Left atrial endocardial fibrosis and intra-atrial thrombosis - landmarks of left atrial remodeling in rats with spontaneous atrial tachyarrhythmias.

INTRODUCTION: Histological abnormalities are common findings in the left atria (LA) of atrial fibrillation (AF) patients. We aimed to assess LA histological abnormalities in our model of spontaneous atrial tachyarrhythmias in rats. MATERIALS AND METHODS: LA sampling was performed in 12 spontaneously hypertensive rats (SHRs) and eight age-matched Wistar-Kyoto (WKY) rats. Tissue sections were stained with Masson's trichrome and Hematoxylin-Eosin-Safran and examined with a light microscope. A 0 to 3 scoring system was used to quantify the severity of LA structural abnormalities. LA von Willebrand factor (vWF) content was also assessed using immunohistochemical staining. RESULTS: In six of the eight SHRs, LA fibrosis, inflammatory infiltrates, and myocyte necrosis of varying grades of severity were observed. The most frequent feature was endocardial fibrosis, which was observed in six SHRs and in none of the WKY rats. Intra-atrial thrombosis was found in three SHRs and in none of the WKY rats. The intensity of vWF-related fluorescence was higher in the atrial endocardium of SHRs compared to age-matched WKY rats. CONCLUSIONS: Our findings reinforce the role of LA structural abnormalities in atrial arrhythmogenicity. However, two SHRs did not present LA histological abnormalities despite the presence of arrhythmias. This finding suggests that the LA remodeling-atrial tachyarrhythmia relationship could be highly nonlinear and that atrial fibrosis is more likely to be a facilitator of atrial arrhythmogenicity, rather than a prerequisite. We also provide evidence that intra-atrial thrombosis accompanies LA structural remodeling in arrhythmic rats. Increased endocardial platelet adhesion molecule vWF could contribute to this increased thrombogenicity.

[The sympathetic baroreflex is enhanced during emotional stress in rats]. / Sensibilisation du baroréflexe sympathique durant le stress émotionnel chez le rat.

The sympathetic component of the baroreceptor reflex might play a major role in limiting hypertensive effects of emotional stress. However, it has been suggested that this type of stress inhibits or even suppresses the baroreflex. The aim of the present study was, therefore, to determine the effects of emotional stress on the sympathetic baroreflex in conscious rats. In 11 Sprague Dawley rats, arterial pressure (AP) and renal sympathetic nerve activity (RSNA) were recorded simultaneously before and during exposure to a mild emotional stressor (jet of air). Under both conditions, baroreflex function curves relating AP and RSNA were constructed by fitting a sigmoid function to RSNA and AP measured during sequential nitroprusside and phenylephrine administrations. Air-jet stress significantly (P<0.01) increased the mean levels of AP (from 112 +/- 2 to 124 +/- 2 mmHg), heart rate (from 381 +/- 10 to 438 +/- 18 beats/min) and RSNA (from 0.80 +/- 0.14 to 1.49 +/- 0.23 microV). Sympathetic baroreflex function curves were shifted to a higher level of AP, and this was accompanied by an increase (P<0.01) in the maximum gain (from 9.0 +/- 1.3 to 16.2 +/- 2.1 normalized units (NU)/mmHg). The latter effect was a consequence of an increase (P<0.01) in the maximal range of variations of RSNA (from 285 +/- 33 to 619 +/- 59 NU). Finally, the operating range of the sympathetic baroreflex, which corresponds to the AP range over which the reflex is able to alter RSNA, was increased (from 34 +/- 2 to 41 +/- 3 mmHg; P<0.01). In conclusion, the baroreflex control of RSNA is sensitized and operates over a larger range during emotional stress in rats, which suggests that renal vascular tone, and possibly AP, are very efficiently controlled by the sympathetic nervous system under this condition.

Frequency response of renal sympathetic nervous activity to aortic depressor nerve stimulation in the anaesthetized rat.

1. The contribution of central baroreceptor reflex pathways to the dynamic regulation of sympathetic nervous activity (SNA) has not been properly examined thus far. The aim of this study was to characterize the transfer function of the central arc of the baroreceptor reflex (from baroreceptor afferent activity to SNA) over a wide range of frequencies. 2. In nine baroreceptor-intact and six sino-aortic baroreceptor-denervated rats anaesthetized with urethane, the renal SNA was recorded while applying sinusoidal stimulation to the aortic depressor nerve at 26 discrete frequencies ranging from 0.03 to 20 Hz. At each modulation frequency, cross-power spectrum analysis using a fast Fourier transform algorithm was performed between the stimulation and renal SNA, which provided the transfer function of the central arc. 3. In both baroreceptor intact and denervated rats, the transfer gain increased by a factor of about three between 0.03 and 1 Hz. At higher frequencies, the gain decreased but remained above the static gain of the system up to 12 Hz. There was a slight phase lead up to 0.4 Hz, then a continuously increasing phase lag. A three-element linear model satisfactorily described the experimental transfer function. The model combined a derivative gain (corner frequency approximately 0.15 Hz), an overdamped second-order low-pass filter (natural frequency approximately 1 Hz) and a fixed time delay (approximately 100 ms). 4. These results indicate that the central arc of the baroreceptor reflex shows derivative properties that are essential for compensating the filtering of fast oscillations of baroreceptor afferent activity and thus for the generation of fast oscillations of renal SNA (e.g. those related to the cardiac cycle).

[Autoregulation of renal blood flow and blood pressure variability in the conscious rat]. / Autorégulation du débit sanguin rénal et variabilité tensionnelle chez le rat éveillé.

It is often proposed that autoregulatory mechanisms prevent acute changes in systemic blood pressure (BP) from being transmitted to the glomerular capillary circulation. However, it is not known whether renal blood flow (RBF) is still autoregulated when the kidney is exposed to exaggerated BP fluctuations, in particular hypertensive episodes. The aim of the present study was therefore to evaluate the efficacy of renal autoregulatory responses in an animal model of BP lability, the sinoaortic denervated (SAD) rat. BP and RBF were simultaneously recorded in 8 SAD (2 wks before study) and 8 baroreceptor intact (INT) Sprague-Dawley rats during approximately 3 h of spontaneous activity. The left kidney used for RBF recordings was denervated to prevent the interference of changes in renal sympathetic tone with autoregulatory responses. The SAD procedure modified neither the mean BP nor the mean RBF levels (111 +/- 1 mmHg and 11.3 +/- 1.3 mL/min in INT rats: 113 +/- 6 mmHg and 11.1 +/- 0.9 mL/min in SAD rats). However, SAD strongly increased the BP variability (coefficient of variation: 5.9 +/- 0.2% and 18.2 +/- 1.1% in INT and SAD rats, respectively). In spite of this marked BP lability, RBF variability was not significantly affected by the SAD procedure (9.1 +/- 0.8% and 12.4 +/- 1.6% in INT and SAD rats, respectively). In SAD rats, spontaneous hypertensive episodes (top 1% of BP values: 174 +/- 10 mmHg) did not induce increases in RBF (10.5 +/- 1.0 ml/min). Fast Fourier transform analysis revealed that in SAD rats, autoregulatory mechanisms attenuated approximately 80% of BP fluctuations in the 0.0015-0.01 Hz frequency range, suggesting a major involvement of the tubuloglomerular feedback. In conclusion, autoregulatory mechanisms have an ample capacity to protect the kidney against spontaneous BP fluctuations in the conscious rat. Consequently, BP variability per se is probably not detrimental to the kidney, as long as autoregulatory mechanisms are normally functioning.

Renal blood flow dynamics and arterial pressure lability in the conscious rat.

It is not known whether renal blood flow (RBF) is still autoregulated when the kidney is exposed to large transient blood pressure (BP) fluctuations such as those occurring spontaneously in conscious sinoaortic baroreceptor-denervated (SAD) rats. In this study, BP and RBF were simultaneously recorded in 8 SAD rats (2 weeks before study) and 8 baroreceptor-intact rats during approximately 3 hours of spontaneous activity. The kidney used for RBF recordings was denervated to prevent the interference of changes in renal sympathetic tone with autoregulatory mechanisms. In intact rats, RBF variability (coefficient of variation 9.1+/-0.8%) was larger (P<0.02) than BP variability (5.9+/-0.2%). This was mainly because of slow changes in RBF that were unrelated to BP and also to a prominent oscillation of RBF of approximately 0.25-Hz frequency. Autoregulatory patterns were identified at frequencies <0.1 Hz and provided a modest attenuation of BP fluctuations. In SAD rats, RBF variability (12.4+/-1.6%) was lower (P<0.02) than BP variability (18.2+/-1.1%). Autoregulation powerfully attenuated BP changes <0.1 Hz (normalized transfer gain 0.21+/-0.02 in the 0.0015- to 0.01-Hz frequency range) but at the expense of an oscillation located at approximately 0.05 Hz that possibly reflected the operation of the tubuloglomerular feedback. Large transient hypertensive episodes were not translated into RBF changes in SAD rats. We conclude that autoregulatory mechanisms have an ample capacity to protect the kidney against spontaneous BP fluctuations in the conscious rat. This capacity is not fully used under normal conditions of low BP variability.

Aggregation Behavior in Aqueous Solutions of a New Class of Asymmetric Bipolar Amphiphiles Investigated by Surface Tension Measurements.

Two series of amphiphilic derivatives of lactose have been synthesized. Tensiometric investigations of the critical micellar concentration (CMC) and the area per molecule at interface (calculated by the Gibbs equation) of aqueous solutions were performed. The values measured depend on the number of methylene groups of the alkyl spacer n and that of the side chain m as well as on the ionic strength and temperature. The results show a behavior closely related to that of gemini surfactants: (1) self-assembly phenomena occur at concentrations below 1 mM, (2) at constant n log CMC increases linearly with higher m, and (3) the influence of the temperature on the aggregation phenomenon is comparable. Copyright 2001 Academic Press.

Effect of alpha-adrenoceptor blockade on the 0.4 Hz sympathetic rhythm in conscious rats.

1. The present study examined the origin of the 0.4 Hz rhythm in renal sympathetic nerve activity (RSNA) in rats. It was anticipated that, after elimination of 0.4 Hz oscillations of arterial pressure (AP) by alpha-adrenoceptor blockade, the persistence or disappearance of a 0.4 Hz rhythm in RSNA would point to an endogenous (central oscillator) or baroreflex origin, respectively. 2. Arterial pressure and RSNA were recorded in seven conscious rats, before and after acute alpha-adrenoceptor blockade with phentolamine (5 mg/kg, i.v.). In each condition, power and coherence spectra were calculated over 15 min periods of rest. 3. In control conditions, highly coherent AP and RSNA oscillations were observed near 0.4 Hz. After phentolamine administration, spectral power in the mid-frequency (0.27-0.74 Hz) band was significantly reduced for both AP and RSNA and maximum power was shifted towards 0.7 Hz. 4. The disappearance of the RSNA rhythm at 0.4 Hz after phentolamine administration favours the hypothesis of a baroreflex origin. The new oscillation near 0.7 Hz can derive either from the activity of a previously unrecognized central oscillator or from a faster feedback mechanism involving cotransmitters of noradrenaline acting with shorter time constants (e.g. ATP).

Norepinephrine reuptake, baroreflex dynamics, and arterial pressure variability in rats.

This study examined the effect of norepinephrine reuptake blockade with desipramine (DMI) on the spontaneous variability of the simultaneously recorded arterial pressure (AP) and renal sympathetic nerve activity (SNA) in conscious rats. Acute DMI administration (2 mg/kg iv) depressed AP Mayer waves ( approximately 0.4 Hz) and increased low-frequency (<0.2 Hz) components of AP variability. DMI decreased renal SNA variability, especially due to the abolition of oscillations related to Mayer waves. To examine whether DMI-induced changes in AP and renal SNA variabilities could be explained by alterations in the dynamic characteristics of the baroreceptor reflex loop, the frequency responses of mean AP to aortic depressor nerve stimulation were studied in urethan-anesthetized rats. DMI accentuated the low-pass filter properties of the transfer function without significantly altering the fixed time delay. The frequency responses of iliac vascular conductance to stimulation of the lumbar sympathetic chain were studied in an additional group of anesthetized rats. DMI did not markedly alter the low-pass filter properties of the transfer function and slightly increased the fixed time delay. These results suggest that the DMI-induced decrease in the dynamic gain of the baroreceptor reflex is responsible for the decreased spontaneous renal SNA variability and the accompanying increased AP variability. The "slowing down" of baroreflex responses cannot be attributed to an effect of DMI at the vascular neuroeffector junction.

Acute cardiovascular effects of the alpha2-adrenoceptor antagonist, idazoxan, in rats: influence of the basal sympathetic tone.

Intravenous administration of the alpha2-adrenoceptor antagonist, idazoxan, elicits variable cardiovascular effects, depending on experimental conditions. In this study, the effects of idazoxan were investigated in rats with high, low, or no basal sympathetic tone. In a group of conscious Sprague-Dawley rats (n = 9), mean arterial pressure (MAP), heart rate (HR), and renal sympathetic nervous activity (RSNA) were recorded. Idazoxan (250 microg/kg, i.v.) induced a transient decrease in MAP (-12+/-3 mm Hg) that was accompanied by increases in HR (49+/-14 beats/min) and RSNA (53+/-14%). In six of nine rats, a light pentobarbitone anesthesia was given. Basal RSNA was decreased (6.0+/-1.3 microV from 12.8+/-4.1 microV; p<0.05), and the depressor effect of idazoxan was reversed to a pressor effect (21+/-6 mm Hg) associated with bradycardia (-16+/-8 beats/min) and sympathoinhibition (-56+/-15%). In eight conscious intact rats, idazoxan (250 microg/kg, i.v.) attenuated by approximately 40% the pressor response to the selective alpha1-adrenoceptor agonist, cirazoline (0.5 microg/kg, i.v.). In three groups of six to seven ganglion-blocked (chlorisondamine, 2.5 mg/kg, i.v.) conscious rats, idazoxan dose-dependently increased mean arterial pressure (MAP: 39+/-2, 55+/-3, and 69+/-4 mm Hg at 125, 250, and 500 microg/kg, i.v., respectively) with minimal changes in HR. In contrast, the noradrenaline-releasing agent, tyramine (62.5, 125, and 250 microg/kg, i.v.), dose-dependently increased both MAP and HR. The alpha1-adrenoceptor antagonist, prazosin (1 mg/kg, i.v.; n = 8) blunted by approximately 70% (p<0.01) the pressor effect of 250 microg/kg idazoxan. It is concluded that in rats with high sympathetic tone, idazoxan has depressor effects, most likely related to its peripheral alpha-adrenoceptor antagonist properties. In rats with low or no sympathetic tone, idazoxan induced pressor responses mainly secondary to its partial agonist activity at vascular postjunctional alpha1-adrenoceptors.

Effect of desipramine on spontaneous arterial pressure oscillations in the rat.

There has been no previous report on the effect of the noradrenaline uptake inhibitor desipramine on short-term variability of arterial pressure. Mean arterial pressure was recorded in 9 conscious resting rats during 4 consecutive 30-min periods: (1) under baseline conditions, (2) after desipramine administration (2 mg/kg i.v., followed by 1 mg/kg every hour), then after (3) cardiac autonomic blockade with methylatropine and atenolol, and (4) alpha-adrenoceptor blockade with phentolamine. Fast Fourier transform analysis was applied to beat-to-beat data after resampling at 10 Hz of consecutive 205-s time series. Desipramine did not change the mean level and overall variability of mean arterial pressure. However, spectral power in the mid-frequency (0.3-0.5 Hz) band containing the Mayer waves was reduced by more than 80%, and power in the low-frequency (0.05-0.2 Hz) band was enhanced by approximately 50%, especially due to the appearance of a major oscillation centred at 0.095 +/- 0.005 Hz. This slow oscillation was further enhanced after cardiac autonomic blockade and was abolished after alpha-adrenoceptor blockade. In conclusion, desipramine profoundly alters short-term arterial pressure variability in resting rats, mainly by shifting vasomotor waves from 0.4 to 0.1 Hz. Desipramine may prove a valuable pharmacological tool to study the dynamic aspects of arterial pressure control.

Soman-induced hypertension in conscious rats is mediated by prolonged central muscarinic stimulation.

The acetylcholinesterase inhibitor, soman, induces marked and sustained hypertension and tachycardia associated with a convulsive syndrome in rats. The aims of the present study were to distinguish between the cardiovascular and convulsant effects of soman and to determine whether the maintenance of the soman-induced hypertension and tachycardia depends solely on a central muscarinic effect. To this end, using a computerised analysis of blood pressure (BP) in conscious freely moving rats, we examined the consequences on the increase in mean BP (MBP) and heart rate (HR) induced by soman (60 micrograms/kg, i.v.) of 1) a pre-treatment with the anticonvulsant drug diazepam (3 mg/kg, i.v.) and 2) atropine sulphate (10 mg/kg, i.v.) administered 10 or 60 min after the intoxication. Pretreatment with diazepam prevented the convulsions, assessed by electroencephalogram (EEG) recording, but modified neither the magnitude nor the kinetics of the pressor and tachycardic effects of soman (delta MBP = 74 +/- 2 and 73 +/- 5 mmHg, delta HR = 69 +/- 10 and 79 +/- 7 bpm, maximum MBP = 186 +/- 3 and 182 +/- 6 mmHg, maximum HR = 545 +/- 9 and 522 +/- 16 bpm in solvent- (n = 8) and diazepam- (n = 8) pre-treated rats, respectively). Whatever its time of administration, atropine sulphate fully and immediately reversed the rise in BP induced by soman. The soman-induced tachycardia was also suppressed by atropine administered 10 min after soman whereas it persisted when atropine was injected 60 min after the intoxication. These results show that the cardiovascular effects of soman can occur independently of the convulsive syndrome and that the maintenance of the soman-induced hypertension depends entirely on a permanent central muscarinic stimulation.

The arterial baroreceptor reflex of the rat exhibits positive feedback properties at the frequency of mayer waves.

1. Modelling studies have led to the proposal that Mayer waves ( approximately 0.4 Hz in rats) could result from a resonance phenomenon in a feedback control loop. In this study, we investigated the presence of a resonance frequency in the arterial baroreceptor reflex loop, i.e. a particular frequency at which arterial pressure feeds back positively to the baroreceptors. 2. Frequency responses of mean arterial pressure (MAP) to aortic depressor nerve (ADN) stimulation were studied in fifteen urethane anaesthetized, ventilated rats with cardiac autonomic blockade. The ADN was stimulated using rectangular trains of impulses (2 ms, 100 Hz) delivered at frequencies ranging from 0.1 to 1 Hz. Phase angles between impulses and MAP were calculated using cross-spectral analysis based on a fast Fourier transform algorithm. 3. Rhythmic ADN stimulation induced regular MAP oscillations at the expected frequencies that were attenuated by alpha-adrenoceptor blockade and abolished after ganglionic blockade. The relationship between impulse and MAP oscillations was characterized by a strong coherence and a positive phase shift at low frequencies, indicating that impulses led MAP with respect to the out-of-phase pattern. Deviation of the phase from the out-of-phase behaviour was mainly due to the presence of a fixed time delay ( approximately 0.8 s) between ADN stimuli and MAP changes. Phase angles fell to zero at 0.42 +/- 0.02 Hz. 4. In rats, the arterial baroreceptor reflex exhibits a resonance frequency close to the frequency of spontaneously occurring Mayer waves. The reflex therefore seems the most likely origin for the Mayer waves.

Synthetic neoglycolipids for biological applications: correlation between their structures and their interactions with membrane proteins.

Synthetic glycolipids are of interest for their biological applications requiring interactions with membrane proteins. Depending on their structures, new series of glycolipids have applications in extraction of membrane proteins or medical applications as mimics of natural ligands of proteins.

Characterization of a major slow oscillation in the mesenteric circulation of conscious rats.

1. Little is known about spontaneous slow rhythms in regional circulations. The present study was aimed at characterizing low-frequency (LF; 78-269 mHz) oscillations in the mesenteric and hindquarter circulations of conscious rats. 2. Mean arterial pressure (MAP) and indices (pulsed Doppler technique) of mesenteric (n = 25) and hindquarter (n = 23) blood flows were recorded in conscious, freely moving rats during 1 h periods. Fast Fourier transform analysis was applied to beat-to-beat data after resampling at 10 Hz of consecutive 205 s time series. 3. A major oscillation centred at 164 +/- 4 mHz was present in the mesenteric, but not in hindquarter, circulation. Consequently, LF power accounted for approximately 43% of the overall variability of mesenteric blood flow. Cross-spectral analysis performed between MAP and mesenteric blood flow indicated that fractional changes in flow were approximately two-fold of those in MAP, in pressure, at the peak frequency. 4. Acute blockade of the autonomic, renin-angiotensin and vasopressin systems combined with noradrenaline infusion (n = 7) reduced the frequency of the mesenteric blood flow oscillation (115 +/- 6 mHz) but did not change its contribution to overall flow variability (approximately 48%). A clear oscillation was still present after acute inhibition of nitric oxide (NO) synthesis with NG-nitro-L-arginine methyl ester (n = 8), but was virtually absent in chronically guanethidine-sympathectomized rats (n = 12). 5. In conclusion, the mesenteric blood flow of conscious rats exhibits a major slow oscillation that originates in the mesenteric vasculature and is not secondary to the activity of the major pressor systems or to the cyclic release of NO. Because of the strong attenuation of the oscillation in sympathectomized rats, we suggest that adrenergic vasoconstrictor tone plays a permissive role in its genesis.

Short-term haemodynamic variability in the conscious areflexic rat.

1. Simultaneous measurements of arterial pressure and cardiac output (n = 8), mesenteric blood flow (n = 7) or hindquarters (n = 8) blood flow were performed during 1 h periods in conscious rats, before and after acute pharmacological blockade of the autonomic, renin-angiotensin and vasopressin systems. In the latter condition (areflexic state), arterial pressure was maintained with a continuous infusion of noradrenaline. 2. In the areflexic state, spontaneous fluctuations in arterial pressure were markedly exaggerated, especially depressor episodes. At the onset of these falls in arterial pressure, there was an abrupt and transient decrease in stroke volume and cardiac output. Systemic vasodilatation then developed while cardiac output returned to normal. Regional vasodilatations were also delayed from the onset of the falls in arterial pressure and were usually large enough to maintain blood flow. 3. Both time and frequency domain analyses confirmed that changes in systemic and regional vascular conductances lagged by about 1 s behind arterial pressure changes. 4. These results indicate that, in the absence of neurohumoral influences, autoregulatory-like mechanisms become dominant in the control of systemic and regional circulations and contribute to exaggeration of the spontaneous short-term variability of arterial pressure.

Renin secretion in Lyon hypertensive rats.

In genetically hypertensive rats of Lyon strain (LH), both development and maintenance of hypertension are extremely sensitive to the chronic blockade of the renin-angiotensin system. However, LH rats exhibit a low renin secretory profile as indicated by (1) low basal plasma renin concentration; (2) blunted renin responses to reductions of renal perfusion pressure and beta-adrenoceptor stimulation both in vitro (isolated perfused kidney) and in vivo (conscious rat). None of the latter abnormalities are corrected by chronic sodium deprivation or when hypertension is prevented by hydralazine or perindopril treatment. Future studies will therefore have to elucidate the 'renin paradox' in LH rats.

Synthetic soluble analogs of galactosylceramide (GalCer) bind to the V3 domain of HIV-1 gp120 and inhibit HIV-1-induced fusion and entry.

Galactosylceramide (GalCer) is an alternative receptor allowing human immunodeficiency virus (HIV)-1 entry into CD4-negative cells of neural and colonic origin. Several lines of evidence suggest that this glycosphingolipid recognizes the V3 region of HIV-1 surface envelope glycoprotein gp120. Since the V3 loop plays a key role in the fusion process driven by HIV-1, we decided to synthesize soluble analogs of GalCer with the aim to develop a new class of anti-HIV-1 agents that could neutralize HIV-1 infection through masking of the V3 loop. We describe a short route, in three steps, for the synthesis of soluble analogs of GalCer, using unprotected lactose as the starting sugar. The analogs were prescreened in an assay based on the interaction between a V3 loop-derived synthetic peptide and [3H]suramin, a polysulfonyl compound displaying high affinity for the V3 loop. One of the soluble analogs, i.e. CA52(n15), strongly inhibited the binding of [3H]suramin to the V3 peptide, with an IC50 of 1.2 microM. This molecule was also able to inhibit [3H]suramin binding to recombinant gp120 with similar activity. Using a competition enzyme-linked immunosorbent assay with highly specific anti-gp120 monoclonal antibodies, the region recognized by CA52(n15) could be mapped to amino acids 318-323, which corresponds to the highly conserved consensus motif GPGRAF. Interestingly, the region recognized by suramin, i.e. IQRGP-R-F, was partially overlapping this motif. CA52(n15) was able to inhibit HIV-1-induced cell fusion as well as HIV-1 entry into both CD4(+) and CD4(-)/GalCer+ cells. A structure-activity relationship study showed that: (i) the antiviral activity of soluble analogs of GalCer correlates with V3 loop binding, and (ii) the hydrophobic moiety of the molecule plays an important role in this activity. Taken together, these data show that synthetic analogs of GalCer can inhibit HIV-1 entry into both CD4(-) and CD4(+) cells through masking of the V3 loop.

Renin secretion in conscious Lyon hypertensive rats.

To characterize the renin secretory profile in Lyon hypertensive (LH) rats, renin responses to reductions of arterial pressure and beta-adrenoceptor stimulation were assessed in conscious unrestrained LH (n = 13) and Lyon normotensive (LN, n = 14) rats under normal-salt diet. Mean arterial pressure (MAP) in the infrarenal aorta was recorded beat to beat for 3 h. Then, plasma renin concentration (PRC) was measured 1) in basal conditions, 2) during 10-mmHg stepwise reductions of MAP down to 60 mmHg using a chronically implanted aortic inflatable cuff, and 3) during isoprenaline infusion (62.5, 125, and 250 ng.kg-1.min-1 iv). Compared with LN, LH rats had an elevated MAP (146 +/- 3 vs. 111 +/- 1 mmHg, P < 0.001) and decreased PRC [4.2 +/- 0.6 vs. 8.2 +/- 0.8 ng angiotensin (ANG) I.ml-1.h-1, P < 0.001] and kidney renin content (216 +/- 14 vs. 1,149 +/- 103 micrograms ANG I.h-1.g-1, P < 0.001). Pressure-dependent renin release occurred below 90 mmHg in LN rats and below 80 mmHg in LH rats, and its sensitivity in the low-pressure range did not differ between strains. Isoprenaline-induced increases in PRC were weaker (P < 0.01) in LH than in LN rats. In additional LH and LN rats (n = 6-8), acute ANG II AT1-receptor blockade with losartan (20 mg/kg, followed by 10 mg.kg-1.h-1 iv for 2 h) induced lesser (P < 0.001) PRC increases in LH than in LN rats. Renin responses to isoprenaline remained blunted (P < 0.01) during losartan infusion in LH rats. We conclude that, in LH rats, renin secretion is independent of MAP in the range of its spontaneous variations and is poorly responsive to beta-adrenoceptor stimulation, the alteration of which cannot be explained by an enhanced feedback inhibition by ANG II.

Baroreceptor modulation of regional haemodynamic responses to acute stress in rat.

We examined the effects of chronic sinoaortic denervation (SAD) on regional haemodynamic responses to acute environmental stress in rats. In conscious male intact (n = 12) and SAD (2 weeks before study, n = 7) rats, arterial pressure and blood flow velocities (pulsed Doppler probes) in the subdiaphragmatic aorta, superior mesenteric artery and distal aorta (hindquarters) were simultaneously recorded. In response to air jet stress, intact rats showed modest increases in arterial pressure that were accompanied by vasoconstriction in the mesentery and vasodilatation in the hindquarters. These regional haemodynamic changes were almost balanced, as indicated by the lack of change in the subdiaphragmatic aortic conductance. SAD markedly enhanced the pressor and mesenteric vasoconstrictor responses and blunted the hindquarters vasodilatation. After acute beta-adrenoceptor blockade with propranolol, the stress-induced hindquarters vasodilatation was strongly reduced in the intact rats and was reversed into vasoconstriction in the SAD rats. These results point to an opposing interaction between centrally-induced sympathoexcitation and arterial baroreceptor reflex activation during stress. This probably favours the hyperaemic response in the skeletal muscles at a lower metabolic cost.

Involvement of vasodilator mechanisms in arterial pressure lability after sino-aortic baroreceptor denervation in rat.

1. To examine the regional haemodynamic basis of arterial pressure lability seen after sino-aortic baroreceptor denervation (SAD), simultaneous beat-to-beat recordings of arterial pressure and indices of regional blood flows (Doppler probes around the subdiaphragmatic and lower abdominal aortae and the superior mesenteric artery) were performed in the same conscious rats (n = 7) before, 1 and 14 days after SAD. 2. Acute SAD increased arterial pressure, decreased regional blood flows and vascular conductances, and potentiated the depressor and vasodilator effects of ganglionic blockade with trimethaphan, suggesting sympathetic overactivity. All parameters chronically returned to or near normal. 3. Both acute and chronic SAD increased the variability of arterial pressure and of regional conductances. Arterial pressure lability was characterized by a mixture of depressor and pressor events which were associated with regional vasodilatations and vasoconstrictions, respectively. This haemodynamic pattern was not affected by acute beta-adrenoceptor blockade with propranolol. 4. In conscious rats, the baroreceptor reflex acts to buffer the spontaneous variability of regional vascular conductances and thereby stabilizes arterial pressure. Sino-aortic baroreceptor denervation-induced arterial pressure lability does not depend on the level of sympathetic activation, and is determined by the relative contribution of depressor and pressor events accompanied by extensive vasodilatations and vasoconstrictions, respectively. Vasodilatations are not caused by the stimulation of vascular beta 2-adrenoceptors.