Jean-Luc Elghozi

?1- and ?2-Adrenoceptors in rat cerebral cortex: Effect of frontal lobotomy

SummarySurgical noradrenergic denervation of the cortex via frontal lobotomy was used to destroy the noradrenergic nerve endings and thus give some insight into the distribution of alpha-adrenoceptors. Frontal lobotomy caused a reduction in noradrenaline content in rat cerebral cortex (2.1±0.4 ng/mg protein for lesioned side, 6.0±0.3 mg/mg protein for nonlesioned side), indicating an effective noradrenergic denervation. The differences in 3H-clonidine and 3H-prazosin binding observed following surgery were a significant decrease in the number of α2-adrenoceptors (115.0±4.5 to 91.7±3.2 fmol/mg protein, n=7, P<0.001) and a smaller but significant increase in the number of α1-adrenoceptors (119.7±2.5 to 131.6±5.4 fmol/mg protein, n=7, P<0.05) in the lesioned cortex. Results of this study indicate that α2-adrenoceptors located on presynaptic noradrenergic terminals represent only a small proportion of the total α2-adrenoceptors in rat cerebral cortex.

Relationship between pulse interval and respiratory sinus arrhythmia: a time- and frequency-domain analysis of the effects of atropine

Abstract. Respiratory sinus arrhythmia (RSA) estimation is commonly used as a non-invasive index of cardiac vagal tone. To test this relationship, vagal tone was augmented or blocked using atropine. The study was carried out using 14 healthy volunteers, following beta-adrenoceptor blockade (10xa0mg bisoprolol per os) and during controlled respiration (0.25xa0Hz) in order to limit the confounding effects of cardiac sympathetic tone and respiration pattern changes. Atropine was slowly infused intravenously over a 30-min period up to a vagolytic cumulative dose of 0.04xa0mg/kg. The instant vagal tone was compared to the instant RSA value obtained from a time-/frequency-domain analysis of pulse interval (PI). RSA and PI varied in the same direction with an initial increase corresponding to the early vagomimetic effect of atropine followed by a decrease during the vagolytic phase. The comparative percentage fluctuations of RSA and PI over this large vagal tone range indicate that RSA is more sensitive (about twofold) than PI in reflecting fluctuations around the set point. This dissociated behaviour of PI and heart rate variability could be important to our understanding of the circulatory changes that result from fluctuations in vagal inputs to the sinus node.

Short-term blood pressure and heart rate variability in congenital central hypoventilation syndrome (Ondine's curse)

The effect of CCHS (congenital central hypoventilation syndrome, or Ondines curse) on short-term BP (blood pressure) and HR (heart rate) variability was evaluated in 16-year-old subjects presenting a form of CCHS requiring night ventilatory assistance. The 12 patients were compared with 12 age- and gender-matched healthy volunteers. Recordings were obtained during daytime while the subjects were breathing spontaneously. Continuous BP was measured with a Finapres device in the supine, head-up tilt and standing positions. The manoeuvre of actively standing was also analysed. HR levels were elevated in CCHS subjects at supine rest (+23%) with a reduced HR overall variability (-88%). The low- and high-frequency components of HR variability were affected. BP levels were preserved at rest, but the manoeuvres demonstrated a limited capacity to elevate BP. There was no overshoot in BP during the manoeuvre of actively standing, and steady standing BP levels in patients were not higher than supine BP levels as usually observed in healthy controls. The spontaneous baroreflex sensitivity estimated using the sequence technique or the cross-spectral analysis fell in the patients to approx. one-third of the sensitivity estimated in the healthy controls whatever the position. This cardiovascular profile suggests a predominant vagal dysfunction with signs of vagal withdrawal and baroreflex failure, and relative preservation of the cardiac and vascular sympathetic function. It is likely that the impaired ontogeny of the visceral reflexes, considered now to cause CCHS syndrome, includes the baroreceptive pathway and mainly its vagal component.

Effects of drugs on the autonomic control of short-term heart rate variability.

The autonomic nervous system links the brain and the heart. Efferent links in the neural control of the heart consist of sympathetic and parasympathetic (vagal) fibers innervating the sinus node. Because sympathetic and vagal firing alter spontaneous sinus node depolarization, cardiac rate and rhythm convey information about autonomic influences on the heart. The easy availability of ECG rendered possible the assessment of sinus rhythm as an index of autonomic outflow. The frequency-domain approach uses non-invasive recordings and appears to provide a quantitative evaluation of the autonomic modulation of cardiovascular function. Spectral profiles resulting from vagal or sympathetic blockades at the cardiac (or vascular) level might be used as references to unravel the mechanism of action of the drug under examination. A more comprehensive assessment will be obtained if spectral analysis is used as a complement to existing techniques applied for describing the neurohumoral status of patients (microneurographic recordings, norepinephrine spillover). This review also reports some pitfalls encountered in variability studies.

LCEC monitoring of 5-hydroxyindolic compounds in the cerebrospinal fluid of the rat related to sleep and feeding

A new technique which allows for both the chronic withdrawal of CSF and continuous recording of EEG sleep patterns and food intake in the freely moving rat is described. Liquid chromatography with electrochemical detection (LCEC) was used for the direct assay of tryptophan metabolites in the CSF. Both 5-hydroxyindolacetic acid (5-HIAA) and 5-hydroxytryptophan (5-HTP) were easily detectable. However, serotonin (5-HT) levels were relatively low and 5-hydroxytryptophol (5-HTPhol) and N-methylserotonin (N-Me-5HT) were undetectable in several cases. The continuous monitoring of 5-HIAA and 5-HTP indicated stable values throughout the 3-hr experiments during which no food or small meals were consumed. In the rat which consumed a large meal, both 5-HIAA and 5-HTP significantly increased following that meal. This increase in metabolites may be the result of an increased availability of tryptophan to the brain as a result of the meal. Although this study is preliminary, the described technique can provide further information about the possible relationship between behavioral (sleep and/or feeding) changes and the concomitant neurochemical fluctuations.

Genetic Influences On Cardiovascular Responses To An Acoustic Startle Stimulus In Rats

1. The aim of the present study was to assess the cardiovascular differences among five inbred rat strains (n = 16 per strain), including spontaneously hypertensive rats (SHR), Wistar Kyoto (WKY) rats, Wistar Furth (WF) rats, Fischer (F344) rats and Lewis (Lew) rats and the usual outbred Wistar (W) rat strain (n = 25).

In vivo dopamine release from the anterior hypothalamus of the rat.

The release of dopamine from the anterior hypothalamic/preoptic region of the anesthetized rat was investigated in vivo using a superfusion technique with a push-pull cannula. Dopamine was measured electrochemically after separation by liquid chromatography. The spontaneous release of dopamine was very low but detectable in some experiments. An inhibitor of monoamine oxidase (pargyline) and the immediate precursor of dopamine (L-DOPA) were added to synthetic cerebrospinal fluid superfusing the area. When these substances were present dopamine release was increased considerably and appeared to be stable for a long period of time. Mechanisms contributing to the formation of newly synthetized dopamine are discussed in relation to the releasing effect of d-amphetamine and the inhibiting effect of calcium-free medium. The functional significance of dopamine release was shown by the increased release of dopamine following an increase in blood pressure obtained by an intraarterial injection of blood. Finally, ventral noradrenergic bundle lesion on the same side of the superfusion site considerably enhanced dopamine release which may indicate an inhibitory control of dopamine release by noradrenergic neurons. Furthermore, this experimental procedure provides valuable means for analyzing the effects of pharmacological as well as other manipulations on the dopamine released from a superfused brain area in vivo.

Brain distribution of propranolol in the rat

The distribution and kinetics of D,L-propranolol in rat brain were examined after an intravenous injection of the drug. Measurements in brain areas and blood were performed by means of a sensitive and specific gas liquid chromatographic method. The disappearance rate in cortical areas paralleled that in blood. However D,L-propranolol decreased at a slower rate in hypothalamic and medullary nuclei. Since propranolol is believed to have central hypotensive effects, its retention by certain central nuclei involved in blood pressure regulation is of interest.

Circulating Digitalis-Like Compounds in Essential Hypertension

Inhibitors of the Na+ pump have been proposed as participating in sodium excretion, extracellular fluid regulation, and in the rise of blood pressure. The presence of digitalis-like compounds in human plasma has been investigated by comparing the effects of plasma extracts to those of ouabain in 4 tests. - competition with ouabain for binding to the Na+ pump, - inhibition of Na+ and K+ dependent hydrolysis - inhibition of serotonin uptake by human platelets - central hypertensive effect Plasma fractions exhibited digitalis-like properties in the 4 tests. The effects of plasma extracts of 42 normotensive subjects (21 with family history of hypertension) and 38 patients with essential hypertension (15 with antihypertensive treatment) and 9 patients with chronic renal failure were compared. Plasma from Forty per cent of untreated hypertensive patients and normotensives with hypertensive heredity had a high inhibition level. Inhibition was enhanced in beta-blocker treated patients and decreased in those on diuretics. No digitalis-like activity was observed in uremic plasma. These observations strongly suggest the presence of digitalis-like compound(s) in human plasma and point to its possible association with hypertension.

Elastin mutation is associated with a reduced gain of the baroreceptor – heart rate reflex in patients with Williams syndrome

Abstract Microdeletion of chromosome 7q, encompassing the elastin locus, has been identified in patients with Williams syndrome (WS). This study tested the hypothesis that loss of medial elastin affects the discharge of baroreceptors and consequently the baroreflex sensitivity (BRS). Eight untreated patients with WS (14.8 ± 2.4 y, m ± SEM) were compared to 8 healthy subjects (15.1 ± 2.3 y). Blood pressure (BP) was recorded using a Finapres® monitor in the supine position. Systolic BP (SBP) levels were 117.8 ± 4.4 mmHg in WS compared to 110.9 ± 5.7 in controls (ns). Pulse rate (PR, taken as a surrogate for heart rate) was higher in the WS (89.6 ± 1.0 vs 74.1 ± 2.3 beats/min in controls, P < 0.01). The variance (total power) of PI variability was reduced in WS subjects. The amplitudes of the low frequency (LF, 0.1 Hz) and high frequency (HF, respiratory) PI component (modulus) were reduced in WS (210.5 ± 4.3 vs 34.6 ± 2.6 ms, P = 0.02 for LF, 13.1 ± 2.5 vs 39.3 ± 8.5 ms, P = 0.01 for HF). The gain of the SBP-PI transfer function was diminished in the low frequency (LF, 0.1 Hz) and the HF range as well (5.8 ± 0.7 vs 12.1 ± 1.8 ms/mmHg for LF, P < 0.01 and 6.2 ± 1.0 vs 21.7 ± 4.6 ms/mmHg for HF, P < 0.01). The BRS obtained with the sequence technique was also reduced in WS (8.2 ± 0.9 vs 21.5 ± 2.9 ms/mmHg in controls, P < 0.001). The percent of beats involved in baroreflex sequences observed in WS was also diminished to 20 % compared to 48 % in controls (P < 0.001). In conclusion a BRS reduction associated with a PR elevation was observed in normotensive WS subjects. It is likely abnormal elastic fiber assembly at the arterial level alters baroreceptor discharges.