 5-HT1 site) had little activity. Among antagonists that have nanomolar affinities for all four (5-HTlA, S-HTIB, S-HTlc, and 5-HTID) 5-HT1 binding site subtypes, methiothepin, followed by methysergide, showed potent activity against tachycardia induced by 5-HT, 5-CT, and/or BEA 1654; metergoline was poorly effective. Mesulergine, which has 246Saxena highest affinity for 5-HT1c binding subtype, also showed antagonist activity, but this effect was less than that of methiothepin or methysergide. It was concluded that the functional 5-HT1-like receptors mediating cardioacceleration in the cat do not seem to be related to any of the 5-HT1 binding site subtypes identified so far.

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5‐Carboxamidotryptamine is a selective agonist at 5‐hydroxytryptamine receptors mediating vasodilatation and tachycardia in anaesthetized cats

Abstract: IWe have attempted to characterize the 5-hydroxytryptamine (5-HT) receptors mediating bronchoconstriction, vasodilatation, vasodepression and tachycardia in anaesthetized cats following bilateral vagosympathectomy and P-adrenoceptor blockade with propranolol.

Cited by 71 publications

References 17 publications

5‐Hydroxytryptamine‐induced tachycardia in the pig: possible involvement of a new type of 5‐hydroxytryptamine receptor

5‐Hydroxytryptamine‐induced tachycardia in the pig: possible involvement of a new type of 5‐hydroxytryptamine receptor

Canine renovascular responses to sumatriptan and 5‐carboxamidotryptamine: modulation through endothelial 5‐HT₁‐like receptors by endogenous nitric oxide

Further characterization of 5‐hydroxytryptamine₁‐like receptors mediating tachycardia in the cat: No apparent relationship to known subtypes of the 5‐hydroxytryptamine₁ binding site

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5‐Carboxamidotryptamine is a selective agonist at 5‐hydroxytryptamine receptors mediating vasodilatation and tachycardia in anaesthetized cats

Abstract: IWe have attempted to characterize the 5-hydroxytryptamine (5-HT) receptors mediating bronchoconstriction, vasodilatation, vasodepression and tachycardia in anaesthetized cats following bilateral vagosympathectomy and P-adrenoceptor blockade with propranolol.

Cited by 71 publications

References 17 publications

5‐Hydroxytryptamine‐induced tachycardia in the pig: possible involvement of a new type of 5‐hydroxytryptamine receptor

5‐Hydroxytryptamine‐induced tachycardia in the pig: possible involvement of a new type of 5‐hydroxytryptamine receptor

Canine renovascular responses to sumatriptan and 5‐carboxamidotryptamine: modulation through endothelial 5‐HT1‐like receptors by endogenous nitric oxide

Further characterization of 5‐hydroxytryptamine1‐like receptors mediating tachycardia in the cat: No apparent relationship to known subtypes of the 5‐hydroxytryptamine1 binding site

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Canine renovascular responses to sumatriptan and 5‐carboxamidotryptamine: modulation through endothelial 5‐HT₁‐like receptors by endogenous nitric oxide

Further characterization of 5‐hydroxytryptamine₁‐like receptors mediating tachycardia in the cat: No apparent relationship to known subtypes of the 5‐hydroxytryptamine₁ binding site