Reduction of cephalic arteriovenous shunting by ergotamine is not mediated by 5‐HT 1 ‐like or 5‐HT 2 receptors

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1 Though it is well known that the antimigraine drugs ergotamine and dihydroergotamine reduce carotid arteriovenous anastomotic shunting, it is uncertain whether a 5-HT1-like receptor is responsible for this effect. Using a high dose of methiothepin (3 mg kg-1), which completely blocks the carotid vascular effects of sumatriptan, we have attempted to study the role of 5-HT1-like receptors in the carotid vascular effects of ergotamine as well as dihydroergotamine in anaesthetized pigs. 2 Both ergotamine and dihydroergotamine increased arterial blood pressure and decreased heart rate. 3 The ergot alkaloids reduced dose-dependently total carotid blood flow and conductance as a result of a selective decrease in the arteriovenous anastomotic fraction. The nutrient fraction increased, particularly to bones, tongue and salivary glands with ergotamine and to ears, head skin, bones and salivary glands with dihydroergotamine. In contrast, dural vascular conductance tended to decresae. 4 Methiothepin (3mg kg-') partially antagonized the decrease in total carotid and arteriovenous anastomotic blood flow and conductance by the ergot alkaloids; the ED30 for ergotamine and dihydroergotamine (agonist dose eliciting a 30% decrease in arteriovenous anastomotic conductance) was raised by 3.1 and 5.2 fold respectively. 5 These results indicate that the effects of ergotamine and dihydroergotamine are partly mediated by methiothepin-sensitive receptors, which may probably belong to either 5-HT1-like or a2-adrenoceptor category. However, an important part of the effect of ergot alkaloids is left after methiothepin and this could be mediated by other, perhaps novel, receptors.

Section: Systemic Haemodynamicsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Carotid vascular effects of ergotamine and dihydroergotamine in the pig: no exclusive mediation via 5‐HT₁‐like receptors

Boer

Heiligers

Saxena

1991

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“…In vivo, methysergide selectively constricts the carotid vascular bed (Saxena, 1974). Sumatriptan , ergotamine (Bom et al, 1989a), 5-CT (Saxena & Verdouw, 1985) and 8-OH-DPAT (Bom et al, 1989b) constrict arteriovenous shunts, although the effects of ergotamine may not be mediated by 5-HT1-like or 5-HT2 receptors (Bom et al, 1989a). If closing arteriovenous shunts decreases vascular permeability following trigeminal stimulation, than leakage induced by intravenously administered neuropeptides (substance P or neurokinin A) should have been blocked as well.…”

Section: Receptor Localizationmentioning

confidence: 99%

Further characterization of the putative 5‐HT receptor which mediates blockade of neurogenic plasma extravasation in rat dura mater

Buzzi

Moskowitz

Peroutka

et al. 1991

102

1 We describe the effects of pretreatment with 5-hydroxytryptamine (5-HT) receptor agonists and antagonists on neurogenically-mediated plasma protein extravasation (["25I]-albumin) in rat dura mater and in extracranial tissues (temporalis muscle fascia, conjunctiva, eyelid and lip) induced by electrical stimulation of the right trigeminal ganglion. 2 Leakage of [25I]-bovine serum albumin from blood vessels in dura mater following high intensity stimulation (1.2 mA, Sims, 5Hz for 5min) was significantly reduced by the intravenous administration of drugs active at 5-HT receptors with some selectivity for the 5-HT1 receptor subtypes: 5-carboxamidotryptamine (5-CT) (threshold dose, 1ngkg-1); 5-benzyloxytryptamine (5-BT) (10, 30 or 100augkg-1); 8-hydroxydipropylaminotetralin (8-OH-DPAT) (300pigkg-1); and as previously reported, sumatriptan (lOOpugkg -), dihydroergotamine (DHE) (SOugkg 1), ergotamine tartrate (lOO1ugkg 1) and chronically administered methysergide (1 mgkg-1).3 The putative 5-HT receptor antagonist, metergoline lOOpgkg-1, inhibited partially the effect of sumatriptan in dura mater providing additional evidence for a 5-HT1 receptor subtype-mediated mechanism, although it was not effective against 5-CT (1 ng kg-1). Methiothepin (300,ug kg-1) did not affect the response to sumatriptan. When administered at high concentrations (1 mg kg 1) methiothepin and metergoline decreased plasma protein extravasation in rat dura mater. 4 Pretreatment with the 5-HT2 receptor antagonists pizotifen, 300pugkg 1, or ketanserin, 300,ugkg ', or the 5-HT3 receptor antagonists MDL 72222, 300,ugkg-1, or ICS 205-930, 300pgkg-1, did not affect plasma protein leakage following electrical trigeminal stimulation. Blockade by sumatriptan of plasma protein extravasation was not inhibited by pizotifen (300,ug kg-1) or MDL 72222 (300pg kg-').5 The 5-HT receptor(s) mediating this response were present only on intracranial tissues innervated by the trigeminal nerve; plasma protein extravasation in extracranial tissues was not blocked by pretreatment with the equivalent or higher concentrations of the above drugs following low intensity trigeminal stimulation (0.1 mA, 5 ms, 5 Hz). 6 The putative 5-HT receptor(s) mediating this response were not present on sympathetic fibres innervating dura mater since unilateral removal of the superior cervical ganglion did not prevent the development of plasma protein extravasation nor did it affect the blockade by sumatriptan IOOpug kg-'. 7 The above pharmacological data suggest that intracranial vessels possess 5-HT receptor(s) which are coupled to inhibition of neurogenically-mediated plasma protein extravasation. These receptors cannot be detected on extracranial cephalic blood vessels innervated by the trigeminal nerve, although available evidence strongly suggests that the 5-HT receptors reside on perivascular trigeminal nerve fibres. The rank order of effective doses (threshold concentrations; 5-CT < 5-BT < DHE < sumatriptan < 8-OHDPAT) is most consistent with a 5-HTlB-or 5-HTlD-mediated response, ...

“…In vivo, these drugs cause an increase in resistance in the carotid vascular bed of different species; this increase seems to be localized only in arteriovenous anastomoses in this vascular bed, because capillary blood flow remains either unchanged or is even increased (see Saxena, 1978;Bom et al, 1989;Perren et al, 1989;Den Boer et al, 1991a,b).…”

Section: Introductionmentioning

confidence: 99%

Lack of effect of the antimigraine drugs, sumatriptan, ergotamine and dihydroergotamine on arteriovenous anastomotic shunting in the dura mater of the pig

Boer

Somers

Saxena

1992

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1 In anaesthetized animals, the antimigraine drugs, sumatriptan, ergotamine and dihydroergotamine, reduce carotid arteriovenous anastomotic shunting. Within the carotid vascular bed arteriovenous anastomoses are located, amongst other places in the dura mater, which is a putative site of the pain during a migraine attack. 2 In this investigation, we have localized and measured the arteriovenous shunting within the carotid vascular bed of the pig by using simultaneous intracarotid injections of radiolabelled microspheres of three different sizes (10, 15 and 50gm), which provides an index of blood flow via arteriovenous anastomoses larger than approximately 14, 27 and 90 gm diameter, respectively. The effects of sumatriptan (0.3 mg kg-'), ergotamine (0.02 mg kg-'), dihydroergotamine (0.1 mg kg-') and saline were studied by repeating the injections of 15 and 50 gm spheres after the treatments. 3 There was no difference in shunting or entrapment between the 10 and 15 gm microsphere, indicating the absence of arteriovenous anastomoses with a diameter between 14 and 27 gm. 4 Arteriovenous anastomoses with a diameter between 27 and 90 gm, as indicated by the difference in blood flow measured by 15 and 50 gm spheres, were located in the dura mater, ears, skin, fat and, to a lesser extent, in the skeletal muscles and eyes. 5 Sumatriptan, ergotamine and dihydroergotamine reduced the overall flow in the smaller arteriovenous anastomoses (diameter between 27 and 90 gm), and even more in larger shunts (wider than 90 gm).6 Locally, blood flow in the smaller arteriovenous shunts was reduced in the skin and fat, but not in the dura mater, ears, eyes and muscles. It is not possible to determine in which tissues blood flow in the larger arteriovenous anastomoses was reduced. 7 Tissue blood flow measured with 15 gm microspheres remained unchanged after the three antimigraine drugs, implying a lack of effect on capillary flow. 8 It is concluded that in the anaesthetized pigs the only evident effect of these antimigraine drugs on carotid haemodynamics is a decrease in blood flow in both smaller and larger arteriovenous anastomoses; the smaller arteriovenous anastomoses were affected in the skin and fat, but not in other tissues.