Valérie Oréa

Linear modelling analysis of baroreflex control of arterial pressure variability in rats

The objective of the present study was to examine whether a simple linear feedback model of arterial pressure (AP) control by the sympathetic nervous system would be able to reproduce the characteristic features of normal AP variability by using AP and renal sympathetic nerve activity (RSNA) data collected in conscious sinoaortic baroreceptor denervated (SAD) rats. As compared with baroreceptor‐intact rats (n= 8), SAD rats (n= 10) had increased spectral power (+ 680%) of AP in the low frequency range (LF, 0.0003–0.14 Hz) and reduced power (−19%) in the mid‐frequency range (MF, 0.14–0.8 Hz) containing Mayer waves. In individual SAD rats, RSNA data were translated into ‘sympathetic’ AP time series by using the RSNA–AP transfer function that had been previously characterized in anaesthetized rats. AP ‘perturbation’ time series were then calculated by subtracting ‘sympathetic’ from actual AP time series. Actual RSNA and AP ‘perturbation’ time series were introduced in a reflex loop that was closed by using the previously identified baroreflex transfer function (from baroreceptor afferent activity to RSNA). By progressively increasing the open‐loop static gain, it was possible to compute virtual AP power spectra that increasingly deviated from their progenitor spectra, with spectral power decreasing in the LF range (as a result of baroreflex buffering of haemodynamic perturbations), and increasing in the MF band (as a result of increasing transients at the resonance frequency of the loop). The most accurate reproduction of actual AP and RSNA spectra observed in baroreceptor‐intact rats was obtained at 20–30% of the baroreflex critical gain (open‐loop static gain resulting in self‐sustained oscillations at the resonance frequency). In conclusion, while the gain of the sympathetic component of the arterial baroreceptor reflex largely determines its ability to provide an efficient correction of slow haemodynamic perturbations, this is achieved at the cost of increasing transients at higher frequencies (Mayer waves). However, the system remains fundamentally stable.

Unprovoked atrial tachyarrhythmias in aging spontaneously hypertensive rats: the role of the autonomic nervous system

Experimental models of unprovoked atrial tachyarrhythmias (AT) in conscious, ambulatory animals are lacking. We hypothesized that the aging, spontaneously hypertensive rat (SHR) may provide such a model. Baseline ECG recordings were acquired with radiotelemetry in eight young (14-wk-old) and eight aging (55-wk-old) SHRs and in two groups of four age-matched Wistar-Kyoto (WKY) rats. Quantification of AT and heart rate variability (HRV) analysis were performed based on 24-h ECG recordings in unrestrained rats. All animals were submitted to an emotional stress protocol (air-jet). In SHRs, carbamylcholine injections were also performed. Spontaneous AT episodes were observed in all eight aging SHRs (median, 91.5; range, 4-444 episodes/24 h), but not in young SHRs or WKY rats. HRV analysis demonstrated significantly decreased low frequency components in aging SHRs compared with age-matched WKY rats (P < 0.01) and decreased low/high frequency ratios in both young (P < 0.01) and aging (P = 0.01) SHRs compared with normotensive controls. In aging SHRs, emotional stress significantly reduced the number of arrhythmic events, whereas carbamylcholine triggered AT and significantly increased atrial electrical instability. This study reports the occurrence of unprovoked episodes of atrial arrhythmia in hypertensive rats, and their increased incidence with aging. Our results suggest that autonomic imbalance with relative vagal hyperactivity may be responsible for the increased atrial arrhythmogenicity observed in this model. We also provide evidence that, in this model, the sympatho-vagal imbalance preceded the occurrence of arrhythmia. These results indicate that aging SHRs may provide valuable insight into the understanding of atrial arrhythmias.

Baroreflex control of renal sympathetic nerve activity and spontaneous rhythms at Mayer wave's frequency in rats.

The effects of sedation with pentobarbital sodium (15 mg/kg followed by 15.9+/-1.2 mg/kg/h, i.v.) on arterial pressure (AP) Mayer waves and accompanying oscillations of renal sympathetic nerve activity (RSNA) were examined in rats (n=8). As compared with values observed in the conscious state, pentobarbital significantly (P<0.05) decreased AP (from 119+/-2 to 93+/-3 mm Hg), heart rate (HR; from 427+/-11 to 355+/-11 beats/min) and RSNA (from 1.20+/-0.27 to 0.62+/-0.13 microV). The baroreflex control of RSNA was analyzed by fitting a sigmoid logistic function to changes in RSNA and AP observed during nitroprusside and phenylephrine administrations. During pentobarbital infusion, the RSNA-AP relationship was reset towards lower AP values, but neither its maximum gain nor its gain at resting AP were significantly altered (from 6.3+/-1.0 to 5.8+/-1.4 and from 3.2+/-0.5 to 3.8+/-1.3 normalized units (n.u.)/mm Hg, respectively). Spectral power in the frequency band containing Mayer waves (0.29-0.73 Hz) was significantly decreased by pentobarbital for both AP (from 4.65+/-0.90 to 0.95+/-0.25 mm Hg2) and RSNA (from 1437+/-245 to 488+/-79 n.u.2). This effect was mainly secondary to the attenuation of strongly coherent oscillations of both variables at approximately 0.4 Hz. Although previous experimental evidence points to a major involvement of the sympathetic limb of the arterial baroreceptor reflex in the genesis of Mayer waves, the present study indicates that the amplitude of these oscillations cannot be used as a quantitative index of sympathetic baroreflex sensitivity.

A New Pyrroline Compound Selective for I1-Imidazoline Receptors Improves Metabolic Syndrome in Rats

Symptoms of the metabolic syndrome (MetS), such as insulin resistance, obesity, and hypertension, have been associated with sympathetic hyperactivity. In addition, the adiponectin pathway has interesting therapeutic potentials in MetS. Our purpose was to investigate how targeting both the sympathetic nervous system and the adipose tissue (adiponectin secretion) with a drug selective for nonadrenergic I1-imidazoline receptors (I1Rs) may represent a new concept in MetS pharmacotherapy. LNP599 [3-chloro-2-methyl-phenyl)-(4-methyl-4,5-dihydro-3H-pyrrol-2-yl)-amine hydrochloride], a new pyrroline derivative, displaced the specific [125I]para-iodoclonidine binding to I1R with nanomolar affinity and had no significant affinity for a large set of receptors, transporters, and enzymes. In addition, it can cross the blood-brain barrier and has good intestinal absorption, permitting oral as well as intravenous delivery. The presence of I1Rs was demonstrated in 3T3-L1 adipocytes; LNP599 had a specific stimulatory action on adiponectin secretion in adipocytes. Short-term administration of LNP599 (10 mg/kg i.v.) in anesthetized Sprague-Dawley rats markedly decreased sympathetic activity, causing hypotension and bradycardia. Long-term treatment of spontaneously hypertensive heart failure rats with LNP599 (20 mg/kg PO) had favorable effects on blood pressure, body weight, insulin resistance, glucose tolerance, and lipid profile, and it increased plasma adiponectin. The pyrroline derivative, which inhibits sympathetic activity and stimulates adiponectin secretion, has beneficial effects on all the MetS abnormalities. The use of one single drug with both actions may constitute an innovative strategy for the management of MetS.

Baroreflex control of lumbar and renal sympathetic nerve activity in conscious rats

This study compared the baroreflex control of lumbar and renal sympathetic nerve activity (SNA) in conscious rats. Arterial pressure (AP) and lumbar and renal SNA were simultaneously recorded in six freely behaving rats. Pharmacological estimates of lumbar and renal sympathetic baroreflex sensitivity (BRS) were obtained by means of the sequential intravenous administration of sodium nitroprusside and phenylephrine. Sympathetic BRS was significantly (P < 0.05) lower for lumbar [3.0 +/- 0.4 normalized units (NU)/mmHg] than for renal (7.6 +/- 0.6 NU/mmHg) SNA. During a 219-min baseline period, spontaneous lumbar and renal BRS were continuously assessed by computing the gain of the transfer function relating AP and SNA at heart rate frequency over consecutive 61.4-s periods. The transfer gain was considered only when coherence between AP and SNA significantly differed from zero, which was verified in 99 +/- 1 and 96 +/- 3% of cases for lumbar and renal SNA, respectively. When averaged over the entire baseline period, spontaneous BRS was significantly (P < 0.05) lower for lumbar (1.3 +/- 0.2 NU/mmHg) than for renal (2.3 +/- 0.3 NU/mmHg) SNA. For both SNAs, spontaneous BRS showed marked fluctuations (variation coefficients were 26 +/- 2 and 28 +/- 2% for lumbar and renal SNA, respectively). These fluctuations were positively correlated in five of six rats (R = 0.44 +/- 0.06; n = 204 +/- 8; P < 0.0001). We conclude that in conscious rats, the baroreflex control of lumbar and renal SNA shows quantitative differences but is modulated in a mostly coordinated way.

Pyridostigmine enhances atrial tachyarrhythmias in aging spontaneously hypertensive rats

This study examined whether chronic administration of pyridostigmine, a reversible cholinesterase inhibitor, would exacerbate episodes of spontaneous atrial tachyarrhythmia (AT) in conscious, aging, spontaneously hypertensive rats (SHRs). Telemetric recordings of electrocardiogram (ECG, n = 5) and ECG/arterial pressure (n = 3) were performed in male 49‐week old SHRs. After a 1‐week period of continuous recording under baseline conditions, rats were implanted with osmotic minipumps that delivered pyridostigmine (15 mg/kg/day subcutaneously) for either 1 (n = 8) or 3 (n = 5) weeks. In the latter case, sympathovagal balance was assessed during the last infusion week by measuring heart rate (HR) changes in response to administration of cardiac autonomic blockers. An additional 1‐week recording was performed after explantation of minipumps. Significant (P = 0.02) reductions in HR with no consistent changes in arterial pressure were observed. Frequency and duration of AT episodes were increased by pyridostigmine (0.01 ≤ P ≤ 0.07). This increase was sustained across the 3‐week treatment period and reversible after cessation of treatment. Autonomic blockade revealed that intrinsic HR was above (P = 0.04) resting HR, pointing to a shift of sympathovagal balance towards vagal predominance. However, the respiratory‐related component of HR variability (high‐frequency power of RR interval) was lowered (P = 0.01) by pyridostigmine treatment, indicating reduced vagal modulation of HR. The results are consistent with a pathogenic role of the parasympathetic nervous system in the aging SHR model, and raise the possibility that sustained vagal activation may facilitate atrial arrhythmias.

Role of the sympathetic nervous system in cerebrovascular responses to air-jet stress in rats

This study examined the role of sympathetic nerves in the control of cerebral hemodynamics during air-jet stress. In adult male Sprague-Dawley rats, blood flow velocity (pulsed Doppler) was measured in both internal carotid arteries 1 week after excision of one superior cervical ganglion. Blood pressure (BP) and carotid blood flows (CBFs) were simultaneously recorded during exposure to air-jet stress. In 5 out of 13 rats, stress was applied after β2-adrenoceptor blockade with ICI 118551 (0.4 mg/kg, then 0.2 mg/kg/h, i.v). Stress evoked an immediate rise in BP, CBFs, and vascular conductances. Vasodilatation was much larger on the denervated side than on the intact side (mean ± SEM: 78 ± 7 versus 19 ± 4%; P < 0.02) and lasted about 10 s. Thereafter, blood flows returned to or near normal and showed parallel variations while BP remained elevated. There was, therefore, a net vasoconstriction on both sides. In ICI 118551-treated rats, the initial vasodilatation was not significantly reduced on the denervated side (64 ± 4%), but the subsequent vasoconstriction was enhanced (P < 0.05) on both sides. In conclusion, air-jet stress evokes an immediate, short-lasting vasodilatation through a mechanism unrelated to β2-adrenoceptor stimulation. Sympathetic nerves powerfully limit this phenomenon, and thus contribute to protect the cerebral circulation from stress-induced BP surges.

Effect of chronic cervical ganglionectomy on the spontaneous variability of internal carotid blood flow in the conscious rat.

The role of sympathetic innervation in the control of spontaneous fluctuations of cerebral blood flow is still poorly understood. In conscious, unrestrained rats, blood flow velocity (pulsed Doppler) was measured in both internal carotid arteries 1 week after either excision of the right superior cervical ganglion (n= 8) or sham surgery (n= 6). Using Fourier‐based techniques, spectral power of each carotid blood flow (CBF) was computed over the whole recording period (246 min), which was segmented into nine consecutive 27.3 min periods. Variability of CBF (spectral power) was ∼40% higher (P < 0.02) on the denervated than on the intact side at frequencies <1 Hz. Coherence between left and right CBFs was similar in the two groups of rats, except in the 0.01–0.1 Hz frequency range where it was lower (P < 0.05) in rats with unilateral sympathectomy (0.54 ± 0.03) than in intact rats (0.74 ± 0.06). In this frequency range, mathematically removing the influence of arterial pressure had little effect on coherence between CBFs in both groups of rats, so that coherence remained significantly lower in rats with unilateral sympathectomy (0.52 ± 0.03) than in intact rats (0.70 ± 0.06). This study indicates that sympathetic innervation has an overall buffering influence on CBF variability. This modulatory role is especially important in a frequency range corresponding to slow fluctuations of CBF (lasting from 10 to 100 s), which are essentially unrelated to fluctuations of arterial pressure.

Very high frequency components of renal sympathetic nerve activity in conscious rats

The aim of this study was to examine whether multifibrenal sympathetic nerve activity (RSNA) of conscious rats contains frequency components of biological interest at frequencies above 25Hz. RSNA was recorded in 10 conscious Sprague-Dawley rats under baseline conditions and during infusion of vasoactive drugs that reflexly altered the mean RSNA level. The RSNA signal was band-pass filtered (300-3000Hz) before being sampled at 10,000Hz. The analytic envelope of this raw signal was then extracted using the Hilbert transform, and 132-s periods were submitted to Fourier transform analysis. Spectral power was computed from 0 to 25Hz and from 25 to 3000Hz (P(25-3000)). P(25-3000) was reduced by about 80% after either ganglionic blockade or euthanasia, which indicated that it was of biological origin and derived from the activity of postganglionic sympathetic neurons. After subtraction of post-mortem spectral power, basal P(25-3000) contributed 59.8+/-2.4% of total power. P(25-3000) was strongly barosensitive and thus, accounted for a major part of the reflex changes in total power. In each of the 10 rats, P(25-3000) was linearly correlated with the mean RSNA level (0.984+/-0.003) and even more so with the spectral power in the 0-25Hz frequency range (0.994+/-0.001). In conclusion, the RSNA of conscious rats contains very high frequency components that account for about 60% of the total spectral power and are modulated by the baroreceptor reflex. A reasonable approximation of this power can be obtained by computing spectra up to 25Hz.

Vascular reactivity to angiotensin II alone or combined with a thromboxane A2 mimetic in the isolated perfused kidney of Lyon hypertensive rats

The aim of this study was to evaluate whether thromboxane A2‐prostaglandin H2 (TP) receptor activation potentiates the renal vasoconstrictor effect of Angiotensin II (Ang II) in genetically hypertensive rats of the Lyon strain (LH). Concentration‐response curves (CRCs) to Ang II (5 pM to 10 nM), to the specific TP receptor agonist U46619 (7.5–960 nM) and to a mixture of Ang II + U46619 (fixed molar ratio of 1 : 9) were obtained in single‐pass perfused kidneys isolated from 8 week‐old LH and low blood pressure (LL) control rats. Baseline vascular resistance was significantly increased in LH compared to LL kidneys. Comparison of the CRCs obtained for Ang II and U46619 showed that, in both strains, Ang II was about 100 times more potent than U46619. For both drugs, the pD2 or slope values did not differ among the two strains. Co‐activation of TP receptors, analyzed with the method of Pöch and Holzmann, tended to potentiate the effects of Ang II in LH but not in LL kidneys.