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Biomedical subjects

H E Connor

Publications and source records attributed to H E Connor.

50 records · Page 3Linked to original sources
PubMed1989

The pharmacology of the novel 5-HT1-like receptor agonist, GR43175.

We describe the identification of a novel drug, GR43175, for the acute treatment of migraine. GR43175 is a tryptamine analogue with a very selective agonist action at a 5-HT1-like receptor subtype first identified in the dog saphenous vein. Using this drug as a research probe, we have now shown that this 5-HT receptor type predominates in the carotid circulation, which explains the remarkably selective vasoconstrictor action of GR43175 in vivo in the carotid arterial bed of dogs and cats. Its vasoconstrictor action can be shown to be localized even further to arteriovenous anastomoses (shunts) within the carotid circulation, in such a way that blood flow to the brain as well as to extracerebral capillary beds remains unaffected or may even be increased. In the treatment of migraine demonstrated to date, the impressive effectiveness of GR43175 must reinforce the evidence in favour of an important vascular component being involved in the aetiology of the disease. The question is again raised as to whether the opening of carotid shunts is involved, as suggested by Heyck. If not, an alternative vascular locus needs to be identified.

Animals↗
PubMed1989

Influence of the endothelium on contractile effects of 5-hydroxytryptamine and selective 5-HT agonists in canine basilar artery.

1. We have investigated the influence of endothelial damage on the cerebrovascular reactivity to 5-hydroxytryptamine (5-HT) and some selective 5-HT agonists in canine basilar artery. 2. 5-HT, alpha-methyl 5-HT, GR 43175 (3-[2-dimethyl amino] ethyl-N-methyl-1H-indole-5-methane sulphonamide) and 5-carboxamidotryptamine (5-CT) produced concentration-dependent contractions of untreated dog basilar artery with a functional endothelium. Following endothelial damage by perfusion with Triton X-100 (0.1%), which abolished the relaxant response to substance P, the maximum contractile effect of 5-HT, alpha-methyl 5-HT, GR 43175 and 5-CT was markedly enhanced although there was little change in the EC50 values. Endothelial damage did not modify the vasoconstrictor effect of the thromboxane agonist, U46619, or potassium chloride. 3. Neither 5-HT nor 5-CT caused relaxation of untreated canine basilar arteries contracted with prostaglandin F2 alpha, U46619, uridine triphosphate or potassium chloride. 4. These results suggest that canine basilar artery spontaneously releases endothelium-derived relaxing factor which can attenuate the vasoconstrictor effect of 5-HT and selective 5-HT agonists. This effect appeared to be specific since the vasoconstrictor response to U46619 was not modified. 5. These results demonstrate that the cerebrovascular endothelium can markedly influence the reactivity of the vascular smooth muscle of canine basilar artery to 5-HT and 5-HT1-like receptor agonists. However we could find no evidence that 5-HT receptor activation stimulates endothelial cell function as it does in some other blood vessels.

Animals↗
PubMed1989

Characterization of 5-HT receptors mediating contraction of canine and primate basilar artery by use of GR43175, a selective 5-HT1-like receptor agonist.

1. The aim of this study was to characterize the 5-hydroxytryptamine (5-HT) receptor which mediates contraction of canine and primate isolated basilar artery by use of a variety of selective 5-HT agonists and antagonists. 2. 5-HT, alpha-methyl 5-HT and the selective 5-HT1-like receptor agonists, GR43175 and 5-carboxamidotryptamine (5-CT), each caused contraction of canine and primate basilar artery with a rank order of agonist potency of 5-CT greater than or equal to 5-HT greater than GR43175 greater than alpha-methyl 5-HT. The 5-HT1-like receptor agonists, GR43175 and 5-CT, produced maximum effects which were less than that produced by 5-HT or alpha-methyl 5-HT. 3. In canine basilar artery, ketanserin (0.1-1 microM) caused some depression of the maximum effect of 5-HT but produced little or no shift of the concentration-effect curve. The contractile effects of GR43175 were not modified by ketanserin (1 microM), MDL72222 (1 microM) or cyanopindolol (1 microM). However, the effects of 5-HT and GR43175 were specifically antagonized by methiothepin (0.1 microM); the mean agonist concentration-ratios were 33 and 48 respectively. 4. In primate basilar artery, ketanserin (1 microM) again caused a small depression of the 5-HT maximum response but had not effect against GR43175-induced contractions. In contrast, methiothepin (0.1 microM) antagonized both 5-HT- and GR43175-induced contractions; the mean agonist concentration-ratios were 35 for both. 5. These results demonstrate that a large component of the effects of 5-HT in canine and primate basilar artery is produced by stimulation of a 5-HT1-like receptor. This receptor can be characterized by the high potency of the novel, selective agonist, GR43175, and susceptibility to blockade by methiothepin. However, there also appears to be a population of 5-HT2 receptors in these prepAarations which contribute to the contractile effects of 5-HT.

Animals↗
PubMed1989

5-HT1-like receptors mediate 5-hydroxytryptamine-induced contraction of human isolated basilar artery.

1. The 5-hydroxytryptamine (5-HT) receptor mediating contraction of endothelium denuded human basilar artery has been characterized in vitro. 2. 5-HT and a variety of 5-HT agonists contracted human isolated basilar artery with a rank order of agonist potency, 5-carboxamidotryptamine (5-CT) greater than 5-HT identical to methysergide greater than GR43175 much greater than 8-OHDPAT much greater than 2-methyl-5-HT. The maximum response produced by these agonists differed. 3. None of the agonists relaxed human basilar artery when tone was elevated with prostaglandin F2 alpha, indeed further contraction was seen. 4. The contractile responses of human basilar artery to 5-HT and the selective 5-HT1-like agonist GR43175 were highly reproducible whilst those to 5-CT were not. 5. The contractile response to both 5-HT and GR43175 was resistant to antagonism by ketanserin and GR38032, thus excluding activation of 5-HT2 and 5-HT3 receptors. The contractile action of 5-HT and GR43175 was also not antagonized by (+/-)-cyanopindolol, excluding the activation of receptors similar to 5-HT1A and 5-HT1B recognition sites identified in ligand binding studies. 6. In marked contrast, methiothepin was a potent antagonist of the contractile actions of both 5-HT and GR43175, with a pA2 value of 8.8 against both agonists. Methiothepin (100 nM) had no effect on the contractile response to the thromboxane A2-mimetic U46619. 7. We conclude that 5-HT and GR43175 contract the human isolated basilar artery by activating the same receptor type. This receptor appears identical to the 5-HT1-like receptor causing contraction of the dog isolated saphenous vein and cerebral blood vessels from the dog and primate.

Basilar Artery↗
PubMed1988

GR43175, a selective agonist for the 5-HT1-like receptor in dog isolated saphenous vein.

1. We describe the actions of a novel and selective 5-HT1-like receptor agonist, GR43175, in a range of isolated tissue preparations containing different 5-hydroxytryptamine (5-HT) receptor types. 2. GR43175 was a potent agonist at 5-HT1-like receptors mediating contraction of the dog isolated saphenous vein and also at those inhibiting neuronally mediated contractions in the same preparations. For both actions, GR43175 was approximately four times weaker than 5-HT. 3. GR43175 was devoid of agonist properties at 5-HT1-like receptors mediating relaxation of the cat isolated saphenous vein. 4. GR43175 was devoid of agonist properties at 5-HT2 receptors mediating contraction of the rabbit isolated aorta, pig coronary artery, greyhound coronary artery and beagle femoral artery. 5. GR43175 was devoid of agonist properties at 5-HT3 receptors mediating depolarization of the rat isolated vagus nerve. 6. The contractile response to GR43175 in the dog isolated saphenous vein was selectively antagonized by methiothepin but was resistant to antagonism by the 5-HT2 receptor blocking drug ketanserin and the 5-HT3 receptor blocking drug MDL 72222. Methiothepin antagonized the contractile action of 5-HT and GR43175 to an equal extent suggesting that both agonists act at the same receptor. 7. The results demonstrate that GR43175 is a highly selective agonist for the 5-HT1-like receptors found in the dog saphenous vein. The absence of an action of GR43175 at 5-HT1-like receptors mediating relaxation of the cat isolated saphenous vein provides further evidence that 5-HT1-like receptors are heterogeneous.

Animals↗
PubMed1987

Role of endothelium in haemoglobin-induced contraction of dog basilar artery.

Haemoglobin (10 nM-30 microM) caused contraction of dog isolated basilar artery. In preparations which were perfused with Triton X-100 (0.1%) for one min to remove the endothelium, substance P relaxation was abolished but haemoglobin-induced contractions were unchanged. Endothelium removal or damage was confirmed histologically. These results suggest that the integrity of the endothelium is not essential for haemoglobin to produce contraction in dog basilar artery.

Animals↗
PubMed1987

Do adrenaline-containing neurones from the rostral ventrolateral medulla excite preganglionic sympathetic cell bodies?

Experiments were performed to investigate whether descending vasomotor neurones from the rostral ventrolateral medulla (RVL) utilize adrenaline as a neurotransmitter. Electrical stimulation of the RVL caused marked, short lasting, reproducible increases in blood pressure and heart rate in anaesthetised atropine methylbromide-treated rats. These effects probably reflect activation of cell bodies rather than fibres of passage since injection of L-glutamate into the same area also produced tachycardia and vasopressor responses. The effects of RVL stimulation were unchanged after bilateral adrenalectomy but were markedly reduced by guanethidine (1 mg/kg, i.v.) suggesting that the tachycardia and vasopressor responses were mediated via increased sympathetic tone to the heart and vasculature. Pretreatment with the phenylethanolamine-N-methyl transferase (PNMT) inhibitor LY134046 (1 mg intracisternally, and 40 mg/kg i.p. daily for 1 day or 5 days) did not modify either the tachycardia or vasopressor response to stimulation of the RVL. Resting blood pressure and heart rate were also unchanged. Cardiac preganglionic sympathetic nerves supplying the heart arise from the C7-T2 region of the spinal cord. Phentolamine and propranolol were injected intrathecally (i.t.) in this region, in an attempt to block the spinal receptors at which any adrenaline, released locally during RVL stimulation, might be expected to act in order to elicit the characteristic tachycardia. Phentolamine (10 and 100 micrograms i.t.) and propranolol (1 microgram i.t.) did not modify the tachycardia but propranolol (10 and 100 micrograms i.t.) caused a dose-dependent reduction. These doses of propranolol (10 and 100 micrograms i.t.) also produced blockade of peripheral beta-adrenoreceptors. The failure of PNMT inhibition to modify the tachycardia or vasopressor response to RVL stimulation and the lack of effect of intrathecally injected alpha-and beta-adrenoreceptor antagonists (at doses which do not exert peripheral effects) against the RVL stimulation-induced tachycardia suggests that adrenaline does not subserve a spinal neurotransmitter role, at the C7-T2 region.

Adrenergic alpha-Antagonists↗
PubMed1986

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

We have attempted to characterize the 5-hydroxytryptamine (5-HT) receptors mediating bronchoconstriction, vasodilatation, vasodepression and tachycardia in anaesthetized cats following bilateral vagosympathectomy and beta-adrenoceptor blockade with propranolol. 5-HT (1-100 micrograms/kg-1 i.v.) caused dose-related bronchoconstriction and tachycardia but variable and complex effects on diastolic blood pressure and carotid arterial vascular resistance. In contrast, 5-carboxamidotryptamine (5-CT; 0.01-1 micrograms kg-1 i.v.) caused consistent, dose-related decreases in diastolic blood pressure and carotid arterial vascular resistance and increases in heart rate. 5-CT did not cause bronchoconstriction. The 5-HT-induced bronchoconstriction was dose-dependently antagonized by methiothepin, methysergide and ketanserin (10-100 micrograms kg-1 i.v.). The highest doses used of these antagonists did not antagonize bronchoconstriction induced by prostaglandin F2 alpha. The high potency of all three antagonists indicate a 5-HT2-receptor mediated effect. The 5-HT- and 5-CT-induced tachycardia as well as the 5-CT-induced vasodepressor and carotid arterial vasodilator responses were dose-dependently antagonized by low doses of methiothepin (10-100 micrograms kg-1 i.v.) and by high doses of methysergide (100-1000 micrograms kg-1 i.v.) but were little affected by ketanserin in doses up to 1000 micrograms kg-1 i.v. These selective effects of 5-CT appear to be mediated by '5-HT1-like' receptors.

Animals↗
PubMed1982

Clonidine-induced potentiation of reflex vagal bradycardia in anaesthetized cats.

The interactions between clonidine and the selective alpha 1- and alpha 2-adrenoceptor antagonists, prazosin and yohimbine, on the angiotensin-induced reflex vagal bradycardia have been investigated in propranolol-treated chloralose-anaesthetized cats. Clonidine (1-10 microgram intracisternally) had little effect on the pressor responses to angiotensin, only slightly increased the peak but markedly increased the duration of the reflex bradycardia. Neither prazosin nor yohimbine (200 microgram intracisternally of either antagonist) had any effect on the reflex bradycardia to angiotensin. Yohimbine greatly diminished the clonidine-induced potentiation of the response, but prazosin was without effect. Clonidine appears to potentiate the vagal reflex bradycardia by stimulating central alpha 2-adrenoceptors.

Animals↗
PubMed1981

Postsynaptic spinal alpha-adrenoceptors mediate effects of intrathecal clonidine.

The cardiovascular effects of intrathecal administration of clonidine were examined after depletion of spinal cord noradrenaline or 5-hydroxytryptamine by pretreatment with 6-hydroxydopamine or 5,6-dihydroxytryptamine. Despite marked reduction in spinal noradrenaline or 5-hydroxytryptamine levels, resting blood pressure and heart rate were unchanged and the clonidine-induced hypotension and bradycardia were unimpaired. The results suggest that intrathecal clonidine acts via inhibitory spinal alpha-adrenoceptors located postsynaptically on the preganglionic nerve cell bodies.

Animals↗
PubMed1981

Pharmacological characteristics of spinal alpha-adrenoreceptors in rats.

1 Spinal alpha-adrenoreceptors involved in cardiovascular control have been investigated using selective alpha-adrenoreceptor agonists and antagonists in urethane-anaesthetized rats. 2 Intrathecal injections of clonidine, alpha-methylnoradrenaline, guanfacine and M7 at the C7-T1 level reduced blood pressure and heart rate. In contrast, phenylephrine, 5-hydroxytryptamine and procaine had little or no effect. These results suggest the involvement of spinal alpha 2-adrenoreceptors. 3 The fall in blood pressure produced by clonidine appeared to be attributable to a reduction in heart rate and stroke volume. Lower body vascular resistance was unchanged. 4 The clonidine-induced bradycardia was antagonised by prazosin, WB4101, piperoxan or yohimbine. Their relative potencies suggest that alpha 1-rather then alpha 2-adrenoreceptors mediate this response. 5 piperoxan and yohimbine clearly prevented the clonidine-induced fall in blood pressure; prazosin and WB4101 also appeared to antagonise clonidine but these results were complicated by the fact that these antagonists themselves reduced blood pressure. 6 It was difficult to interpret these results simply in terms of alpha 1- or alpha 2-adrenoreceptors. Thus spinal alpha-adrenoreceptors may be different from peripheral alpha 1- or alpha 2-adrenoreceptors.

Adrenergic alpha-Antagonists↗
PubMed1976

Exchange, balance, and formal organization in psychotherapeutic interactions.

Psychotherapeutic interactions in crisis situations are analyzed in terms of the "sociodynamic" concepts of exchange, balance, and formal organization. It is argued that psychodynamic interpretations of crisis intervention therapy tend to be incomplete and nonsystematic and, thus, fail to produce adequate predictions, explanations, and control of psychotherapeutic outcomes. Small-group principles and methods are applied to selected crisis cases to illustrate gains in prediction and control over psychiatric approaches.

Adolescent↗