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

Abstract

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.

Interactions of GR127935, a 5-HT1B/D receptor ligand, with functional 5-HT receptors

“…and MDL 72222 (500 µg×kg -1 , i.v.) blocked, respectively, the second and the first phase responses produced by 30 µg×kg -1 of 5-HT in the heart (Saxena andVillalón 1990, 1991). Our finding that only the vasopressor response to 5-HT elicited in intact as well as vagosympathectomized rats was significantly antagonized by 500 and 1500 µg×kg -1 of GR127935 suggests that the drug produces a moderate blockade of vascular 5-HT 2A receptors.…”

“…administration of 5-HT produced a triphasic response on the arterial blood pressure of rats with intact vagus; this response consists of an initial hypotension associated with a brief, but intense, bradycardia via the von Bezold-Jarisch reflex (mediated by 5-HT 3 receptors), followed by a vasopressor effect (mediated by 5-HT 2A receptors) and, finally, a longer-lasting hypotension (mediated by 5-HT 1 -like, probably 'orphan' and/or 5-ht 7 receptors) (Saxena andVillalón 1990, 1991;unpublished observations). After bilateral resection of vagosympathetic trunks, the initial hypotension due to reflex bradycardia was abolished, consistent with the concept that the von Bezold-Jarisch reflex is elicited by stimulation of 5-HT 3 receptors located on sensory vagal nerve endings 428 Fig.…”

“…For example, it is nowadays clear that the cardiovascular effects of 5-HT are mediated by several different receptor types, including 5-HT 1 -like, 5-HT 2 , 5-HT 3 and 5-HT 4 receptors (Saxena andVillalón 1990, 1991). Notwithstanding, the exact identity of 5-HT 1 -like receptor mediating vascular contraction is in debate, although several lines of pharmacological evidence (see Hoyer et al 1994) suggest a close resemblance with the 5-HT 1B/D (formerly designated as 5-HT 1Dß and 5-HT 1Dα , respectively; see Hartig et al 1996) receptor subtypes.…”

“…This notion has been hampered because of the lack of compounds acting selectively at 5-HT 1B/D receptor subtypes, but the advent of GR127935, a piperazinylbenzanilide derivative with high affinity for and selective antagonist activity at 5-HT 1B/D receptors (Clitherow et al 1994), will hopefully overcome this obstacle. Indeed, some studies already show that GR127935 potently antagonizes: (i) contralateral turning in guinea-pigs induced by the 5-HT 1B/D receptor agonist GR56764 (3-(2-methylaminoethyl)-1H-indole-5-yl-1H-[1, 2, 4]triazol-3-yl)-methyanol; Skingle et al 1996); (ii) sumatriptan-evoked inhibition of 5-HT release in the guinea-pig dorsal raphe nucleus (Clitherow et al 1994;Starkey and Skingle 1994); and (iii) sumatriptan-induced contraction of porcine carotid arteriovenous anastomoses (De Vries et al 1996), canine external carotid vessels , rabbit isolated saphenous vein (Valentin et al 1996) and canine basilar artery (Skingle et al 1996); several of these responses have been previously described as being mediated by 5-HT 1 -like receptors (see Saxena andVillalón 1990, 1991).…”

“…For this purpose, the effect of GR127935 has been studied on several functional responses mediated by different 5-HT receptors: (i) sumatriptan-induced decrease in carotid blood flow in the rabbit (5-HT 1 -like); (ii) 5-HT-induced hypotension in the rat and tachycardia in the cat ('orphan' 5-HT 1 -like); (iii) 5-HT and/or DOI-induced pressor responses in the rat and cat as well as the secondary phase of urinary bladder contraction in the cat (5-HT 2A ); (iv) 5-HT-induced bradycardia (von BezoldJarisch reflex) in the rat and the early phase of urinary bladder contraction in the cat (5-HT 3 ); and (v) 5-HT-induced tachycardia in pigs (5-HT 4 ) (for references, see Saxena andVillalón 1990, 1991;Hoyer et al 1994;Choppin and O'Connor 1996).…”