Preventing sudden cardiac death: the impact of beta-blockers on the brain.
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Adrenergic beta-Antagonists↗
Biomedical subjects
J H Coote
Publications and source records attributed to J H Coote.
Intramedullary blood vessels of the spinal cord express V1a vasopressin receptors: visualization by a biotinylated ligand.
The neurohypophysial peptide hormone [Arg8]vasopressin (AVP) has well documented pressor effects in the periphery. These are mediated by vasopressin receptors (VPRs) of the V1a subtype, expressed by vascular smooth muscle cells, which induce vascular contraction when activated. AVP also has effects on the vasculature of the brain, where it has been reported to induce both vasodilation and vasoconstriction. The responsiveness of blood vessels of the spinal cord, however, has received little attention. To determine the morphology and distribution of blood vessels within the spinal cord, vessels were vizualised using a mouse anti-rat smooth muscle alpha actin IgG as primary antibody and fluorescein isothiocyanate-conjugated anti-mouse IgG secondary antibodies. A complementary vizualisation strategy which detected the endogenous peroxidase activity of red blood cells within vessels was also utilised. The characteristics of the structures observed using both visualisation strategies were typical of blood vessels. VPRs were localized using recently characterized high affinity biotinylated analogue of AVP (PhAcAL(Btn)VP), which is selective for the V1a subtype of VPR. PhAcAL(Btn)VP:VPR complexes were subsequently visualized by avidin-Texas red. The pharmacological characteristics of these sites were established using selective analogues of vasopressin and oxytocin. This confirmed that V1a receptors were indeed being visualized. The structures observed following visualization of VPRs had the same morphology as the vasculature revealed by the anti smooth muscle alpha-actin antibody. It can therefore be concluded that the blood vessels of the spinal cord express VPRs and are potentially responsive to AVP. Furthermore, VPRs were detected on capillaries of the microvasculature. As these capillaries are devoid of smooth muscle, VPRs must be expressed by endothelial cells as well as by smooth muscle cells. This distribution of VPRs would enable AVP to regulate local blood flow. The source of the AVP could be the general circulation, or perhaps more likely, to be local release from vasopressinergic hypothalamic neurones which are known to innervate specific regions of the spinal cord.
Animals↗
Modulation of cardiac autonomic control in humans by angiotensin II.
Angiotensin II (Ang II) exerts an inhibitory action on vagal activity in animals and may also facilitate sympathetic activity. The object of this study was to compare autonomic activity resulting from equivalent steady-state baroreflex activation during intravenous Ang II infusion with that resulting from a control infusion of phenylephrine. Eight healthy subjects aged 22 to 34 years were studied in a single-blind, randomized, prospective crossover study. Autonomic activity was determined by computer analysis of RR interval variability in the time and frequency domains. Despite equal experimental hypertension with Ang II and phenylephrine infusion, at peak infusion rates the mean RR interval was significantly shorter with Ang II (983 +/- 179 milliseconds; mean +/- SD) than with phenylephrine (1265 +/- 187 milliseconds, P < .01). The variability of RR intervals was not significantly different, but the variability (median interquartile difference) of RR interval successive differences was significantly lower with Ang II (66 milliseconds) than with phenylephrine (104 milliseconds, P < .02). Power spectral analysis revealed the power of the 0.25-Hz component in normalized units to be significantly smaller during Ang II infusion (20.5 +/- 12.7 U) than during phenylephrine (38.2 +/- 14.7 U, P < .05), whereas the power of the 0.1-Hz component was significantly greater during Ang II infusion (67.8 +/- 17.1 U) than phenylephrine (38.8 +/- 20.3 U, P < .05). Measures of vagal modulation of heart rate were significantly attenuated, and sympathetic modulation appeared to be increased during Ang II infusion compared with control phenylephrine infusions. These observations may underlie reports of increased vagal activity during angiotensin-converting enzyme inhibitor therapy.
Adult↗
Medicine and mechanisms in altitude sickness. Recommendations.
Acute mountain sickness (AMS) has long been recognised as a potentially life-threatening condition afflicting otherwise healthy normal individuals who ascend rapidly to high altitude where the partial pressure of oxygen (pO2) in the air is reduce. The symptoms of AMS (e.g. headache, poor appetite and nausea, fatigue and weakness, dizziness or light-headedness and poor sleep) are probably a consequence of disturbances in fluid balance brought about by severe tissue hypoxia. AMS can be prevented by an adequately slow ascent, which is the best method, but for those with limited time there are several drug therapies that provide a relatively good protection. Acetazolamide (250 mg twice daily or 500 mg slow release once daily), taken before and during, ascent is probably the treatment of choice; it improves gas exchange and exercise performance and reduces the symptoms of AMS in most individuals. Dexamethasone (4 mg, 4 times daily) is more of value for short term treatment or prevention, and should never be used for more than 2 to 3 days. Prophylactic use of progesterone looks promising, but more studies are required.
Acetazolamide↗
Bulbospinal catecholamine neurones and sympathetic pattern generation.
Populations of neurones containing noradrenaline, dopamine and possibly adrenaline project to the spinal cord where they innervate sympathetic preganglionic neurones (SPN). Studies are described which illustrate the actions of catecholamines on SPN and which suggest ways in which the catecholamine neurones could regulate the cardiovascular system. Experiments on rats using, intrathecal application of drugs to the spinal cord, iontophoresis, or superfusion of drugs whilst recording either postganglionic nerve activity, extracellularly or intracellularly from SPN respectively, reveal that catecholamines may excite or inhibit SPN. A slow depolarisation is mediated by alpha 1 adrenoceptors whereas alpha 2 adrenoceptors mediate a slow hyperpolarisation. Catecholamines may also excite glycinergic interneurones which elicit fast IPSPs in SPN. By regulating different ionic conductances in the membrane of SPN catecholamines are able to induce SPN to discharge tonically or to oscillate with bursts of action potentials. Furthermore these actions may be modified in the presence of an excitatory amino acid. It is suggested that via these mechanisms differential responses in the sympathetic outflow could be produced.
Animals↗
Mediation of baroreceptor inhibition of sympathetic nerve activity via both a brainstem and spinal site in rats.
1. The possible involvement of a spinal site of sympatho-inhibitory action in the baroreceptor reflex pathways was investigated by determining the effect of phenylephrine-induced, baroreceptor-mediated inhibition on a spinally evoked excitatory response of renal nerve activity before, during and after removal of tonic descending excitatory drive from the rostral ventrolateral medulla (RVLM). 2. Stimulation of descending excitatory axons at the C4 vertebral level evoked a highly reproducible excitatory response (mean variance, 2.2 +/- 0.6%) in a renal sympathetic nerve with a latency of 72 +/- 5.7 ms and duration of 211 +/- 32 ms. 3. Following baroreceptor activation, the magnitude of this spinally evoked response was reduced by 33.5 +/- 4.2% compared with control spinal response. 4. To remove tonic descending excitatory drive, glycine was microinjected bilaterally into the RVLM (RVLM block); this briefly and reversibly abolished spontaneous sympathetic nerve activity. 5. Following RVLM block, the spinally evoked response in a renal sympathetic nerve was inhibited by 16.9 +/- 4.4% during baroreceptor activation. 6. Intrathecal administration of the glycine antagonist strychnine to the lower thoracic segments of the spinal cord virtually abolished this inhibition. 7. It was concluded that baroreceptor inhibition of sympathetic activity occurs at a spinal site as well as a supraspinal one. Glycine is a likely mediator of the inhibition at the spinal site.
Animals↗
Oxytocin acts at V1 receptors to excite sympathetic preganglionic neurones in neonate rat spinal cord in vitro.
Intracellular recordings were made from sympathetic preganglionic neurones (SPNs) in transverse slices of thoraco-lumbar spinal cord of young rats (12-20 days old). A small group of SPNs generally having higher membrane potentials (-70 mV) compared to a remaining group (-66 mV) showed spontaneous oscillations of their membrane potential. Oxytocin superfused in concentrations of 0.1-30 microM had four effects on SPNs, inducing slow depolarisation, EPSPs, IPSPs and brief rhythmic oscillations. The slow depolarisation was unaffected by TTX whereas this abolished the other changes. The oxytocin-induced depolarisation was associated with a slow inward current and was not reversed at membrane potentials negative to EK, it increased at more positive potentials and was still present in low Ca2+ and high Mg2+ solutions. These features of the oxytocin induced current are similar to those of the TTX resistant voltage dependent Na+ current described in brainstem autonomic neurones. Vasopressin superfused at concentrations of 0.1 microM to 30 microM had similar effects on SPNs to those of oxytocin. A comparison of the effects of oxytocin and vasopressin on the same neurones revealed that oxytocin was almost 10 times less potent than vasopressin. The effects of oxytocin were not mimicked by a selective oxytocin agonist but were mimicked by a selective vasopressin V1a agonist and blocked by a selective V1a antagonist. Therefore it is concluded that the effects of oxytocin on SPNs are mediated by the vasopressin V1a receptor. It is suggested that oxytocin and vasopressin terminals in the lateral horn are part of a descending system controlling oscillating networks of SPNs in the spinal cord.
Animals↗
Evidence that sympathetic preganglionic neurones are arranged in target-specific columns in the thoracic spinal cord of the rat.
It is recognised that selective activation of different target-specific sympathetic preganglionic neurones forms the basis of many autonomic responses. The anatomical basis for this could be the spatial arrangement of these neurones in the spinal cord nuclei. The present study tested this possibility in the rat by determining the location in single animals of three distinct groups of sympathetic preganglionic neurones, one group projecting to the superior cervical ganglion, another to the stellate ganglion and one to the adrenal medulla. Sympathetic preganglionic neurones to each of these targets were simultaneously labeled with fluorescent dyes, either Fluorogold, Fast Blue, or Diamidino Yellow. The numbers and general morphology of the neurones were similar to previous descriptions, and they were distributed in four subnuclei, the nucleus intermediolateralis pars principalis, the nucleus intermediolateralis pars funiculus, the nucleus intercalatus spinalis, and the nucleus intercalatus spinalis pars paraependymalis. It was shown that all three groups of neurones were represented in the more medial sympathetic nuclei, but in the nuclei at the lateral border of the intermediate grey matter each one of the three groups of neurones occupied a discrete location. Adrenal medullary sympathetic preganglionic neurones occupied a lateral aspect, the superior cervical ganglion sympathetic preganglionic neurones a medial aspect, and the stellate ganglion sympathetic preganglionic neurones a space between. Some sympathetic preganglionic neurones were double labeled after dye injections into the superior cervical and stellate ganglion thus indicating that they projected to both ganglia.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
A comparison between the adult rat and neonate rat of the architecture of sympathetic preganglionic neurones projecting to the superior cervical ganglion, stellate ganglion and adrenal medulla.
Sympathetic preganglionic neurones (SPN) projecting to the superior cervical ganglion (SCG) and adrenal medulla (AM) in the neonate (< 14 days) and SCG, stellate ganglion (SG) and AM in the adult rat (> 3 months) were retrogradely labelled with cholera B horseradish peroxidase (CBHRP). Labelled neurones were found in 4 four distinct nuclei: the nucleus intermediolateralis thoracolumbalis pars principalis (ILp), a nucleus equivalent to the intemediolateral cell column (IML); the nucleus intermediolateralis thoracolumbalis pars funicularis (ILf); the nucleus intercalatus spinalis (IC) and the nucleus intercalatus pars paraependymatis (ICpe) or central autonomic area (CA). These were represented to a similar extent in both neonate and adult. Neonate and adult SCG, SG and AM-SPN had a similar segmental distribution cervical 8 (C8) to thoracic 5 (T5) for SCG-SPN and thoracic 3 (T3) to thoracic (T13) for AM-SPN whereas adult SG-SPN were distributed over segments C8 to T9. Most labelled neurones (70%) were located in the ILp with one segment containing the highest proportion of SPN. Three morphologically distinct neurones were evident. Fusiform and roundbodied were the most common. Fusiform somata of the ILp were orientated both mediolaterally and rostrocaudally in the neonate but only rostrocaudally in the adult. Dendrites of the SPN in the adult and neonate extended in a dense rostrocaudal band along the ILp, more diffusely into the white matter of the Ilf and in bundles medially towards the central canal (CC). The neonate showed some significant differences. In the ILp, the cell bodies were less tightly packed into a narrow band and into clusters and the dendrites were more diffuse. It was concluded that at 12 days postnatally the organisation of the sympathetic nuclei had still nor reached the adult form. However, there is no extensive realignment of dendrites in the adult so the ILp remains an 'open' nucleus like the neonate.
Adrenal Medulla↗
Role of vasopressin in sympathetic response to paraventricular nucleus stimulation in anesthetized rats.
Vasopressin may play an extrahypothalamic role in the central control of the cardiovascular system, specifically acting as a spinal neurotransmitter in the pathway where the paraventricular nucleus (PVN) alters sympathetic outflow. In this study, the effect of stimulating neuronal cell bodies in the PVN on renal sympathetic nerve activity (RSNA) and the possible involvement of vasopressin in the pathway was investigated in anesthetized rats. The PVN was stimulated by microinjection with 0.2 M D,L-homocysteic acid via a glass micropipette, and the hemodynamic and sympathetic responses were recorded. A computerized sympathetic peak-detection algorithm was applied to recordings of sympathetic discharges to retrieve information about the characteristics of RSNA during PVN stimulation. The algorithm scanned the series of RSNA voltages for significant increases followed by significant decreases in a small cluster of voltage values. Once each synchronized RSNA peak had been detected, its corresponding amplitude and peak-to-peak interval were calculated. PVN stimulation consistently increased the amplitude of RSNA (mean 30 +/- 5.6% over control), arterial pressure, and the peak-to-peak interval of discharges. A V1 vasopressin antagonist intrathecally administered as a 500-pmol dose was subsequently able to completely block the hemodynamic response (blood pressure increase of 14 +/- 5%) and a 35 +/- 6% increase in RSNA in response to PVN stimulation and intrathecal vasopressin. Thus spinal vasopressin is likely to be a neurotransmitter involved in the cardiovascular regulation involving the PVN.
Animals↗
Angiotensin II in the spinal cord of the rat and its sympatho-excitatory effects.
Immunohistochemical studies have shown there is a dense angiotensin-like immunoreactivity of terminals in the sympathetic region of the thoracic and lumbar spinal cord. In the present study measurements were made of the concentration of angiotensin in the spinal cord of rats using radioimmunoassay following two different extraction procedures. These gave concentrations of angiotensin as mean of 108 and 161 pg.g-1 tissue wet weight. Angiotensin II given intrathecally or microinjected into the spinal cord caused an increase in postganglionic sympathetic nerve activity which was blocked by prior application of saralasin. Angiotensin III was without effect. Intracellular recordings from sympathetic preganglionic neurones in-vitro in slices of neonate rat spinal cord showed that angiotensin II produced an increase of excitability of the neurones by a slow depolarisation without the generation of action potentials. This effect still occurred in the presence of TTX. Angiotensin II also could increase synaptic activity, both EPSPs and IPSPs as well as a synaptically induced slow depolarisation being observed suggesting that presympathetic interneurones are also sensitive to the peptide. The evidence indicates that if angiotensin is released from nerve terminals surrounding sympathetic neurones it will enhance the gain of the neurone so that it could more easily be discharged by other excitatory inputs.
Action Potentials↗
Excitatory and indirect inhibitory actions of 5-hydroxytryptamine on sympathetic preganglionic neurones in the neonate rat spinal cord in vitro.
The action of 5-hydroxytryptamine (5-HT) on sympathetic preganglionic neurones (SPN) was studied by intracellular recordings in thin slices of neonatal rat spinal cord in vitro. Superfusion of 5-HT (1-270 microM) to SPN caused a concentration dependent slow depolarization or inward current and an increase in synaptic activity consisting of both EPSPs and IPSPs. The slow depolarization was still present after superfusion with TTX. Similar effects were seen during superfusion with 5-carboxamidotryptamine (5-CT) or alpha-methyl-5-hydroxytryptamine (alpha-me-5-HT). A comparison with the potency of 5-HT was made for 5-CT or alpha-me-5-HT on the same neurone by determining the magnitude of the slow depolarization to different concentrations of agonist. This showed that the apparent potency of the agonists was 5-CT > 5-HT > alpha-me-5-HT even in the presence of fluoxetine, a 5-HT uptake inhibitor. The 5-HT-induced slow depolarization was partially blocked by ketanserin but full recovery was not observed. The results suggest that the excitatory action of 5-HT on SPN is mediated via an atypical 5-HT2 receptor or a 5-HT1C-like receptor. The 5-HT-induced IPSPs were reversibly blocked by superfusion with strychnine, suggesting they were mediated by glycine.
Action Potentials↗
The actions of 5-hydroxytryptamine on the membrane of putative sympatho-excitatory neurones in the rostral ventrolateral medulla of the adult rat in vitro.
Intracellular recordings were obtained in vitro from neurones lying within the rostral ventrolateral medulla of the adult rat. Neurones could be classified into three groups: silent neurones, irregularly firing neurones which had a regular pattern of action-potential generation. Membrane hyperpolarization of regularly firing neurones failed to reveal underlying EPSPs or disrupt the regular pattern of action-potential generation. Superfusion of a high Mg2+, low Ca2+ aCSF did not abolish action-potential generation but the regular pattern of firing of these neurones was lost. 5-Hydroxytryptamine evoked a slow concentration-dependent hyperpolarization in both spontaneously active and silent neurones, accompanied by a decrease in cell-input resistance. This study has provided further evidence for pacemaker-like neurones within the RVLM and for the modulation of these neurones by 5-hydroxytryptamine.
Action Potentials↗
Respiratory changes and structure of sleep in young high-altitude dwellers in the Andes of Peru.
Sleep organisation in eight young [mean (SD); 20.9 (2.6) years] Peruvian high-altitude residents was studied in a laboratory in Cerro de Pasco at 4300 m. Electroencephalograms, electromyograms, electro-oculograms, electrocardiograms, respiratory movements and arterial oxygen saturation were recorded on an 8-channel Medilog recorder and analysed later in England. Haematocrits ranged from 48% to 64% [57.9 (5.6)%]. The amount of slow wave rapid eye movement (REM) sleep was similar to that reported in young lowlanders sleeping at sea level but very different to the disturbed sleep in visitors sleeping at high altitude. All the Peruvians showed episodes of periodic breathing and respiratory apnoeas [29 (15) night-1] resulting in marked arterial oxygen desaturation [81 (4.5)%; changes of 6 (2.5)%]. These events occurred either during stage 2 or REM sleep and were more frequent in those with lower haematocrits. The amount of wakefulness during the night was 2-3 times greater than would be expected in an age-matched lowland population at sea level. The awakenings were strongly associated with apnoeas (P < 0.02) but were negatively correlated with haematocrit, although this was only significant for seven of the subjects (P < 0.05).
Adult↗
Acute systemic hypoxia and the surface ultrastructure and morphological characteristics of rat leucocytes.
We have examined the surface ultrastructure and morphological characteristics of leucocytes obtained from control rats breathing air and rats made acutely hypoxic (breathing 6% O2, for 30 min). Striking ultrastructural and morphological changes occurred in the leucocytes of hypoxic rats. These changes included the appearance of crater-like holes, a reduction in granule size and disruption of the cell membrane. The implications of these findings are discussed.
Animals↗
Sleep of Andean high altitude natives.
The structure of sleep in lowland visitors to altitudes greater than 4000 m is grossly disturbed. There are no data on sleep in long-term residents of high altitudes. This paper describes an electroencephalographic study of sleep in high altitude dwellers who were born in and are permanent residents of Cerro de Pasco in the Peruvian Andes, situated at 4330 m. Eight healthy male volunteers aged between 18 and 69 years were studied. Sleep was measured on three consecutive nights for each subject. Electroencephalographs, submental electromyographs and electro-oculograms were recorded. Only data from the third night were used in the analysis. The sleep patterns of these subjects resembled the normal sleep patterns described by others in lowlanders at sea level. There were significant amounts of slow wave sleep in the younger subjects and rapid eye movement sleep seemed unimpaired.
Adolescent↗
Pharmacological control of altitude sickness.
Acute mountain sickness has long been recognized as a potentially life-threatening condition afflicting otherwise healthy individuals who ascend rapidly to high altitude, where the partial pressure of oxygen in the air is reduced. The symptoms of acute mountain sickness are probably a consequence of disturbances in fluid balance brought about by severe tissue hypoxia. Acute mountain sickness can be prevented by an adequately slow ascent, which is the best method, but for those with limited time there are several drug therapies that provide a relatively good protection. John Coote describes these treatments and their possible mechanisms of pharmacological action.
Acetazolamide↗
Excitation and inhibition of rat sympathetic preganglionic neurones by catecholamines.
The actions of microiontophoretically applied catecholamines on antidromically identified sympathetic preganglionic neurones (SPN) in the upper thoracic spinal cord of the anaesthetized rat were investigated. Noradrenaline (NA) excited the majority of neurones (50/71), however, a significant number were inhibited by the catecholamine (17/71). Adrenaline excited 4/9 SPN and inhibited 2/9. Dopamine had excitatory actions on SPN (3/3). Dual actions of NA on the same SPN were demonstrated, with the actions of the catecholamine being modulated by excitatory amino acids. NA was also shown to induce burst firing in 21% of SPN.
Anesthesia↗