1. It has been suggested that the tachycardic response to
5-hydroxytryptamine (5-HT) in the spinal-transected cat is mediated by '5-HT1-like' receptors since this effect, being mimicked by
5-carboxamidotryptamine (5-CT), is not modified by
ketanserin or
MDL 72222, but it is blocked by
methiothepin,
methysergide or
mesulergine. The present study was set out to reanalyse this suggestion in terms of the IUPHAR
5-HT receptor classification schemes proposed in 1994 and 1996. 2. Intravenous (i.v.) bolus
injections of the
tryptamine derivatives, 5-CT (0.01, 0.03, 0.1, 0.3, 1, 3, 10 and 30 microg kg(-1)),
5-HT (3, 10 and 30 microg kg(-1)) and
5-methoxytryptamine (3, 10 and 30 microg kg(-1)) as well as the atypical
antipsychotic drug,
clozapine (1000 and 3000 microg kg(-1)) resulted in dose-dependent increases in heart rate, with a rank order of agonist potency of 5-CT >>
5-HT >
5-methoxytryptamine >>
clozapine. 3. The tachycardic effects of
5-HT and
5-methoxytryptamine were dose-dependently antagonized by i.v. administration of
lisuride (30 and 100 microg kg(-1)),
ergotamine (100 and 300 microg kg(-1)) or
mesulergine (100, 300 and 1000 microg kg(-1)); the highest doses of these antagonists used also blocked the tachycardic effects of 5-CT.
Clozapine (1000 and 3000 microg kg(-1)) did not affect the 5-HT-induced
tachycardia, but attenuated, with its highest dose, the responses to
5-methoxytryptamine and 5-CT. However, these doses of
clozapine as well as the high doses of
ergotamine (300 microg kg(-1)) and
mesulergine (300 and 1000 microg kg(-1)) also attenuated the tachycardic effects of
isoprenaline. In contrast, 5-HT-, 5-methoxytryptamine- and 5-CT-induced
tachycardia were not significantly modified after i.v. administration of physiological saline (0.1 and 0.3 ml kg(-1)), the 5-HT(1B/1D) receptor antagonist, GR127935 (500 microg kg(-1)) or the 5-HT(3/4) receptor antagonist,
tropisetron (3000 microg kg(-1)). 4.
Intravenous injections of the
5-HT1 receptor agonists,
sumatriptan (30, 100 and 300 microg kg(-1)) and
indorenate (300 and 1000 microg kg(-1)) or the
5-HT4 receptor (partial) agonist
cisapride (300 and 1000 microg kg(-1)) were devoid of effects on feline heart rate per se and failed to modify significantly 5-HT-induced tachycardic responses. 5. Based upon the above rank order of agonist potency, the failure of
sumatriptan,
indorenate or
cisapride to produce cardioacceleration and the blockade by a series of drugs showing high affinity for the cloned
5-ht7 receptor, the present results indicate that the
5-HT receptor mediating
tachycardia in the cat is operationally similar to other putative 5-HT7 receptors mediating vascular and non-vascular responses (e.g. relaxation of the rabbit femoral vein, canine external carotid and coronary arteries, rat systemic vasculature and guinea-pig ileum). Since these responses represent functional correlates of the 5-ht7 gene product, the
5-HT7 receptor appellation is reinforced. Therefore, the present experimental model, which is not complicated by the presence of other
5-HT receptors, can be utilized to characterize and develop new drugs with potential agonist and antagonist properties at functional 5-HT7 receptors.