Effects of 5-HT3 receptor-selective agents on locomotor activity in rats following injection into the nucleus accumbens and the ventral tegmental area.

5-Hydroxytryptamine (5-HT) is involved in the modulation of dopaminergic activity in the mesolimbic system, but its sites of action and the receptors involved are not well understood. Locomotor activity responses in rats were monitored in Animex automated activity boxes following injection of 5-HT3 receptor-selective agents directly into two mesolimbic nuclei, the nucleus accumbens and the ventral tegmental area, via stereotactically implanted injection guide cannulae. Neither spontaneous nor dexamphetamine-stimulated locomotor activity was changed by bilateral intra-nucleus accumbens injection of the selective agonist 2-methyl-5-HT or the selective antagonists ondansetron or granisetron. In contrast, intra-ventral tegmental area injection of 2-methyl-5-HT produced significant long-lasting (approximately 240 min) increases in locomotor activity; intra-ventral tegmental area injection of ondansetron elicited an initial inhibition of spontaneous and dexamphetamine-stimulated locomotor activity (for the 0-30 min period), but granisetron had no effect. The hyperlocomotor response to intra-ventral tegmental area 2-methyl-5-HT was abolished by pretreatment with the catecholamine synthesis inhibitor alpha-methyl-p-tyrosine, or by pretreatment with ondansetron. Methiothepin pretreatment had no effect on the hyperlocomotor response to 2-methyl-5-HT, although methiothepin itself produced an initial increase in spontaneous locomotor activity (for the 60-120 min period). Intra-ventral tegmental area injection of 5-carboxamidotryptamine, alpha-methyl-5-HT or renzapride produced no changes in spontaneous locomotor activity. In some of the ventral tegmental area experiments, other behaviours were also monitored. 2-Methyl-5-HT produced forward locomotion, rearing, and increased wakefulness, but did not appreciably alter circling, grooming or sniffing. Ondansetron alone had no effect on any of these behaviours, but it opposed the 2-methyl-5-HT-induced changes. Methiothepin alone increased forward locomotion and wakefulness but did not alter the other behaviours; it had no effect on the responses to 2-methyl-5-HT. These observations show that 5-HT3 receptors may mediate increased locomotor activity by modulating firing of mesolimbic dopaminergic cell bodies in the ventral tegmental area rather than terminals in the nucleus accumbens.

Ventral tegmental area 5-HT receptors: mesolimbic dopamine release and behavioural studies.

Serotoninergic neurones originating in the dorsal and median raphe nuclei project to mesolimbic structures, including the nucleus accumbens (NAcb) and the ventral tegmental area (VTA), where they may have an important regulatory role. Some evidence from dopamine release, behavioural and binding studies directly implicates involvement of 5-HT3 and 5-HT4 receptors in the NAcb. Other in vivo dopamine release and behavioural experiments in rats have provided evidence for 5-HT3 receptor-mediated enhancement of mesolimbic dopaminergic activity, although the location of the 5-HT3 receptors involved is unknown because the selective 5-HT3 receptor agents used were administered systemically or intracerebroventricularly. This raises the possibility of a VTA site of action; as yet, however, relatively little is specifically known about 5-HT receptors and function in the VTA. Mesolimbic dopamine release in rats, measured in-vivo with microdialysis probes in the NAcb, can be inhibited by tropisetron administered directly into the VTA. In our laboratory, behavioural studies in rats have shown that a sustained hyperlocomotion is produced by 2-methyl-5-HT administered into the VTA via stereotactically implanted guide cannulae. Mesolimbic dopaminergic activation is involved, because pretreatment with the catecholamine synthesis inhibitor alpha-methyl-p-tyrosine abolishes 2-methyl-5-HT-induced hyperlocomotion. The 2-methyl-5-HT hyperlocomotor response is blocked by prior intra-VTA injection of ondansetron but is not affected by methiothepin, and intra-VTA 5-carboxamidotryptamine, alpha-methyl-5-HT or renzapride were without effect, thus a 5-HT3 receptor in the VTA mediates the 2-methyl-5-HT response. These in vivo dopamine release and behavioural studies therefore confirm that 5-HT3 receptors in the VTA can mediate increased locomotor activity, by modulating the firing of mesolimbic dopaminergic cell bodies.

Beneficial haemodynamic effect of indomethacin during endotoxin shock in anaesthetized pigsputative involvement of nitric oxide?

Endotoxin shock was induced in 31 anaesthetized pigs by infusion of 5 mug/kg of Escbeicbia coli endotoxin (LPS) over 60 min into the superior mesenteric artery. Fifteen of these pigs died within 30 min of the start of LPS infusion whereas the remaining 16 survived the experimental period of 2 h. In a group of nine pigs indomethacin (2 mg/kg, i.v.)was inected 20-25 rain after the start of LPS infusion at which time mean arterial blood pressure (MABP) had decreased below 40 mmHg indicating imminent death. Indomethacin immediately reversed the hypotension. In another group of five pigs, N(G)-nitro L-arginine-methyl ester (L-NAME, 1 and 3 mg/kg)was iniected 10 and 5 min, respectively, before the expected death without any beneficial effect on the hypotension. Three rain after the last dose of L-NAME, indomethacin (2 mg/kg, i.v.) was iniected. In three animals the hypotension was reserved by indomethacin, although this beneficial effect was delayed in comparison with the LP-Streated group not receiving L-NAME. Four pigs were pretreated with L-NAME, 3 mg/kg, i.v., 10 min prior to LPS infusion. All pretreated animals tended to die within 30 min of the start of the LPS infusion. Five rain before the expected death (20-25 rain after the start of LPS infusion) indomethacin (2 mg/kg) was inected. In three of these animals indomethacin reversed hypotenston and prevented death. Interestingly, this rise in the MABP developed very slowly. These results suggest that the beneficial effect of indomethacin in endotoxin shock might be related partially to interference with nitric oxide, which is not the only factor determining blood pressure levels during endotoxic shock.

International Union of Pharmacology classification of receptors for 5-hydroxytryptamine (Serotonin).

It is evident that in the last decade or so, a vast amount of new information has become available concerning the various 5-HT receptor types and their characteristics. This derives from two main research approaches, operational pharmacology, using selective ligands (both agonists and antagonists), and, more recently, molecular biology. Although the scientific community continues to deliberate about the hierarchy of criteria for neurotransmitter receptor characterisation, there seems good agreement between the two approaches regarding 5-HT receptor classification. In addition, the information regarding transduction mechanisms and second messengers is also entirely consistent. Thus, on the basis of these essential criteria for receptor characterisation and classification, there are at least three main groups or classes of 5-HT receptor: 5-HT1, 5-HT2, and 5-HT3. Each group is not only operationally but also structurally distinct, with each receptor group having its own distinct transducing system. The more recently identified 5-HT4 receptor almost undoubtedly represents a fourth 5-HT receptor class on the basis of operational and transductional data, but this will only be definitively shown when the cDNA for the receptor has been cloned and the amino acid sequence of the protein is known. Although those 5-HT receptors that have been fully characterised and classified to date (and, hence, named with confidence) would seem to mediate the majority of the actions of 5-HT throughout the mammalian body, not all receptors for 5-HT are fully encompassed within our scheme of classification. These apparent anomalies must be recognised and need further study. They may or may not represent new groups of 5-HT receptor or subtypes of already known groups of 5-HT receptor. Even though the cDNAs for the 5-ht1E, 5-ht1F, 5-ht5, 5-ht6, and 5-ht7 receptors have been cloned and their amino acid sequence defined, more data are necessary concerning their operational and transductional characteristics before one can be confident of the suitability of their appellations. Therefore, it is important to rationalise in concert all of the available data from studies involving both operational approaches of the classical pharmacological type and those from molecular and cellular biology.(ABSTRACT TRUNCATED AT 400 WORDS)

An endogenous antitoxin to the lethal venom of the funnel web spider, Atrax robustus, in rabbit sera.

1. An endogenous antitoxin fraction was isolated from non-immune rabbit sera by affinity chromatography with robustoxin bound to the solid support. 2. Robustoxin is the sole lethal toxin in the venom of the male funnel web spider, Atrax robustus. 3. The fraction was found to contain IgG and IgM immunoglobulins. 4. This fraction prevented or reversed the lethal actions of the crude venom in newborn mice, in mouse phrenic nerve-hemidiaphragm preparations, and in anaesthetized monkeys. 5. The antitoxin fraction is of potential value in the therapy of human envenomation by A. robustus.

Protection of monkeys against the lethal effects of male funnel-web spider (Atrax robustus) venom by immunization with a toxoid.

A stable toxoid was prepared from robustoxin (the lethal polypeptide neurotoxin in the venom of the male funnel-web spider, Atrax robustus) by polymerization with glutaraldehyde. This material was non-toxic in new-born mice. Administration of the toxoid to three Macaca fascicularis monkeys (50-80 micrograms/kg s.c. at 14-day intervals for 8-12 weeks) produced no toxic effects; anti-robustoxin antibodies were detected in serum samples by immunodiffusion tests within 13-27 days. In vivo evidence of successful protection with the toxoid was obtained by challenging the monkeys with male A. robustus venom (50 micrograms/kg i.v.) under anaesthesia with pentobarbitone (one monkey), or with ketamine, halothane and nitrous oxide, 1-26 weeks after the last injection of the toxoid. Only minor respiratory, cardiovascular and skeletal motor disturbances were produced, and all monkeys recovered fully and uneventfully. Challenge with the same dose of venom in non-immunized or robustoxin N-terminal decapeptide ovalbumin conjugate-treated monkeys resulted in typical lethal neurotoxic effects, culminating in severe hypotension or death from circulatory and respiratory failure within 280 min.

5-HT2 receptor antagonists and migraine therapy.

5-Hydroxytryptamine (5-HT; serotonin) has been implicated in the pathophysiology of migraine, and several drugs with potent 5-HT2 receptor blocking activity (methysergide, pizotifen, cyproheptadine and mianserin) have been recognized as being clinically effective in migraine prophylaxis, although the selective 5-HT2 receptor antagonist ketanserin (the principal agent used to identify 5-HT2 receptor-mediated actions) seems to be ineffective in migraine. Pizotifen is the most widely used 5-HT2 receptor antagonist in migraine prophylaxis, because of its superior efficacy compared with cyproheptadine, and because the incidence and severity of adverse effects with pizotifen is lower compared with methysergide and mianserin. These agents have additional antagonistic effects at histamine H1, muscarinic cholinergic, alpha 1-adrenergic, alpha 2-adrenergic and dopamine receptors, but drugs which are selective for these non-5-HT receptors appear to be of no benefit in migraine. Actions mediated by 5-HT2 receptors which could be of relevance to migraine comprise cranial vasoconstriction, increased cranial capillary permeability and platelet aggregation, and some central nervous system effects and neuroendocrine functions. Although pizotifen, cyproheptadine and mianserin are considered to be relatively specific for 5-HT2 receptors, these agents and methysergide all share a high affinity for 5-HT1C binding sites; ketanserin, however, has little affinity for these sites, thus activation of 5-HT1C receptors may be an important step in the pathogenesis of migraine. It is not yet known which 5-HT1C receptor-mediated actions of 5-HT are relevant to migraine, but some behavioural actions and cranial vasodilatation via release of endothelium-derived relaxing factor may be involved.(ABSTRACT TRUNCATED AT 250 WORDS)

Mechanisms involved in serotonin-induced vasodilatation.

In vitro investigations have identified three major mechanisms which could contribute to the vasodilator action of serotonin (5-hydroxytryptamine, 5-HT): direct vascular smooth muscle relaxation; prejunctional inhibition of noradrenaline release from vascular sympathetic nerve terminals; and release of endothelium-derived relaxing factor (EDRF). In vivo studies have shown that in pig and cat common carotid circulations, rabbit hindquarter and mesenteric circulations, and rat systemic vasculature, direct vascular smooth muscle relaxation may be the predominant mechanism involved, but the contribution of EDRF release remains to be established. In other circulations in vivo (dog femoral and common carotid), prejunctional inhibition of vascular sympathetic tone is the predominant mechanism responsible for serotonin-induced vasodilatation. All of these actions are mediated by 5-HT1-like receptors, but different subtypes seem to be involved in each of these mechanisms. The prejunctional inhibitory receptor has been the most studied; depending on the tissue, these subtypes may resemble 5-HT1A, 5-HT1B, 5-HT1C or 5-HT1D binding sites, or the contractile receptor in dog saphenous vein.

The classification of 5-hydroxytryptamine receptors.

1. The current classification of receptors for 5-hydroxytryptamine (5-HT) is based on functional studies, and encompasses three main receptor types. 2. 5-HT1-like receptors mediate inhibition of release of various neurotransmitters from central and peripheral sites, smooth muscle contraction and relaxation (and release of endothelium-derived relaxing factor), tachycardia, a variety of behavioural actions (for example, forepaw treading, hypothermia, hyperphagia, drug discriminative stimulus properties, nociceptive pathway modulation, and anxiolytic, anti-aggressive and prosexual effects), and central neuronal excitatory and inhibitory activity. Selective antagonists for this receptor are not yet available, but the 5-HT2 receptor antagonists methysergide and methiothepin have appreciable affinity for 5-HT1-like receptors, and 5-carboxamidotryptamine is a selective agonist. 3. 5-HT2 receptors mediate smooth muscle contraction, platelet aggregation, increased capillary permeability, some behavioural syndromes (for example, head twitch and wet-dog shakes) and drug discriminative stimulus properties, central neuroexcitatory effects, and some neuroendocrine functions. Ketanserin and cyproheptadine are selective antagonists. 4. 5-HT3 receptors mediate peripheral afferent and efferent neuroexcitatory actions, anxiogenic effects, and modulation of cytotoxic drug-induced emesis, gastric emptying, and dopamine-related mesolimbic hyperactivity. Selective antagonists include cocaine, MDL 72222 and ICS 205-930; 2-methyl-5-HT is a selective agonist.

Actions of robustoxin, a neurotoxic polypeptide from the venom of the male funnel-web spider (Atrax robustus), in anaesthetized monkeys.

Robustoxin, a polypeptide consisting of a chain of 42 amino acid residues in a known sequence, has been isolated by cation exchange chromatography from the crude venom of the male funnel-web spider (Atrax robustus). Physiological activity or toxicity in the venom fractions was detected by production of fasciculation in mouse phrenic nerve-hemidiaphragm preparations and by lethality in new-born mice. In the present experiments in Macaca fascicularis monkeys anaesthetized with pentobarbitone, robustoxin (5-30 micrograms/kg infused i.v. over 5 min) produced immediate disturbances in respiration (including dyspnoea and apnoea), blood pressure and heart rate followed by severe hypotension (mean systemic blood pressure less than 50 mmHg) or death due to respiratory and circulatory failure within 196 min. Robustoxin also produced lachrymation, salivation, generalized skeletal muscle fasciculation and a parallel increase in body temperature, and increased firing in skeletal motor and autonomic nerves. These effects closely resembled those produced by i.v. infusions over 5 min of 50 micrograms/kg of crude venom from male A. robustus spiders. Crude venom from female A. robustus spiders (500 micrograms/kg i.v. over 5 min) produced some of the effects elicited by robustoxin and crude venom from male spiders, but to a much less marked extent. It was concluded that robustoxin is responsible for the neurotoxic and lethal effects of human envenomation by male A. robustus spiders.

Nimodipine-induced changes in the distribution of carotid blood flow and cardiac output in pentobarbitone-anaesthetized pigs.

In view of the claimed effectiveness of nimodipine in migraine and its possible selectivity for cerebral vessels, we investigated the effects of nimodipine in anaesthetized pigs on the fractionation of carotid arterial blood flow into non-nutrient (arteriovenous anastomoses; AVAs) and nutrient (capillary) parts, and on regional tissue blood flows and vascular conductances. Intracarotid infusions of nimodipine (0.05-1.25 microgram kg-1 min-1) redistributed carotid blood flow in favour of its nutrient compartment, particularly to the skeletal muscles and tongue. Vascular conductance in the non-nutrient (AVAs) compartment decreased (40%), most likely, as a result of 'steal' following profound (5.5 fold) arteriolar dilatation. Intravenous infusions of nimodipine (0.05-6.25 micrograms kg-1 min-1) caused hypotension, bradycardia, a decrease in conduction in the non-nutrient fraction, and an increase in conduction in the nutrient fraction (mostly in the skeletal muscles, but also in the gastrointestinal tract, cerebral hemispheres, heart and adrenals). Probably due to the hypotensive effect, only skeletal muscle blood flow increased. The nimodipine-induced increase in vascular conductance in the skeletal muscles showed regional variation; the effect was most pronounced in the cheek muscles, followed by the muscles of the chest, abdominal, trunk and gluteal regions. We conclude that: AVA flow seems to represent a 'reserve' perfusion which can be readily diverted to tissues in the case of increased metabolism and/or vasodilatation, though the overall response to nimodipine of carotid blood flow distribution qualitatively resembles that to some antimigraine drugs, the relevance of such acute effects in the prophylactic usefulness of nimodipine in migraine remains to be ascertained, and nimodipine lacks a selective cerebral vasodilator action in the anaesthetized pig.

Proposals for the classification and nomenclature of functional receptors for 5-hydroxytryptamine.

As a result of controversy in the literature regarding the classification and nomenclature of functional receptors for 5-hydroxytryptamine (5-HT), a framework for classification is proposed. The formulation of these proposals has only been made possible by the recent advent of new drug tools. It is considered that there are three main types of 5-HT receptor, two of which have been well characterised pharmacologically, using selective antagonists, and which it is proposed to name 5-HT2 and 5-HT3. These two groups broadly encompass the "D" and "M" receptors, respectively, which Gaddum identified in the guinea-pig ileum (Gaddum and Picarelli, 1957). The 5-HT2 receptor, which mediates a variety of actions of 5-HT, has been definitively shown to correlate with the 5-HT2 binding site in the brain. No binding studies in brain tissue have yet been published with radiolabelled ligands specific for 5-HT3 receptors. A number of other actions of 5-HT appear to be mediated via receptors distinct from 5-HT2 or 5-HT3 receptors. Since selective antagonists are not yet available, these receptors cannot be definitively characterised, although in many cases they do have some similarities with 5-HT1 binding sites, which are a heterogeneous entity. Criteria are proposed for tentatively classifying these receptors as "5-HT1-like" (Table 1). Definitive characterisation of these receptors will await the identification of specific antagonists. This classification of 5-HT receptors into three main groups (Table 1) is based largely, but not exclusively, on data from studies in isolated peripheral tissues where definitive classification is possible. However, it is believed that this working classification will be relevant to functional responses to 5-HT in the central nervous system.

Analysis of the heart rate effects of 5-hydroxytryptamine in the cat; mediation of tachycardia by 5-HT1-like receptors.

The effects of 5-hydroxytryptamine (5-HT) on heart rate in anaesthetized cats were analysed both in intact animals and after spinal section plus vagotomy. The intact cat responded to 5-HT (3, 10 and 30 micrograms X kg-1, i.v.) with a brief, but intense, bradycardia and a longer-lasting hypotension. Administration of MDL 72222, a selective antagonist of M-type 5-HT receptors, blocked bradycardia elicited by 5-HT without affecting that caused by stimulation of the vagus nerve. In spinal cats the same doses of 5-HT increased heart rate and blood pressure. These effects remained essentially unchanged after bilateral adrenalectomy, guanethidine, propranolol and burimamide, suggesting that 5-HT acted directly on the myocardium and blood vessels. The tachycardic responses to 5-HT in spinal cats were little affected by 0.5 mg X kg-1 doses of MDL 72222 or of the 5-HT2 receptor antagonists, ketanserin, ritanserin or cyproheptadine. In contrast, the non-selective 5-HT receptor antagonist, methysergide, which binds to both 5-HT1 and 5-HT2 recognition sites in rat brain membranes, potently antagonized the 5-HT-induced tachycardia in doses of 0.05 to 0.5 mg X kg-1. However pizotifen and mianserin, two other 5-HT2 antagonists which show poor affinity for 5-HT1 recognition sites, were also effective against the tachycardic response to 5-HT in doses of 0.5-4.5 mg X kg-1. The pressor responses to 5-HT in the spinal cat were markedly inhibited by all six 5-HT2 antagonists at a dose of 0.5 mg X kg-1.(ABSTRACT TRUNCATED AT 250 WORDS)

Mechanisms involved in the vasodilator action of 5-hydroxytryptamine in the dog femoral arterial circulation in vivo.

The possibility that the vasodilator effect of 5-hydroxytryptamine (5-HT) in vivo involves a presynaptic inhibitory effect on sympathetic nerve activity was investigated in the femoral arterial circulation of pentobarbitone-anaesthetized dogs. The vasodilator effect of intraarterial (i.a.) 5-HT was abolished following ganglion blockade with mecamylamine, and remained inhibited after restoration of femoral vascular tone with i.a. ornipressin. These procedures had no effect on the vasodilator response to i.a. acetylcholine. The vasoconstrictor response to i.a. noradrenaline was not inhibited by mecamylamine. These findings suggest that a presynaptic inhibition of sympathetic neurotransmission is responsible for 5-HT-induced vasodilatation in vivo. Pizotifen (0.1-0.4 mg/kg i.v.) inhibited the 5-HT dilator response, but the doses required were too high to be commensurate with an action at 'D' type 5-HT receptors. Ketanserin (0.1-0.4 mg/kg i.v.) specifically inhibited the dilator response to 5-HT; higher doses (1-4 mg/kg i.v.) also inhibited noradrenaline-induced vasoconstriction. Ketanserin, at all doses used, reduced systemic blood pressure and femoral vascular resistance. The effects of the lower doses of ketanserin (0.1-0.4 mg/kg) cannot be due to peripheral alpha-adrenoceptor antagonism; blockade of the dilator effect of 5-HT may simply be due to inhibition of sympathetic nerve activity by ketanserin itself.

Excitatory 5-hydroxytryptamine receptors in the cat urinary bladder are of the M- and 5-HT2-type.

In anaesthetized cats, a biphasic contraction of the urinary bladder, consisting of an initial spike followed by a longer-lasting contracture, was elicited by 5-hydroxytryptamine (5-HT) in doses of 3-30 micrograms/kg, i.a. Administration of MDL 72222 (30, 100 and 300 micrograms/kg, i.v.), which specifically antagonizes the M-type 5-HT receptors, selectively blocked the spike phase of the 5-HT response. Ketanserin (30, 100 and 300 micrograms/kg, i.v.), on the other hand, eliminated only the second phase of the 5-HT-induced bladder contraction. Injection of MDL 72222 (300 micrograms/kg) after ketanserin (300 micrograms/kg), or of 100 micrograms/kg of methysergide or cyproheptadine, or 300 micrograms/kg of ketanserin after MDL 72222 (300 micrograms/kg), led to blockade of both phases of the response to 5-HT. The contractile response to dimethylphenylpiperazinium (DMPP) remained unaffected. These results clearly show that the early and late phases of the cat urinary bladder contraction elicited by 5-HT are mediated by M and 5-HT2 receptors, respectively.

Hypotensive actions of ketanserin in dogs: involvement of a centrally mediated inhibition of sympathetic vascular tone.

The intravenous (i.v.) administration of ketanserin (0.1-0.4 mg/kg) produced immediate and sustained decreases in systemic blood pressure and heart rate in pentobarbitone-anaesthetized dogs. These doses of ketanserin did not inhibit common carotid vasoconstrictor responses to intraarterial (i.a.) noradrenaline, pre-ganglionic stimulation of the sectioned cervical sympathetic nerve, or i.v. nicotine, thus the effects of ketanserin are not due to blockade of vascular alpha-adrenoceptors, adrenergic neurone blockade, or ganglionic blockade. Systemic pressor responses to i.v. nicotine, which produces sympathetic activation by both central and ganglionic stimulating actions, and to common carotid artery occlusion, were inhibited by 0.1-0.4 mg/kg of ketanserin i.v. These results suggest that in the anaesthetized dog, the hypotensive action of ketanserin involves a centrally mediated inhibition of sympathetic tone. Peripheral vascular 5-HT2 receptor blockade does not appear to be responsible for the hypotensive effect of ketanserin in this model, although this does not preclude the involvement of such a mechanism in its clinical antihypertensive action.

Evidence for a central component to the hypotensive action of ketanserin in the dog.

The mechanisms responsible for the hypotensive action of ketanserin are controversial. Vascular 5-HT2-receptor blockade, resulting in inhibition of serotonin-induced vasoconstriction and amplification of other vasoconstrictors, has been suggested by some investigators, but others have concluded that vascular alpha-adrenoceptor blockade is responsible. In our experiments using pentobarbitone-anaesthetized dogs, ketanserin (0.1-0.4 mg/kg i.v.) produced immediate and sustained falls in systemic arterial blood pressure and vascular resistance in the common carotid and femoral arterial circulations. Constrictor responses to noradrenaline in these circulations were unaffected by 0.1-0.4 mg/kg i.v. of ketanserin; alpha-adrenoceptor blockade was only produced by higher doses (1-4 mg/kg i.v.). Constrictor responses in the common carotid circulation to preganglionic cervical sympathetic nerve stimulation and to nicotine were not inhibited by 0.1-0.4 mg/kg of ketanserin. The systemic pressor responses to nicotine and common carotid artery occlusion, however, were reduced by these doses of ketanserin. These results suggest that alpha-adrenoceptor blockade is not responsible for the hypotensive action of 0.1-0.4 mg/kg of ketanserin, and that a centrally mediated inhibition of sympathetic nerve activity is involved.

Actions of indoramin on rabbit and human vasculature in vitro.

The antagonist effects of indoramin were investigated in rabbit perfused ear artery, common carotid artery, and human perfused temporal artery preparations. Indoramin was a potent competitive antagonist of the constrictor effects of noradrenaline (NA) in all three preparations, pA2 values being 7.77 for the ear artery, 8.20 for the common carotid artery and 7.46 for the human temporal artery. The constrictor actions of serotonin (5-hydroxytryptamine, 5-HT) were competitively antagonized by indoramin. The pA2 values obtained in the rabbit common carotid and human temporal artery (5.92 and 6.25, respectively), were lower than those for NA in the same preparations and lower than that obtained in the rabbit perfused ear artery (7.55). Indoramin was a potent competitive antagonist (pA2:8.31) of histamine-induced vasoconstriction in the rabbit perfused ear artery preparation. These results can be explained on the basis of previous findings that the action of 5-HT in the rabbit ear artery is mediated via an alpha-adrenoceptor, and that the rabbit common carotid artery contains true 5-HT receptors. The findings suggest that specific 5-HT receptors may be present in the human temporal artery and that alpha-adrenoceptor antagonism may be the pharmacological property of most relevance to the efficacy of indoramin in migraine prophylaxis.