Evaluation of the regional cerebral vasodilatory capacity before carotid endarterectomy by the acetazolamide test

To estimate the regional perfusion pressure and possibly the stump pressure during carotid endarterectomy, cerebral blood flow (CBF) measurements including a vasodilatory test were performed preoperatively. CBF was measured by ¹³³Xe inhalation and emission tomography. An intravenous dose of 1g acetazolamide (Diamox) was used as cerebral vasodilator. Thirty-six patients with a clinical history of previous strokes (9 cases) or transient ischaemic attacks (27 cases) were studied. Nine of the patients showed occlusion of the contralateral internal carotid artery (ICA). The percent flow increase induced by Diamox in the ipsilateral hemisphere correlated to the ICA pressure was measured before clamping (n = 32, r = 0.55, p < 0.001). In 12 of the 36 patients, Diamox caused a significant change in the flow distribution indicating a restricted regional vasodilatory capacity and a reduced regional perfusion pressure. In addition, these 12 patients showed a low stump pressure (<50 mmHg). However, 8 additional patients had uniform CBF increases at the Diamox test, but showed low stump pressures. It is concluded, that preoperative tests of the cerebral vasodilational capacity can be used to identify most patients with a low ICA pressure, and a substantial fraction of patients that will develop a low stump pressure upon ICA clamping during operation. In these patients with abnormal Diamox tests surgical reconstruction is particularly indicated, but, at the same time the perioperative risks are presumably highest in this group.     

Blood-brain barrier dysfunction after amphetamine administration in rats

Summary Amphetamine administration to rats anaesthetized with nitrous oxide resulted in protein extravasation in the brain, particularly in the frontoparietal cortex. The drug is known to increase the cerebral blood flow in the same areas, indicating a vasodilatory action on the cerebral vessels. Protein leakage could be prevented by lowering the blood pressure and, to a large extent, also by hyperventilation. This suggests that the permeability disturbance is caused by the mechanical stress which results from high intraluminal pressure in combination with vasodilatation.The pharmacological effect of amphetamine is caused by a catecholamine release in the central nervous system and in the periphery. The vasodilatory effect of amphetamine could be either a direct effect on the cerebral vessels or could be secondary to an increased cerebral metabolism. The vasodilatory betaadrenergic receptors in the cerebral vessels are of beta₁ type. Practolol, a selective beta₁-receptor antagonist which can prevent the vasodilatory effect of isoprenaline on cerebral vessels, did not influence the amphetamine induced protein leakage. In contrast, propranolol, a non-selective beta-receptor blocking drug which earlier has been shown to prevent catecholamine induced increase of CBF and oxygen consumption, diminished or prevented the protein leakage. It is likely that the cerebral vasodilatation caused by amphetamine, at least in part, is secondary to an increased cerebral metabolism induced by a catecholamine release.     

Effect of flunarizine on cerebral blood flow in baboons with or without focal cerebral ischaemia

In baboons with or without regional cerebral ischaemia (achieved by transorbital clip of the middle cerebral artery), cerebral blood flow (CBF) was measured using the intra-arterial Xenon-133 technique during steady-state, slight hypotension, and hypocapnia before and after administration of various doses of the calcium antagonist flunarizine (0.5 mg kg^–1, 1.0 mg kg^–1, or 10 μg kg^–1 min^–1 over 30 min). In normal baboons flunarizine did not alter CBF significantly, but at reduced blood pressure it increased CBF by 19.9% owing to exaggerated vasodilatory autoregulation. During hypocapnia flunarizine impaired the physiological reduction in CBF owing to reduced vasoconstriction. In baboons with cerebral ischaemia, CBF measurements were stable and comparable with those in a control group using an arterial clip unless flunarizine was added. In a group of five flunarizine-treated animals, mean CBF after positioning of the clip was higher than in the control group. However, the increase in mean CBF varied significantly between animals, indicating that a secondary reduction in CBF due to postischaemic pathophysiological processes was not prevented consistently.     

FOS induction in brain associated with seizure and sustained cortical vasodilation in anesthetized rat.

PURPOSE: By estimating the anatomical distribution of neurons expressing c-fos protein, we sought to establish whether the intrinsic neural systems known to be implicated in the cerebrovascular regulation were activated during the increase in cortical blood flow associated with epileptic seizures. METHODS: A single unilateral microinjection of the cholinergic agonist, carbachol, in the thalamic generalized convulsive seizure area was used in anesthetized rats to elicit recurrent episodes of electrocortical epileptiform activity and an increase in cortical blood flow. Neuronal expression of Fos protein was analyzed to identify activated brain regions. RESULTS: We identified two cortical vasodilatory responses: a sustained cortical vasodilatory response associated with the continuous low-frequency, high-amplitude spiking and a transient cortical vasodilatory response invariably related to the recurrent spike-burst activity. The sustained cortical blood flow began to increase at 55-65 min, remaining significantly (p < 0.05) increased and reaching at the end of the experiment < or =182+/-17% of the prestimulated control. The electrocortical epileptic activity and the cerebral cortical vasodilation were associated with a marked increase in Fos immunoreactivity in the entorhinal and piriform cortices, the dentate gyrus, the hippocampus, and the amygdala. Fos-positive neurons also were found in specific thalamic nuclei, the cerebral cortex, the caudate-putamen, the hypothalamus, the pontine parabrachial nuclei, the dorsal raphe, and the rostral ventrolateral medulla. CONCLUSIONS: These results provide evidence that convulsive seizures elicited by cholinergic stimulation of the thalamus, in addition to limbic and somatic motor systems, activate central autonomic nuclei and their pathways, including those implicated in cerebrovascular regulation.     

Sympathetic nerve activity restrains reflex vasodilatation in heart failure

Background Blunted reflex muscle vasodilatory response during exercise in heart failure (HF) patients may be secondary to augmented vasoconstriction. We tested the hypothesis that the exaggerated sympathetic nerve activity restrains the reflex muscle vasodilatation during exercise in HF patients. Methods We studied the reflex vasodilatory response (plethysmography) during 3 min static handgrip exercise at 30% maximal voluntary contraction in 10 advanced HF patients (45 ± 3year, NYHA Functional Class III/IV) and 10 age-matched normal controls (NC, 40 ± 3year, P = 0.23) during intra-arterial infusion of: (1) saline control; and (2) alpha-adrenergic blocker (phentolamine). Results Baseline forearm vascular conductance (FVC) was lower in HF patients than in NC (2.07 ± 0.2 vs. 4.26 ± 0.6 units, respectively; P = 0.002). FVC responses during exercise increased significantly in NC, but not in HF patients (delta changes: 1.05 ± 0.4 vs. 0.05 ± 0.2 units, respectively). Phentolamine significantly increased resting FVC in HF patients (from 2.07 ± 0.2 to 5.74 ± 0.7 units, P = 0.00004) and restored reflex vasodilatory responses during exercise (delta changes: from 0.05 ± 0.2 to 1.82 ± 0.9 units) eliminating the difference in FVC between both groups. Conclusions The blunted reflex muscle vasodilatory response during exercise in advanced HF patients is, at least in part, due to the increase in sympathetic nerve activity.     

Peroxynitrite reduces vasodilatory responses to reduced intravascular pressure, calcitonin gene-related peptide, and cromakalim in isolated middle cerebral arteries.

Vasodilatory responses to progressive reductions in intravascular pressure or to calcitonin gene-related peptide (CGRP) or cromakalim were determined in rodent middle cerebral arteries (MCAs) before and after treatment with peroxynitrite (ONOO-). Middle cerebral artery diameters in isolated, pressurized MCAs were measured as intravascular pressure was reduced from 100 to 20 mm Hg in 20-mm Hg increments before and after inactive ONOO-, pH-adjusted ONOO-, or 10, 20, or 40 micromol/L ONOO- was added to the bath. In other MCAs, responses to CGRP (1 x 10-9 - 5 x 10-8) or cromakalim (3 x 10-8 - 8 x 10-7) were measured before and after the addition of 25 micromol/L ONOO-. Inactive ONOO- (n = 6, P = 0.40), pH-adjusted ONOO- (n = 6, P = 0.29), and 10 micromol/L ONOO- (n = 6, P = 0.88) did not reduce vasodilatory responses to reduced intravascular pressure. Middle cerebral arteries treated with 20 (n = 6, P < 0.0001) and 40 (n = 6, P > 0.0001) micromol/L ONOO- constricted significantly when intravascular pressure was reduced. Vasodilatory responses to CGRP or cromakalim were reduced by ONOO- (P > 0.02, n = 6 and P > 0.01, n = 7, respectively). ONOO- had no effect on vasoconstriction in response to serotonin or vasodilation in response to KCl. These studies demonstrate that ONOO- reduces multiple cerebral vasodilatory responses.     

Stimulation of the rat mesolimbic dopaminergic system produces a pressor response which is mediated by dopamine D-1 and D-2 receptor activation and the release of vasopressin

Treatment with dopamine receptor agonists has been shown to induce centrally mediated effects on cardiovascular regulation. We have investigated the effect on blood pressure and heart rate of stimulating the release of endogenous dopamine in the brain from the mesolimbic/mesocortical (A10) dopaminergic system of conscious Sprague-Dawley rats. Stimulation of the region of origin of the A10 dopaminergic system, the ventral tegmental area (VTA), with local micro-injection of the substance P analogue DiMe-C7, produced a dose-dependent increase in blood pressure and heart rate. The injection of 10 nmol of DiMe-C7 produced a maximum increase in blood pressure of 15–20 mmHg at 10 min following administration and a maximum tachycardia of 70–80 B/min. Intravenous pretreatment with the dopamine D-1 receptor antagonist SCH 23390 (0.1 mg/kg) or the dopamine D-2 receptor antagonist raclopride (0.5 mg/kg) markedly inhibited the pressor response and revealed a bradycardia. Furthermore, the pressor response and tachycardia were completely blocked by pretreatment with the vasopressin V-1 receptor antagonist, Pmp¹,O-Me-Tyr²-[Arg⁸]vasopressin (10 μg/kg). Pretreatment with the ganglion blocker, pentolinium (10 mg/kg), had little effect on the blood pressure response, however it attenuated the tachycardia. Micro-injection of 10 nmol of DiMe-C7 into a region 2 mm dorsal to the VTA had little effect on blood pressure yet produced a marked bradycardia. The administration of DiMe-C7 into the region of origin of the nigrostriatal A9 dopaminergic system, the substantia nigra, produced a slight but significant increase in blood pressure with little effect on heart rate. Intracerebroventricular administration of DiMe-C7 also produced a pressor response with a more pronounced tachycardia. The blood pressure responses produced by intranigral or i.c.v. injection of DiMe-C7 were not inhibited by pretreating the rats with raclopride. These results suggest an involvement of the mesolimbic A10 dopaminergic system in the regulation of blood pressure and heart rate through the activation of dopamine D-1 and D-2 receptors and vasopressin release.     

An animal model of nicotinic-acid-induced vasodilation: effect of haloperidol, caffeine and nicotine upon nicotinic acid response

Background: The normal vasodilatory response to ingestion of nicotinic acid (NA) is impaired in some patients with schizophrenia. It is unclear whether the impairment is a feature of the disorder itself or to a confounding factor such as neuroleptics, caffeine or nicotine use. Methods: To address this question in a controlled manner, we have developed an animal (rat) model of NA-induced vasodilation, in which response is monitored by measuring change in skin temperature. Results: We observed that (i) acute administration of acetylsalicylic acid (100 mg/kg), caffeine (2.5 mg/kg) and haloperidol (0.1 or 0.5 mg/kg) and (ii) chronic administration of haloperidol (0.2 mg/kg/day) significantly inhibited NA (30 mg/kg) response, whereas neither acute (0.25 mg/kg) or chronic (0.5 mg/kg/day for 14 days) administration of nicotine, or chronic administration of caffeine (5 mg/kg/day for 14 days) had any significant effect upon NA response. Conclusions: Our data suggest that at least one drug commonly used to treat schizophrenia (haloperidol) can interfere with the vasodilatory response to NA. Studies using non-medicated patients with schizophrenia are required to determine whether reduced vasodilatory response to NA in schizophrenia is a feature of the disorder or a consequence of treatment.     

Neurokinin-1 receptors and spinal cord control of blood pressure in spontaneously hypertensive rats

In this study we examined blood pressure and heart rate responses to intrathecal administration of a synthetic NK1-receptor agonist, H₂N–(CH₂)₄–CO–Phe–Phe–Pro–NmeLeu–Met–NH2 (GR 73,632), in spontaneously hypertensive rats (SHR) and their progenitor strain, the Wistar–Kyoto rat (WKY). Sodium pentobarbitone anaesthetised rats with implanted intrathecal catheters were paralysed (pancuronium dibromide) and artificially ventilated. Injection of GR 73,632 at the T9 spinal level evoked dose-dependent increases in mean arterial pressure (MAP) in WKY and SHR. SHR had a lower MAP response threshold than WKY but increase in response with increasing dose was less in SHR than WKY. Biphasic blood pressure responses at high doses were observed in both strains. Prior administration of the NK1-receptor antagonist (3aR,7aR)-7,7-diphenyl-2-[1-imino-2(methoxyphenyl)ethyl] perhydroisoindol-4-one (RP 67,580) significantly reduced the pressor response in WKY but not SHR. The depressor response was not attenuated in either strain.     

GABA receptors in bovine cerebral blood vessels: Binding studies with [3H]muscimol

[³H]Muscimol, a potent GABA agonist used to label GABA receptor sites in brain and invertebrate striated muscle, was found to bind specifically to sites in a crude membrane fraction prepared from bovine cerebral blood vessels. Specific [³H]muscimol binding was saturable of high affinity (K_d = 41 nM), and was selectively inhibited by GABA, specific GABA agonists, and the antagonist bicuculline with potencies similar to what has been found for GABA receptors in mammalian brain. GABA and several GABA agonists including muscimol have been reported to dilate isolated cerebral arteries, but not peripheral blood vessels. The pharmacology of the [³H]muscimol binding site correlated well with that of the vasodilatory response. No significant specific [³H]muscimol binding was detected in aorta and mesenteric arteries. The characteristics of the cerebrovascular muscimol binding site thus are indicative of a physiologically relevant GABA receptor associated with cerebral blood vessels. These findings suggest a direct role for GABA in cerebral vascular function.     

GABA receptors in bovine cerebral blood vessels: Binding studies with [H]muscimol

[³H]Muscimol, a potent GABA agonist used to label GABA receptor sites in brain and invertebrate striated muscle, was found to bind specifically to sites in a crude membrane fraction prepared from bovine cerebral blood vessels. Specific [³H]muscimol binding was saturable of high affinity (K_d = 41 nM), and was selectively inhibited by GABA, specific GABA agonists, and the antagonist bicuculline with potencies similar to what has been found for GABA receptors in mammalian brain. GABA and several GABA agonists including muscimol have been reported to dilate isolated cerebral arteries, but not peripheral blood vessels. The pharmacology of the [³H]muscimol binding site correlated well with that of the vasodilatory response. No significant specific [³H]muscimol binding was detected in aorta and mesenteric arteries. The characteristics of the cerebrovascular muscimol binding site thus are indicative of a physiologically relevant GABA receptor associated with cerebral blood vessels. These findings suggest a direct role for GABA in cerebral vascular function.     

BLOOD-BRAIN BARRIER DYSFUNCTION IN ACUTE ARTERIAL HYPERTENSION AFTER PAPAVERINE-INDUCED VASODILATATION

Vasodilatation induced by papaverine increased the vulnerability of cerebral vessels to acute hypertension as demonstrated by more extensive extravasation of Evans blue albumin and macroscopic or microscopical haemorrhages. As the tension in the vessel wall is the product of pressure and internal radius, divided by the thickness of the vessel wall, dilated precapillary resistance vessels would be exposed to higher tension than non-dilated. Also the strain on capillaries and venules would increase because a higher pressure will be propagated to these small vessels. The results support our earlier proposal that the increased cerebrovascular permeability seen in severe acute hypertension is due to a vessel wall damage caused by rapid distension. Regional cerebral blood flow studied with ¹²⁵I-antipyrine indicates that the flow is higher in areas with blood-brain barrier dysfunction, further contradicting the ischaemic theory on permeability changes in hypertension.     

Influence of a central cholinergic mode of action on the regulation of the intact and disturbed cerebral blood flow (author's transl)]

Cerebral chemical vasomotor reactivity and autoregulation were tested in normal baboons before and after intravertebral, intravenous and (or) intracarotid infusion of atropine and neostigmine. Furthermore, disordered cholinergic neurotransmission and dysautoregulation after acute experimental cerebral infarction have also been investigated. Intravertebral injection of atropine suppressed the increase of CBF by inhalation of 5% CO2 and enhanced the decrease of CBF induced by hyperventilation, but did not appreciably affect autoregulatory response. On the other hand, cerebral autoregulatory vasoconstriction during increases of CPP was significantly reduced following both intravertebral and intracarotid neostigmine infusion. Cerebral vasodilatory reactivity to CO2 inhalation was significantly enhanced only following intravertebral neostigmine and cerebral vasoconstrictive response to hyperventilation was not influenced by neostigmine. Following experimental cerebral infarction regional dysautoregulation was found in infarcted gray matter and correlated significantly with increased AChE levels in the same zones of cortex and basal ganglia. Intravenous infusion of scopolamine restored autoregulation to the ischemic zones. The results thus obtained support the view that central cholinergic cerebrovascular influences exist and are vasodilatory in nature. Furthermore, in acute experimental cerebral infarction disordered cholinergic neurotransmission seems to play a role in vasoconstrictive dysautoregulation.     

Estimation of cerebrovascular reactivity using transcranial Doppler, including the use of breath-holding as the vasodilatory stimulus.

BACKGROUND AND PURPOSE: A proportion of individuals with carotid artery stenosis show a reduced cerebrovascular reserve as measured by a reduced cerebral arterial vasodilatory response to carbon dioxide. Two methods of quantifying this vasodilatory response, using transcranial Doppler ultrasonography, have been in general use: the total range of vasodilation between hypocapnia, induced by hyperventilation, and hypercapnia induced by breathing carbon dioxide, and the response to breathing a fixed concentration of 5% carbon dioxide. We studied whether it is possible to use the rise in carbon dioxide occurring during breath-holding as the vasodilatory stimulus. METHODS: Using transcranial Doppler, cerebral reactivity to carbon dioxide was measured in 23 subjects undergoing intravenous digital subtraction angiography of their carotid arteries for symptoms of cerebrovascular disease. A breath-holding method was compared with the two previous methods, which required administration of carbon dioxide. RESULTS: All three methods gave results that correlated highly significantly with the degree of carotid stenosis, although the correlation was highest when the full vasodilatory range was measured. This method was adopted as the gold standard, and the other methods were compared with it. The breath-holding method correlated at least as well (rho = 0.67) as the 5% CO2 method (rho = 0.64). It identified a similar group of low reactors to our gold standard method, whereas the 5% CO2 method gave some discrepant results. CONCLUSIONS: The breath-holding method offers potential as a convenient, well-tolerated screening method of assessing carbon dioxide reactivity not requiring the administration of carbon dioxide, although further validation against more established methods of measuring cerebrovascular reserve is first required.     

Cardiovascular, biochemical and hormonal changes during food-induced hypotension in chronic autonomic failure

The cardiovascular, biochemical and hormonal responses to a standard test meal have been investigated in patients with chronic autonomic failure and normal subjects. In autonomic failure there was a rapid (within 15 min), substantial and prolonged fall in blood pressure after the meal. A marked fall in blood pressure also occurred after a liquid meal of similar composition and caloric content, with no change in blood pressure in age-matched subjects with normal autonomic function. In autonomic failure after the test meal the blood pressure reached its nadir (45% fall) after 60 min, and had not returned to pre-meal levels after 3 h. There were no changes in cutaneous and forearm blood flow. In the normal subjects there were no changes in blood pressure after the meal; forearm blood flow fell and cardiac output increased. In autonomic failure there were no changes in plasma noradrenaline levels, unlike the normal subjects. Plasma adrenaline levels were unchanged in both groups. There was a similar rise in levels of plasma renin activity in both groups. The haematocrit and plasma osmolality did not change in either group. Changes in plasma glucose and plasma insulin levels were similar in both groups. The responses of 3 pancreatic gut peptides, neurotensin, pancreatic polypeptide and enteroglucagon, were greater in autonomic failure. Basal levels and responses of vasoactive intestinal polypeptide, cholecystokinin-8 and somatostatin were similar in both groups. The motilin response was greater in normal subjects. We conclude that in patients with autonomic failure there was a rapid, substantial and prolonged fall in blood pressure after a meal. This reduction in blood pressure was not counteracted by an increase in sympathetic nervous activity and other compensatory changes, as occur normally. It was unlikely that osmotic effects of the meal or gut secretions resulted in a significant loss of intravascular fluid into the gut. The fall in blood pressure probably results from vasodilatation within the splanchnic circulation, to which pancreatic and gastrointestinal hormones with vasodilatory actions may contribute.     

Cerebral blood flow in experimental intracranlal mass lesions: Part I: The compression phase

We have shown that a rebound of intracranial pressure (ICP) occurring after decompression of an intracranial mass lesion is a threshold phenomenon dependent upon the cerebral perfusion pressure (CPP) during compression and the duration of the compression. In the present study regional cerebral blood flow (rCBF) was measured during balloon compression of a degree critical for the development of a postdecompression rebound. The effects were compared with those of hydrostatically raised pressure which under similar conditions rarely produces a rebound of ICP. Disproportionately marked reductions in flow occurred in the hemisphere ipsilateral to the balloon, especially in white matter and in cortex adjacent to the balloon with flow values of, respectively, 1.1 ± 0.9 and 6.4 ± 3.4 ml 100 g^–1 min^–1. The differences in flow between balloon and hydrostatic compression were found to be due to an increased cerebrovascular resistance (CVR) caused by a direct compressive effect by the balloon overriding the generalized vasodilation which occurs in response to the raised ICP. Thus the increase in CVR attributable to compression by the balloon added to the reduction in CPP caused by the diffuse increase in ICP. As a consequence flow in large regions of the brain was reduced below the thresholds for structural infarction and for ischaemic damage to the blood-brain barrier.     

Excitatory action of N-methyl- -aspartate on the rat locus coeruleus is mediated by nitric oxide: an in vivo voltammetric study

Biochemical, electrophysiological and behavioural studies have provided evidence that activation of N-methyl- -aspartate (NMDA) receptors contributes to the hyperactivity of noradrenergic neurons of the locus coeruleus (LC) in precipitated opioid withdrawal. Recently, it was demonstrated that central administration of nitric oxide (NO) synthase inhibitors suppresses this hyperactivity suggesting that NO mediates the NMDA receptor activation of LC in opioid withdrawal. Using a combination of microdialysis and in vivo voltammetry, this study examined whether local application of NMDA to the LC in opioid naive animals mimics the NO-dependent LC response seen in opioid withdrawal. In the urethane anaesthetized rat, perfusion of the LC (2 μl min⁻¹) with a solution of NMDA (5 mmol) via a microdialysis probe for 9 min resulted in a rapid and robust increase (290.1±32.2% above baseline) in the catechol oxidation current (CA·OC) recorded from the LC using differential normal pulse voltammetry (DNPV). The NMDA microdialysis also produced a large increase in the blood pressure (150.4±6.9% above baseline). An injection of the non-competitive NMDA receptor antagonist (+)MK-801 (0.5 mg kg⁻¹ i.v.), given 45 min after the start of NMDA application, rapidly returned both the CA·OC signal and the blood pressure response to baseline levels. Pretreatment of animals with intraventricular nitric oxide synthase (NOS) inhibitor, N^ω-nitro- -arginine methyl ester ( -NAME) (100 μg) significantly inhibited NOS activity in the LC, PAG-PVG and cerebellum. This dose of -NAME, administered prior to application of NMDA by microdialysis abolished the NMDA-induced rise in the CAOC recorded in the LC and the increase in systolic blood pressure. The results show that in voltammetry experiments, NMDA produces hyperactivity of LC and hypertension, responses that are dependent upon the synthesis of NO. Thus, in opioid naive rats, regional NMDA application via microdialysis mimics characteristics of the LC response that occur during the antagonist-precipitated opioid withdrawal.     

The differential effect of CB1 receptors on the discharge of afferent and efferent fibres supplying the rat jejunum

Background The cannabinoid receptor (CB₁) is expressed on GI sensory neurons and is suggested to play a role in food intake, inflammation and nociception. Expression of CB₁ in the nodose is influenced by nutritional status. Our aim was to determine the functional response of afferent and efferent fibres supplying the proximal jejunum to the CB₁ agonist docosatetraenylethanolamide (DEA) in fed and fasted animals. Methods Experiments were performed on anesthetized rats, either fed ad libitum or fasted for 24 h. Blood pressure was recorded via the carotid artery and the proximal jejunum intubated to measure intraluminal pressure. A single paravascular nerve bundle was isolated and attached to an electrode for recording either afferent or efferent impulse traffic. Key Results Docosatetraenylethanolamide (1 mg kg⁻¹, i.v.) had a depressor effect on blood pressure but surprisingly had little effect on afferent nerve activity in fed animals. In fasted animals the afferent response to DEA was augmented, however, the blood pressure effect was attenuated. In contrast, DEA caused a significant and prolonged increase in efferent firing, which was diminished in fasted animals. Bilateral cervical vagotomy had no effect on the DEA‐mediated efferent response, however, hexamethonium (10 mg kg⁻¹) abolished excitation and unmasked an inhibitory effect of DEA. Conclusions & Inferences Docosatetraenylethanolamide has only a modest effect on intestinal afferent firing but a profound effect on efferent function, which is modulated by changes in nutritional status. The persistent response after vagotomy and block by hexamethonium suggests DEA is acting centrally, although there may be an inhibitory effect at the level of the postganglionic sympathetic neuron.     

Vasodilatory actions of calcitonin gene-related peptide and nitric oxide in parenchymal microvessels of the rat hippocampus

Calcitonin gene-related peptide (CGRP) and nitric oxide (NO) are potent dilators in a variety of vascular beds. Recent evidence suggests that NO may serve as an intermediary messenger for CGRP and/or CGRP may serve as an intermediary messenger for NO in the expression of vasodilation. The present study was designed to provide an initial characterization of the responses to NO and CGRP in parenchymal microvessels and to determine whether NO and/or CGRP act as intermediaries for one another. Microvessels in the parenchyma of in vitro hippocampal slices from rat brain were examined using computer-assisted videomicroscopy. The resting diameter of the microvessels ranged from 9 to 26 μm. Treatment with the nitric oxide synthase inhibitor, N^G-nitro-l-arginine ( -NNA; 100 μM) constricted vessels to 64.2% ± 3.0% of resting luminal diameter. Sodium nitroprusside (SNP; 1 μM), a donor of NO, reversed the -NNA-induced vasoconstriction by 77.0% ± 15.0%. CGRP alone (10 nM) elicited a small but significant vasodilatory effect on resting vascular tone (2.3% ± 0.6%). In the presence of -NNA, CGRP elicited a significant dose-dependent vasodilatory response, and 10 nM CGRP elicited a sizeable response, reversing the -NNA-induced constriction by 84.3% ± 15.5%. This CGRP-induced dilation was inhibited by pretreatment with the CGRP receptor antagonist, CGRP fragment (8–37) (1 μM). In contrast, pretreatment with 1 μM CGRP fragment (8–37) did not attenuate the SNP-induced dilation in the presence of -NNA. Taken together, these findings demonstrate that CGRP and NO are potent dilators of parenchymal microvessels, and that NO provides a substantial relaxant effect on resting tone. In addition, the results indicate that CGRP is not a necessary intermediary in NO-induced dilation, and that NO is not a necessary intermediary in CGRP-induced dilation in parenchymal microvessels.     

Morphine blocks the bradycardia associated with severe hemorrhage in the anesthetized rat

Progressive hemorrhage in the absence of tissue injury produces a biphasic response: an initial tachycardia, vasoconstriction and maintenance of arterial blood pressure by the baroreflex, followed by bradycardia, vasodilatation and hypotension due to the activation of a second ‘depressor’ reflex. The present study has investigated the effect of morphine (a μ-opioid receptor agonist) on the cardiac chronotropic response to a progressive hemorrhage at 2% total estimated blood volume (BV) min⁻¹ in the anesthetized rat. In control rats (20 μl saline intracerebroventricularly, i.c.v.) heart period initially decreased significantly (P < 0.05) by a maximum of 5.4 ± 0.8 ms from a baseline of 147.3 ± 2.2 ms after a blood loss of 8.3 ± 1.5% BV, and then increased significantly by a maximum of 43.0 ± 5.5 ms above the baseline after the loss of 34.5 ± 1.6% BV. Blood pressure was initially maintained and then fell during the hemorrhage. The increase in heart period was prevented by treatment with morphine (10 μg i.c.v.), and the fall in blood pressure delayed significantly. These effects of morphine were prevented by pretreatment with naloxone (20 μg i.c.v.). Intravenous (i.v.) administration of morphine (10 μg) had no effect on the response to hemorrhage. However, a clinically relevant dose of 0.5 mg · kg⁻¹ morphine (i.v.) abolished the bradycardia and delayed the fall in blood pressure associated with hemorrhage. These results indicate that morphine, acting on central nervous opioid receptors, can abolish the bradycardia and delay the hypotension associated with progressive hemorrhage, a pattern of response reminiscent of the effects of musculo-skeletal injury on the response to blood loss.