Carotid Vascular Resistance Research Articles

The influence of the trigeminal ganglion on carotid blood flow in anaesthetized guinea-pigs.

1. The influence of the trigeminal ganglion on the carotid circulation has been investigated by measuring electrical stimulation-induced alterations in carotid arterial blood flow and resistance in anaesthetized guinea-pigs. The effects of several receptor antagonists were assessed to determine which neurotransmitters are involved in regulating carotid blood flow. 2. Arterial blood pressure and carotid vascular resistance were reduced by electrical stimulation (0.5 mA, 1 ms, 5 Hz, 60 s) of the trigeminal ganglion ipsilateral to the carotid artery from which flow was measured. No consistent effect of electrical stimulation on carotid blood flow was observed. However, when guinea-pigs were pretreated with guanethidine (30 mg kg-1, s.c., 24 h prior to experiments), stimulation produced little change in blood pressure, while carotid blood flow was increased and vascular resistance decreased, consistent with vasodilatation in the cranial circulation. Stimulation of the trigeminal ganglion contralateral to the carotid artery from which blood flow was measured, had little effect on either carotid blood flow or vascular resistance. 3. In animals pretreated with guanethidine, intravenous administration of the vasoactive intestinal polypeptide (VIP) receptor antagonist, [p-Cl-D-Phe6,Leu17]-VIP (50 micrograms kg-1) significantly attenuated the increase in carotid blood flow and decrease in carotid vascular resistance evoked by trigeminal ganglion stimulation. Responses evoked by trigeminal ganglion stimulation were, however, unaffected by intravenous injection of the tachykinin NK1 receptor antagonists, GR82334 (0.3 mg kg-1) and CP-99,994 (0.4 mg kg-1), calcitonin gene-related peptide (CGRP) receptor antagonist, CGRP8-37 (0.9 mg kg-1) and the ganglion blocking agent, hexamethonium (10 mg kg-1). 4. It is concluded that in the guanethidine-pretreated guinea-pig, electrical stimulation of the trigeminal ganglion increases carotid blood flow and produces an accompanying decrease in carotid vascular resistance, consistent with the dilatation of carotid blood vessels. The transmitter mediating this effect is most likely to be VIP.

Afferent and efferent components of the cardiovascular reflex responses to acute hypoxia in term fetal sheep.

1. We studied the effects of acute isocapnic hypoxia on arterial and central venous pressures, carotid and femoral blood flows and heart rate in intact and carotid denervated fetal sheep between 118 and 125 days gestation, after pre-treatment with either saline, atropine or phentolamine. Electrocortical activity (ECoG) and the incidence of fetal breathing movements (FBM) were also compared between intact and carotid denervated fetuses. 2. There were no significant differences between intact and denervated fetuses in any variable measured during normoxia. Soon after the onset of hypoxia a marked bradycardia occurred in intact, but not in denervated fetuses. Femoral blood flow and femoral vascular resistance (perfusion pressure/femoral blood flow) increased in intact, but not in denervated fetuses. Carotid blood flow increased in both groups of fetuses during hypoxia, but carotid vascular resistance did not change. During hypoxia, the incidence of FBM and low-voltage ECoG was similarly reduced in both groups of fetuses. 3. Atropine produced a rise in fetal heart rate during the control period in intact but not in denervated fetuses. At the onset of hypoxia atropine prevented the initial bradycardia seen in intact fetuses. In denervated fetuses a further increase in heart rate occurred throughout the hypoxia. 4. All denervated fetuses treated with phentolamine died during the hypoxic challenge, but nine out of fourteen intact fetuses treated with phentolamine survived. 5. In intact fetuses which survived hypoxia after treatment with phentolamine, the increase in arterial blood pressure was smaller and the increase in femoral resistance did not occur. In these fetuses a rise in heart rate occurred in hypoxia. Carotid vascular resistance decreased during hypoxia after administration of phentolamine. 6. Our results indicate that the initial cardiovascular responses of the late gestation sheep fetus to hypoxia are reflex, and that the carotid chemoreceptors provide the afferent limb of this reflex. The bradycardia is mediated through a muscarinic pathway, as it is blocked by atropine. The femoral vasoconstriction is mediated through an alpha-adrenergic mechanism, mediated both neurally by a carotid chemoreflex and via catecholamines released directly from the adrenal medulla. Both these components are blocked by phentolamine. 7. The differences in survival between intact and denervated fetuses during hypoxia after phentolamine suggest that the carotid chemoreflex response to hypoxia involves mechanisms in addition to vagal efferents to the heart and alpha-adrenergic actions at peripheral blood vessels.(ABSTRACT TRUNCATED AT 400 WORDS)

Simultaneous ultrasonic measurement of carotid blood flow and intracerebral haemodynamics in man.

Common carotid blood flow and middle cerebral artery velocities were determined simultaneously by using a range gated Doppler velocimeter and transcranial apparatus in ten subjects. Middle cerebral artery velocities were used as an index of cerebral resistance. Different gas mixture concentrations were breathed in order to change cerebral haemodynamic conditions. In each condition there was a simultaneous modification of blood gases and cervicocerebral haemodynamics in common carotid blood flow and cerebral vascular resistance index. Carotid blood flow and the resistance index in middle cerebral artery changed also on opposite side. Acute hypercapnia in normoxia increases common carotid blood flow by 33% and simultaneously decreases cerebral resistance index by 11%. Normocapnic hyperoxia was associated with a fall in common carotid blood flow by 13% and with an increase in cerebral resistance index by 7%. There was a inter-subject statistically significant relation between common carotid blood flow and index of cerebral resistances (0.78 < r < 0.98). However there was an individual reactivity with large scatter when data from different subjects were pooled. Nevertheless the results provide evidence that changes in middle cerebral artery resistance indices are reflected by common carotid blood flow modifications.

Regional vasodilation to endothelin-1 is mediated by a non-ETA receptor subtype in the anaesthetized rat: effect of BQ-123 on systemic haemodynamic responses

The sustained infusion of 75 nmol/kg per min BQ-123 selectively attenuates the systemic pressor responses to i.v. bolus endothelin-1 in the anaesthetized rat; the initial systemic vasodepression is only attenuated when a 10-fold higher dose of this ETA-selective antagonist is infused. These doses of BQ-123 do not antagonize the haemodynamic actions of angiotensin II or calcitonin gene-related peptide nor do they alter basal systemic haemodynamics. The secondary increase in carotid vascular resistance associated with the systemic pressor actions of endothelin-1 is selectively attenuated by the bolus i.v. administration of BQ-123 (1.6 μmol/kg); the maximum degree of the vasorelaxation that precedes this more sustained constriction is unaltered. Thus, the initial carotid vasodilation observed to endothelin-1, and the associated systemic vasodepression, is mediated by a non-ETA receptor subtype. Furthermore, subtle differences might exist between the receptors mediating mesenteric and carotid vasoconstriction since only the latter is sensitive to BQ-123.

Synergistic internal carotid vasodilator effects of human α‐calcitonin gene‐related peptide and nimodipine in conscious rats

1. In a first series of experiments, male Long Evans rats were chronically instrumented for the measurement of internal carotid blood flow and systemic arterial blood pressure; cardiovascular changes were assessed during and after 30 min infusions of human alpha-calcitonin gene-related peptide (CGRP) (0.06 and 0.6 nmol h-1), or nimodipine (60 and 600 nmol h-1) or human alpha-CGRP plus nimodipine. The effects of human alpha-CGRP or nimodipine on internal carotid vasoconstriction induced by endothelin-1 were also measured. 2. Human alpha-CGRP (0.06 nmol h-1) caused a small (+15%), transient increase in internal carotid blood flow and a tachycardia (+33 beats min-1), but no change in mean blood pressure. Nimodipine (60 nmol h-1) caused a brief internal carotid hyperaemia (+16%) but no changes in blood pressure or heart rate. However, concurrent administration of human alpha-CGRP (0.06 nmol h-1) and nimodipine (60 nmol h-1) caused a sustained increase in internal carotid blood flow (+40%) unaccompanied by significant changes in heart rate or blood pressure. 3. Human alpha-CGRP at a dose of 0.6 nmol h-1 or nimodipine at a dose of 600 nmol h-1 caused substantial reductions in internal carotid vascular resistance (-43 and -40%, respectively); concurrent administration of these doses did not have an additive vasodilator effect. 4. Infusion of endothelin-1 (1.2nmolhV1) for 20min caused incremental constriction of the internal carotid vascular bed; human alpha-CGRP infusion (0.6 and 6.0nmolh-1) begun tOmin after the onset of endothelin-1 infusion reversed this effect (dose-dependently); nimodipine (600nmolh-1) also caused a substantial attenuation of the effects of endothelin-1. 5. In a second series of experiments the haemodynamic effects of human alpha-CGRP and/or nimodipine were assessed in rats chronically instrumented for the measurement of renal, superior mesenteric and hindquarters blood flow together with systemic arterial blood pressure. 6. Administration of human alpha-CGRP (0.06 nmol h-') alone or in conjuction with nimodipine (60nmolh-1) had no significant effects on renal or superior mesenteric vascular resistances, although there was a slight hindquarters vasodilatation. Human alpha-CGRP at a dose of 0.6 nmol -1 caused hypotension, tachycardia and reductions in renal and superior mesenteric blood flows, together with a marked (+31% maximum) hindquarters hyperaemia. Nimodipine at a dose of 600 nmol h-1 caused hypotension, tachycardia and a reduction (-34%) in renal blood flow; mesenteric blood flow was unchanged and there was an increase in hindquarters flow (+ 59%). 7. Concurrent administration of human alpha-CGRP (0.6 nmol h 1) and nimodipine (600 nmol h') did not have an additive hypotensive effect or an enhanced hindquarters hyperaemic effect, but was associated with a marked impairment of renal blood flow (-48%). 8. The present results indicate that concurrent administration of low doses of human alpha-CGRP and nimodipine might be particularly helpful in the acute treatment of patients with cerebral vasospasm and impaired renal perfusion, since this intervention improved internal carotid blood flow without compromising blood flow to the kidney.

The effects of infusions of arginine vasopressin or 1-deamino-8-D-arginine vasopressin on common carotid vascular resistance in conscious, Long Evans rats.

1. Intravenous infusions of arginine vasopressin or 1-deamino-8-D-arginine vasopressin (DDAVP) were given to conscious, Long Evans rats chronically instrumented with bilateral, common carotid, pulsed Doppler probes and intravascular catheters. 2. During infusion of vasopressin at 0.3 nmol min-1 there was an increase in common carotid vascular resistance with no change in mean blood pressure or heart rate. Following infusion there was a common carotid vasodilatation. 3. During infusion of vasopressin at 3.0 nmol min-1 there were increases in mean arterial blood pressure and in common carotid vascular resistances, accompanied by bilateral reductions in flow and in heart rate. Administration of (+)-(CH2)5Tyr(Et)DAVP (a V1-receptor antagonist), during the continued infusion of vasopressin, reversed the effects of the latter on mean blood pressure and heart rate; under these conditions there were increases in common carotid blood flows above baseline, in company with bilateral vasodilatations. The latter effects persisted after cessation of vasopressin infusion. 4. Infusions of DDAVP were without significant effects on any measured cardiovascular variable. 5. The results do not provide straightforward support for the claim that vasopressin acts to promote cerebral perfusion, at least when V1-receptor effects are unopposed. Furthermore, it seems likely tha the vasodilator influence of vasopressin on the common carotid vascular bed is not due to stimulation of V2-receptors.

Regional hemodynamic effects of calcitonin gene-related peptide

Cardiovascular responses to infusions of rat alpha-calcitonin gene-related peptide (CGRP; 0.06, 0.6, 6.0 nmol/h) or rat alpha-atrial natriuretic peptide (ANP; 3.7 nmol/h) were measured in conscious rats. During infusion of the low dose of CGRP, when mean arterial pressure (MAP) was little affected, there were reductions in common carotid, renal, mesenteric, and hindquarter vascular resistances (the magnitude of the responses in the same descending order). However, only flow in the common carotid vessels was increased above base line. After infusion, there was a hindquarter vasoconstriction. During infusion of the higher doses of CGRP, there were dose-related decreases in MAP and increases in heart rate associated with (hyperemic) hindquarter vasodilatations and mesenteric vasoconstrictions. The common carotid vasodilatation peaked with the intermediate dose of CGRP; the changes in renal vascular resistance were not dose related. After infusion of the high dose of CGRP there were persistent (at least 60 min) common carotid and hindquarter vasodilatations and mesenteric vasoconstriction, with a transient overshoot in renal vascular resistance. Infusions of CGRP and ANP matched for their effects on MAP had similar influences on mesenteric hemodynamics, but all other variables were affected differently.

Regional hemodynamic effects of slow-release nicardipine in elderly patients with hypertension: Evaluation by a new ultrasound technique

Blood flow in superficial vessels was measured by means of combined two-dimensional and continuous-wave Doopler echography. In vitro validation of the technique showed precision to within 10% at flow rates greater than 300 ml/min. Assessment of common carotid artery blood flow was used to calculate vascular resistance in a single-blind, crossover study of 16 elderly patients over the age of 60 years (mean 67.7 ± 6.5) with essential hypertension. The pulsatility index of the brachial artery was also determined. Before the study patients had previously received either placebo (twice a day) for 2 weeks or slow-release (SR) nicardipine (40 mg twice a day) for 2 months. During the study patients received a single 40 mg dose of nicardipine SR, after which mean arterial blood pressure decreased from 131 ± 11 to 110 ± 10 mm Hg ( p < 0.001) and from 122 ± 13 to 108 ± 11 mm Hg ( p < 0.001) in patients who had previously received placebo and nicardipine, respectively. Carotid vascular resistance decreased from 14.6 ± 2.9 to 10.4 ± 2.8 mm Hg·sec·ml −1 ( p < 0.001) and from 14.6 ± 4.1 to 11.0 ± 2.0 mm Hg · sec · ml −1 ( p < 0.01), respectively. The pulsatility index of the brachial artery changed from 9.4 ± 4.4 to 9.7 ± 8.3 and from 8.2 ± 4.3 to 9.4 ± 4.1, respectively (not significant). These data show that nicardipine SR reduces resistance both in the common carotid artery and in the brachial artery. Furthermore this drug appears to have an additional effect on the distensibility of the large arteries.

Effect of stimulation of nucleus raphe dorsalis on carotid blood flow. II. The cat.

The dorsal raphe nucleus (DRN) and surrounding midbrain of 74 cats were stimulated both electrically and chemically, and carotid flows were measured with electromagnetic flow probes. Stimulation of the DRN caused a frequency-dependent decrease in common carotid vascular resistance, which was abolished by bilateral section of the facial nerve intracranially. Injection of DL-homocysteic acid into the DRN reproduced the effect of electrical stimulation, indicating that the responses arose from excitation of cell bodies within the DRN, not from fibers of passage. The responses were mediated entirely within the brain stem since they remained intact after high spinal cord section. The vasodilator response was blocked by the intravenous administration of the nicotinic ganglion blocker hexamethonium but not by the alpha-adrenoceptor blocker phentolamine. The responses were unaffected by intravenous administration of methysergide but were markedly reduced after depletion of central serotonin by pretreatment with the serotonin depletor, p-chlorophenylalanine. A poststimulus constrictor response was mediated by release of catecholamines from the adrenal medulla and was blocked by the alpha-adrenoceptor antagonist phentolamine. No response involved supracollicular mechanisms since they persisted after decerebration.

Effect of stimulation of nucleus raphe dorsalis on carotid blood flow. I. The monkey.

The dorsal raphe nucleus (DRN) and surrounding midbrain of 16 anaesthetized monkeys were stimulated electrically, and carotid blood flows were measured with electromagnetic flow probes. Stimulation of the DRN caused a frequency-dependent decrease (vasodilatation) in both internal and external carotid vascular resistance, which was abolished in both circulations by bilateral section of the facial nerve intracranially. These vasodilator responses were unaltered by intravenous administration of muscarinic cholinergic or by alpha- or beta-adrenoceptor antagonists. A postdilatation constrictor response, observed in the external carotid circulation, was blocked by the alpha-adrenoceptor antagonist phentolamine. It is concluded that projections of the DRN through the greater superficial petrosal branch of the facial nerve mediate vasodilatation in both internal and external carotid circulations.

Common carotid haemodynamic and metabolic effects of acutely administered nifedipine in human subarachnoid haemorrhage.

Although the drugs known as "calcium antagonists" exert inhibitory actions on vascular smooth muscle, there are no quantitative data concerning the clinical use of these vasodilator agents in human subarachnoid haemorrhage. In the present clinical study, we have measured the effects of nifedipine (20 mg tablet) on common carotid artery diameter (D) blood flow velocity (V) common carotid blood flow (CCBF) as an index of cerebral blood flow, systolic (Qs) and diastolic (Qd) blood flow fractions using a pulsed Doppler apparatus and on carotid arterial pressure (CAP), heart rate (HR) and oxygen consumption (VO2). Eight patients with subarachnoid haemorrhage were studied during anaesthesia for cerebral angiography. Thirty minutes after sublingual nifedipine, diameter (P less than 0.05), blood flow velocity (P less than 0.001), CCBF (P less than 0.001), Qs (P less than 0.05), and Qd (P less than 0.05) increased with a decrease in Qs/Qd ratio (P less than 0.05). carotid vascular resistance (CVR) fell (P less than 0.02) and oxygen consumption of the brain increased (P less than 0.01). Systolic, diastolic, and mean carotid blood pressure, heart rate, and arteriovenous difference in oxygen were unchanged. The increase in CCBF was closely correlated with the vascular resistance in the control state (r = 0.928, P less than 0.001) and with oxygen consumption (r = 0.869, P less than 0.001). We conclude that in vivo, nifedipine exerts a preferential action on cerebral vessels, vasodilating large arteries and arterioles. This action is more powerful if the vessels are already vasoconstricted. Thus, the use of nifedipine could be fruitful in cerebral ischaemia that is secondary to subarachnoid haemorrhage.

Decreased carotid arterial resistance in cats in response to trigeminal stimulation.

Stimulation of the trigeminal nerve or ganglion in the cat caused a frequency-dependent reduction in carotid vascular resistance. Systemic arterial blood pressure (SABP) decreased at low frequencies (0.2 to 5 sec-1) and increased at higher frequencies, thus increasing carotid blood flow at the higher frequencies. The effect on resistance was predominantly ipsilateral and was unaltered by cervical sympathectomy, but was abolished or substantially reduced by section of the trigeminal root proximal to the ganglion. Diminution of carotid vascular resistance was replicated by stimulation of the greater superficial petrosal (GSP) nerve without any change in SABP. Section of the seventh cranial nerve reduced or abolished the response to stimulation of the trigeminal nerve but not that from the GSP nerve. The trigeminal response was prevented by ganglion-blocking drugs in seven out of eight cats. The resistance response was unaffected by noradrenergic, cholinergic, serotonergic, and histamine-2 blocking agents. No neural connection could be demonstrated between the GSP and the trigeminal ganglion, and the vascular response to GSP stimulation persisted after trigeminal section. It is concluded that activation of the trigeminal system increases carotid blood flow by a pathway involving the seventh cranial nerve, the GSP and Vidian nerves, and a parasympathetic synapse employing an unconventional transmitter. A varying proportion of the response (greatest in the third division) may be mediated by antidromic activation of trigeminal nerves. These findings may have clinical implications for the vascular changes of migraine and other facial pain.

Effects of locus coeruleus stimulation on carotid vascular resistance in the cat

The locus coeruleus was stimulated in 62 cats in order to investigate the effect on cephalic blood flow and cephalic vascular resistance. Flow was measured by electromagnetic flow probes applied to the common carotid artery. Stimulation over a range of frequencies (0.2-200 s-1) produced a frequency-dependent fall in carotid vascular resistance, greater on the ipsilateral side. This response was not affected by either cervical sympathectomy or spinal cord section. The response was blocked by bilateral section of the facial nerve but was not abolished by classical cholinergic, histaminergic or adrenergic blocking agents. Stimulation of the locus coeruleus also resulted in a pressor response through spinal mechanisms in which coeruleo-hypothalamic projections were not involved. A post-stimulation constriction in the carotid vasculature followed the dilator response and was attributed to release of catecholamines from the adrenal medulla.

Differential effects on the internal and external carotid circulation of the monkey evoked by locus coeruleus stimulation

Electrical stimulation at 1–200/s of the locus coeruleus in 12 Macaca nemestrina monkeys caused a frequency-dependent drop in vascular resistance in the extracerebral circulation which was twice as great on the side stimulated. Accompanying this dilatation of the extracerebral vasculature was a frequency-dependent rise in internal carotid vascular resistance, usually seen only on the side ipsilateral to stimulation. This constrictor response was maximal at low frequencies of stimulation and minimal at higher frequencies. Neither the dilator nor constrictor responses were affected by sectioning of the vagus nerve or sympathetic trunk in the neck. The simultaneous occurrence of intracranial vasoconstriction and extra cranial vasodilatation has not been demonstrated previously, and bears a remarkable resemblance to the vascular changes of migraine.

Effects of histamine H1- and H2-receptor antagonists in the cranial circulation of the monkey.

SUMMARY1. The effects of the histamine H2‐receptor antagonists, metiamide and cimetidine, and the Hi‐receptor antagonist, mepyramine, on cranial vasodilator and systemic vasodepressor responses to histamine have been investigated in anaesthetized monkeys.2. In monkeys treated with successively increasing intravenous doses of 0.25, 1 and 5 mg/kg of metiamide, histamine‐induced decreases in external and internal carotid vascular resistances were blocked, but systemic vasodepressor responses were not affected.3. In monkeys treated similarly with 0.25, 1 and 5 mg/kg of cimetidine, external carotid vascular responses to histamine were blocked, but internal carotid vascular and systemic vasodepressor responses to histamine were not affected.4. In monkeys treated similarly with 0.5, 2 and 10 mg/kg of mepyramine, histamine‐induced systemic vasodepressor responses were blocked, but responses in the external and internal carotid circulations were unaffected.5. In those monkeys treated with mepyramine after initial H2‐receptor antagonist treatment, blockade of internal, but not external, carotid vascular responses to histamine appeared to be increased.6. The histamine antagonists did not affect cranial vascular responses to noradrenaline, serotonin, prostaglandin E1 or bradykinin. Metiamide and cimetidine had no appreciable direct effects, but mepyramine produced short‐lasting changes (vasodilatation followed by vasoconstriction).7. These results indicate that H2‐receptors are involved in the external and internal carotid vascular effects of histamine. Hi‐Receptors do not appear to contribute to the external carotid vasodilator response to histamine, but their possible involvement in the internal carotid response cannot be excluded.

Effects of low doses of clonidine in the monkey cranial circulation

Migrane therapy using low doses of clonidine has been based on the proposal that clonidine directly inhibits vascular smooth muscle reactivity. In anaesthetized monkeys in which internal and external carotid vascular resistances were measured, the only significant effects of clonidine administered acutely (0.5 and 2 μg · kg −1 i.v.) or chronically (2 μg · kg −1 i.m. daily for 7 days) on cranial vascular responses to the constrictions noradrenaline and 5-hydroxytryptamine, and the dilators histamine, prostaglandin E 1 and bradykinin, were small potentiations of some of the responses. Acute clonidine initially increased blood pressure and constricted the cranial vasculature, then induced hypotension without involvement of the cranial circulation. It also decrease the external carotid vasoconstrictor response to low frequency cervical sympathetic nerve stimulation. The low chronic dose of clonidine had no hypotensive effect. The pressor response to common carotid occlusion was inhibited by both acute and chronic clonidine. These experiments thus provide no evidence that clonidine inhibits vascular reactivity at doses equivalent to those used in migraine.

RELATIONSHIP BETWEEN CEREBRAL BLOOD FLOW CHANGES AND CORTICAL EXTRACELLULAR FLUID pH DURING CEREBRAL METABOLIC DEPRESSION INDUCED BY ALTHESIN

Baboons anaesthetized with halothane and nitrous oxide in oxygen were given Althesin 0.05 ml kg-1 i.v. Cerebral blood flow (c.b.f.) was measured by an electromagnetic flowmeter and by xenon clearance whilst extracellular fluid (e.c.f.) pH of the parietal cortex was measured with a micro pH electrode. Carotid blood flow (carBF) began to decrease and carotid vascular resistance (carVR) to increase 2.0 s (SEM 0.3) after the slowing of the e.e.g. produced by Althesin, while e.c.f. pH began to change to alkaline 10.5 s (SEM 1.0) after the e.e.g. change. The first statistically significant increase in mean e.c.f. pH occurred 25 s after the Althesin-induced change in the e.e.g. The duration of the changes in carVR and e.c.f. pH were 7 and 5 min respectively. It is concluded that the change in e.c.f. pH cannot have initiated the increase in carVR which followed the cerebral matabolic depression produced by Althesin. The later alkaline shift in e.c.f. pH may, however, have maintained the increased carVR during the duration of cerebral metabolic depression produced by Althesin.

Effects of methyserrgide, pizotifen and ergotamine in the monkey cranial circulation

Internal and external carotid vascular resistances were measured, in anaesthetized monkeys, to assess the direct cranial vascular effects of i.v. methysergide, pizotifen and ergotamine, and their effects on the cranial vascular responses to the constrictors 5-hydroxytryptamine and noradrenaline and the dilator histamine, prostaglandin E 1 and bradykinin. Methysergide reduced responses to 5-HT, and tended to potentiate the external carotid responses to noradrenaline. Pizotifen blocked responses to histamine; it tended to reduce internal carotid responses to 5-HT, but it potentiated external carotid 5-HT responses. Ergotamine reduced responses to 5-HT and noradrenaline, but this was probably related to its cranial vasoconstrictor effects, especially in the external carotid circulation. Methysergide induced weak transient cranial vasoconstriction and pizotifen had no direct effects. These findings may be relevant to the therapeutic actions of these drugs in migraine, since the doses used approximated to those used clinically.

Time course of the cerebral circulatory response to metabolic depression.

Baboons anesthetized with halothane and N2O/O2 were given an intravenous steroid anesthetic (Althesin; Glaxo Laboratories Ltd., U.K.). The drug bolus was labeled with 99mTc, and the time from central venous injection to peak radioactivity in the brain was designated drug brain arrival (DBA-peak). The electroencephalogram slowed 1.2 +/- 0.9 s after DBA-peak (P greater than 0.2), and approximately 2 s after DBA-peak, internal carotid blood flow (ICarBF) decreased and calculated internal carotid vascular resistance (ICarVR) rose. During this 2-s delay in the cerebrovascular response to the arrival of a cerebral metabolic depressant in the brain, the decrease in mean cortical Pco2 was calculated to be less than 0.26 mmHg from cortical CO2 solubility, and less than 0.32 mmHg from cortical CO2 diffusivity, which indicated that mean cortical Pco2 changes do not control cerebral blood flow (CBF). The unaltered time course of the changes in EEG, ICarBF, and ICarVR after acute cervical sympathectomy and alpha-adrenergic receptor blockade excluded the involvement of the sympathetic nervous system in the vasoconstrictor response. Intracarotid Althesin showed that the cerebral vasoconstriction was not a direct effect of the drug. The postulated link between the effects of Althesin on CBF and cerebral metabolism remains to be elucidated but is probably indirect, involving the brainstem.

Regional vascular resistance and heart rate responses mediated through H 1- and H 2-histamine receptors in the unanaesthetised rabbit

The effects of histamine infusions (10—100 μg/kg/min) on heart rate and hindlimb, carotid, mesenteric and renal vascular resistance were investigated in unanaesthetised rabbits after “total” autonomic effector block to abolish reflex effects. Histamine caused a rise in heart rate that was predominately due to stimulation of H 2-receptors (blocked by metiamide). Hindlimb and carotid vascular resistance did not change significantly during histamine infusion. However, after blocking H 2-receptors with metiamide histamine infusions produced dose-related vasoconstriction in these beds while after H 1-receptor block with mepyramine histamine caused dose-related vasodilatation indicating that H 1- and H 2-receptors mediated opposite vascular effects which were of similar magnitude. By contrast, histamine infusion caused vasodilatation in both the mesenteric and renal vasculature before giving antagonists. This dilatation was mediated by both H 1- and H 2-receptors as either receptor antagonist attenuated the response. These studies suggest that H 1-receptors in the same species mediate vasoconstriction in some beds and vasodilatation in others while H 2-receptors mediate vasodilatation in all the beds studied and also account for most of the increase in heart rate.