Norepinephrine kinetics in freely moving rats.

Norepinephrine (NE) kinetics were investigated in freely moving (FM) and minimally stressed (MS) rats with the isotope dilution technique. 1) The mean NE spillover rate (NE-SOR) was 79 +/- 6 ng. kg(-1). min(-1), and the mean NE metabolic clearance rate (NE-MCR) 179 +/- 9 ml. kg(-1). min(-1) (n = 31). Thus the NE kinetics in FM and MS rats are much faster than in human beings, probably related to a higher sympathetic drive. 2) Whether the magnitude of NE-MCR is related to the level of plasma NE concentration was investigated. No significant correlation was calculated between plasma NE concentration and NE-MCR in 31 control rats. When plasma NE concentration was varied during either acute or chronic infusion of exogenous NE, NE-MCR remained unchanged as long as animal hemodynamics were not altered. When plasma NE concentration was high enough to increase mean arterial pressure (MAP), NE-MCR was decreased. However, when MAP was increased within comparable magnitude, NE-MCR was decreased during NE and increased during epinephrine (Epi) infusion. Thus the existence of an alpha-/beta-adrenergic mechanism involved in the regulation of NE-MCR independent of known hemodynamic mechanisms is suggested. 3) The "epinephrine hypothesis" was revisited in FM and MS rats. At variance with humans, very high plasma Epi concentrations have to be induced to increase NE-SOR in resting rats. Furthermore, NE-MCR was also increased, accounting for the nonsignificant increase of plasma NE concentration. Within the range of Epi concentrations with no effect on NE-SOR, an increase of NE release was revealed when the presynaptic alpha(2)-adrenoreceptors were partially inhibited by yohimbine. This suggests the existence of a second epinephrine hypothesis.

Adrenaline hypothesis: effect of formoterol on noradrenaline release.

1 Originally, the so-called 'adrenaline hypothesis' related the release of noradrenaline (NA) to stimulation of presynaptic beta2-receptors in nerve endings; now it confers a possible role to adrenaline taken up then released by nerves endings. It represents a potentially useful therapeutic pathway. The present study aims to investigate the effects of formoterol, a highly selective beta2-adrenoceptor agonist. 2 It was carried out in freely moving rats, the isotope dilution technique being used to measure the NA spill over rate (NA-SOR) and metabolic clearance rate (MCR). 3 A series of three results are reported. (a) When compared with adrenaline on equimolar basis, formoterol (2.3 micro kg-1 min-1) increased NA-SOR while mean arterial blood pressure was decreased and heart rate increased. Thus, it was difficult to separate a direct presynaptic effect from indirect baroreflex-dependent activation of the sympathetic system. (b) When formoterol was infused at 1 ng kg-1 min-1, a dose empirically defined to induce no haemodynamic effect, NA-SOR was significantly increased, while NA-MCR remained unchanged. (c) The NA-SOR response to formoterol was not amplified by the presynaptic alpha2-adrenoceptor blocker, yohimbine, in contrast to the NA-SOR response to adrenaline. 4 In conclusion, formoterol, a beta2-adrenoceptor agonist, is shown to increase the release and plasma concentration of NA while its clearance was not changed.

Sympathetic activity in the rat: effects of anaesthesia on noradrenaline kinetics.

Noradrenaline (NA) kinetics represent an effective tool for evaluating the activity of the sympathetic system: thus plasma NA concentration, spillover rate (SOR) and metabolic clearance rate (MC) were measured in the rat. The dilution technique was adapted and validated: pithing that caused mechanical destruction of the spinal cord was shown to reduce drastically NA-SOR and plasma NA concentration with no effect on NA-MC. NA-SOR and plasma NA concentration were restored within their normal limits when 2.5 Hz electrical stimulation of the sympathetic roots was superimposed. Normal values of NA kinetics in non-anaesthetised normotensive 12-week-old rats are reported: NA-SOR=196.1+/-26.4 ng/kg/min, NA-MC=413.9+/-38.8 ml/kg/min and plasma NA=486+/-52 pg/ml. NA kinetic was investigated in response to anaesthesia, known to depress excitable tissues of the central nervous system and expected to depress the activity of the sympathetic system. When NA-SOR was significantly reduced during anaesthesia with either sodium pentobarbital or chloralose, plasma NA concentration was not changed because NA-MC was also reduced. Thus, plasma NA concentration can be a misleading marker of the sympathetic activity. The response of the sympathetic activity to four different anaesthetic agents is shown to be heterogeneous, ranging from inhibition to stimulation. Sodium pentobarbital anaesthesia was associated with a statistically significant reduction of both NA-SOR (105.6+/-14.1 ng/kg/min, P<0. 01) and NA-MC (239.3+/-18.7 ml/kg/min, P<0.001) while plasma NA was not changed (438+/-47 pg/ml). Chloralose reduced NA-SOR (101.6+/-20. 1 ng/kg/min, P<0.05) while ketamine did not (150.6+/-35.5 ng/kg/min, n.s.): both compounds reduced NA-MC (257.9+/-27.8 ml/kg/min, P<0.01 and 265.8+/-34.3 ml/kg/min, P<0.05, respectively). Diethyl ether was shown to increase both NA-SOR (472.2+/-111 ng/kg/min, P<0.05) and plasma NA concentration (1589+/-436 pg/ml, P<0.01), while NA-MC remained unchanged. Thus, any investigation of the activity of the sympathetic system in the anaesthetised rat has to take into account the specific effects related to the anaesthetic agent used.

Norepinephrine kinetics in the rat with tail-suspension-induced central hypervolemia, as a model of cardio-vascular deconditioning.

Tail-suspension (TS) in the rat represents an interesting experimental condition to mimic, on Earth, the microgravity-induced cardiovascular deconditioning although the rat's profile of response is partially different from human's. To investigate underlying pathophysiological mechanisms, we have speculated on a decreased activity of the sympathetic system, (sigma S) triggered by the increase of the central venous pressure (CVP) induced by TS. Thus a decreased activity of the sigma S could account, at least partly, for the deconditioning of the cardiovascular system. The sympathetic activity (sigma A) was evaluated through measurement of the norepinephrine (NE) kinetics in rats that were tail-suspended for either 6, 24 or 48 hours. Neither NE spillover rate nor metabolic clearance rate were changed during TS, as compared to control. Thus, TS for a short period of time in the rat is unlikely to trigger a decrease of the sigma A.

Further study on the carotid baroreflex system in the cardiovascular deconditioning induced by head-down tilt.

HYPOTHESIS: The responses of the carotid baroreflex and of the peripheral sympathetic system to stimulations induced by either lower body negative pressure (LBNP -40 mmHg) or cold pressor test were investigated in eight volunteers before and after 48 h in the -6 degrees head-down tilt (HDT). METHODS: Geometry (diastolic diameter and pulsatile distention) and dynamics (cross-sectional compliance and tangential tension) of the bulb and the common carotid artery were investigated using ultrasonic devices, echotracking and aplanation tonometry. The activity of the sympathetic system was evaluated through measurements of plasma concentrations of catecholamines (CAs) and 3,4-dihydroxyphenyl glycol (DHPG). RESULTS: During LBNP -40 mmHg, the pulsed tangential tension was decreased and the pressure amplification, induced by the reflexion of the pressure wave, was increased with no difference between before and after HDT. Since cross-sectional compliance and distensibility coefficient remained unchanged and the carotid contour of the waveform unaltered, it is concluded that the carotid reflexogenic area reads the same message during LBNP whether the cardiovascular system was deconditioned or not. Nonetheless, during LBNP after 48 h HDT, the heart rate accelerated faster and CAs and DHPG concentrations increased out of proportion, suggesting that the peripheral sympathetic activity was more reactive after HDT than before. Finally, forearm vascular resistances were measured in response to cold pressor test; they increased in the same proportion after HDT when compared with before. CONCLUSION: Results indicate that the carotid baroreflex and the peripheral sympathetic system were not deficient after 48 h HDT.

Venous and arterial behavior during normal pregnancy.

To assess the contribution of the arterial and venous systems in the hemodynamic changes of normal pregnancy, we studied blood flow, vascular resistance, venous tone, and the viscoelastic properties ("creep") of the upper and lower limbs (using plethysmography), aortic distensibility (using pulse wave velocity measurements), and cardiac dimensions (using echocardiography) in nine healthy women. Studies were longitudinally performed at the first (10-13 wk) and third (33-38 wk) trimesters of pregnancy in comparison with the period between the third and sixth month after delivery. From the first trimester, heart rate significantly increased while systemic blood pressure and limb vascular resistances did not change significantly and aortic distensibility increased (P < 0.05). Lower limb viscoelastic properties decreased at the third trimester (P < 0.05) and venous tone increased from the first trimester (P < 0.01), whereas little changes were observed at the site of upper limbs. The decrease in calf venous tone was significantly correlated with the increase in left ventricular diastolic diameter at the first (P < 0.001) and the third trimester (P < 0.05). The study provides evidence that during normal pregnancy, changes in the arterial and venous sides of the circulation occur independently of pressure alterations. The increase in venous tone, contributing to preload augmentation, and the decrease in aortic stiffness, reducing afterload, both optimize cardiac function until delivery.

Mechanisms of the cardiovascular deconditioning induced by tail suspension in the rat.

The aim of the present work was to obtain insights into the pathophysiology of cardiovascular deconditioning (CVD) induced by tail suspension (TS) in the rat: during TS, when central venous pressure (CVP) has been normalized (E. Martel, P. Champéroux, P. Lacolley, S. Richard, M. Safar, and J. L. Cuche. J. Appl. Physiol. 80: 1390-1396, 1996), and during simulated orthostatism (SO), when transient episodes of hypotension and bradycardia are disclosed, bradycardia with SO represents a response that seems peculiar to the rat compared with humans. According to basic physiology, a reduced activity of the sympathetic system induced by increased CVP was suspected but was not supported by data obtained through spectral analysis of blood pressure (BP) and heart rate (HR) variability or measurements of plasma catecholamine concentration during TS. Nonetheless, indirect evidence was obtained. During SO, plasma catecholamine concentration was lower in TS rats than in controls, suggesting a reduced synthesis of catecholamines, itself secondary to reduced activity of the sympathetic system. Furthermore, after 48 h of TS, the number of binding sites and affinity of alpha-receptors in rat aorta were increased, compatible with a reduced level of neurotransmitter in the synaptic cleft. A second series of experiments was carried out to study hypotension and bradycardia in TS rats during SO. Hypersensitivity of serotonergic mechanisms was suspected. Two 5-HT3 receptor antagonists (ondansetron and MDL-72222) blocked hypotension and restored tachycardia, basic features of orthostatic adaptation of the circulatory system. Response to the 5-HT3 receptor agonist was measured through dose-response curves of BP and HR after injection of 2-methylserotonin. After low doses, hypotension (10 micrograms/kg) and bradycardia (3 and 10 micrograms/kg) were significantly greater in 48-h TS rats than in controls. Thus CVD in the rat induced by TS appears to implicate at least two mechanisms: reduced activity of the sympathetic system and hypersensitivity of serotonergic mechanisms.

Red blood cells participate in the metabolic clearance of catecholamines in the rat.

The aim of the present study was to investigate the possible role of erythrocytes in the metabolic clearance of catecholamines (CAs) in the rat. Intravenous infusion of exogenous CAs (dopamine -DA-, norepinephrine -NE-, or epinephrine -Epi-) was carried out at increasing doses to cover a range of plasma concentrations from the lower to the upper physiological and to pharmacological levels. Whatever the mechanism(s) underlying the CAs erythrocyte/plasma balance: 1. it seemed more efficient at lower concentrations of CAs; 2. it reached an apparent plateau where plasma and erythrocyte concentrations were not statistically different; 3. finally, saturation was suggested when further increase in plasma concentration was associated with a lower response in erythrocytes. This series of experiments confirms previous reported results with human erythrocytes and suggests that rat erythrocytes could transport CAs from their sites of release to their sites of elimination. In a second series of experiments, the intra-erythrocyte metabolism of CAs was investigated. DA was strikingly increased in plasma and in erythrocytes 2 hours after 1,2-dimethyl-3-hydroxy-4-pyridone (CP20), 100 mg/kg i.p., known to inhibit catechol-O-methyl transferase. Our data demonstrate an increase in glucuro-conjugated DA in vivo (24 hours after CP20 injection) as well as in vitro (3 hours incubation at 37 degrees C), suggesting activation of the glucuroconjugating pathway. Increased glucuroconjugated DA after in vitro incubation demonstrates intra-erythrocyte synthesis while increased concentration in Ringer-Hepes medium demonstrates an inside-out transport of glucuro-conjugate. These data are the first evidence in favour of an intra-erythrocyte glucuro-conjugation of CAs in the rat.

Antihypertensive effects and arterial haemodynamic alterations during angiotensin converting enzyme inhibition.

OBJECTIVE: To assess the respective roles of the anti-hypertensive and blood pressure-independent effects of angiotensin converting enzyme (ACE) inhibition in the changed arterial haemodynamics observed in hypertensive patients with end-stage renal disease (ESRD) treated by haemodialysis. DESIGN AND METHODS: Twelve hypertensive patients with ESRD were included in a double-blind, cross-over study comparing a single 20 mg dose of the ACE inhibitor quinapril versus placebo. Two study periods each of 172 h duration were separated by a 2-week placebo period. Repeated measurements of the following parameters were performed: brachial artery systolic blood pressure (SBP); diastolic blood pressure and mean blood pressure (using a mercury sphygmomanometer); carotid artery SBP and pulse pressure (by applanation tonometry); aortic stiffness (by pulse wave velocity); and the effect of arterial wave reflections in the common carotid artery (the augmentation index, by applanation tonometry). A radioimmunoassay was used to determine plasma angiotensin II levels. Quinaprilat pharmacokinetics were studied using a specific assay. Two-way (time-treatment) analysis of variance for repeated measures, analysis of covariance for two within-factors and a covariate changing with the level of the factor time (pressures measured at each time) and baseline values of the studied parameter as a second covariate were used for statistical analysis. RESULTS: Quinapril treatment induced a long-lasting decrease in arterial wave reflections, which was still observable 172 h after quinapril administration and still present after removing the effect of the decrease in blood pressure. The effect on wave reflections was associated with a more pronounced and sustained decrease in carotid SBP and pulse pressure than that in brachial SBP and pulse pressure. Quinapril administration also induced a long-lasting decrease in aortic pulse wave velocity, but this effect was entirely dependent on parallel changes in blood pressure. Arterial haemodynamic changes were not related to plasma angiotensin II or quinaprilat levels. CONCLUSIONS: The results of this controlled study indicate that, in ESRD patients, ACE inhibition results in a long-lasting, blood pressure-independent decrease in arterial wave reflections. The consequence of this was a decrease in pulsatile pressure load in the central arteries with increased aortic distensibility. The increased aortic distensibility resulted from the decrease in blood pressure. The observed arterial haemodynamic alterations suggest that ACE inhibition induced alterations in arterial wave reflections in the distal parts of the arterial tree.

A dopamine transporter in human erythrocytes: modulation by insulin.

Red blood cells are capable of transport and accumulation of catecholamines. The aim of this paper is to characterize the catecholamine transport system in the human red blood cell and in particular that of dopamine. Dopamine, noradrenaline and adrenaline enter the red blood cell by a similar process, which shows saturation kinetics with Vmax values of 0.54 +/- 0.12, 0.48 +/- 0.08 and 0.63 +/- 0.13 mumol (1 cells)-1 min-1, respectively, and K(m) values of 15.62 +/- 1.19, 5.81 +/- 1.19 and 12.00 +/- 2.97 nM, respectively. Observations based on the dependence of dopamine influx on the transmembrane H+ gradient, and the effect of transport inhibitors such as DMA (dimethyl-amiloride), DIDS (4,4'-diisothiocyanatostilbene 2,2'-disulphonic acid), reserpine, GBR 12909 (1-(2-(di(4-fluoro-phenyl)-methoxy)-ethyl)-4-(3-phenylpropyl)piperazine) , GBR 12935 (1-(2-(diphenyl-methoxy)-ethyl)-4-(3-phenyl-propyl)piperazine), and cyanine suggest that catecholamine transport is not mediated by the Na(+)-H+ exchanger, the anion exchanger or a system similar to that responsible for dopamine uptake in either synaptosomes or the proximal tubule. However, choline inhibits the influx of dopamine with an IC50 value of 17 microM and stimulates the efflux of dopamine with a K(m) value of 8.20 microM. These results strongly suggest that dopamine is transported by the choline exchanger previously reported to be present in red blood cells. Probenecid inhibits dopamine uptake with an IC50 of 0.63 microM. The presence of insulin receptors in human red blood cells, and the relationship between insulin and catecholamine levels in the plasma led us to investigate the effect of insulin on catecholamine transport. In fasting subjects, dopamine, adrenaline and noradrenaline influxes were higher than in fed subjects. Furthermore, the addition of exogenous insulin to red blood cells from fasting subjects significantly reduced the influx of catecholamines while no effect was observed when insulin was added to red blood cells obtained from fed subjects. The present study shows that catecholamines, and in particular dopamine, are transported in red blood cells via an exchanger which is possibly the choline transport system. The activity of this transporter is regulated by insulin. These results support a role for red blood cells as a storage pool for circulating catecholamines.

Central hypervolemia in the conscious rat: a model of cardiovascular deconditioning.

The aim of the present study as to investigate whether increased central hypervolemia induced by tail suspension (TS) in the rat is an appropriate model of cardiovascular deconditioning (CVD). First, the physiological relationship between central venous pressure (CVP) and extracellular fluid volume (ECFV) was studied. TS (20 degrees) increased CVP (5.8 +/- 0.7 vs. 2.8 +/- 0.8 mmHg; P < 0.01). After 24 h of TS, CVP had returned to control range while ECFV was reduced by 19%. CVP kinetics during 24 h of TS was not affected by either reduction (-20%) or augmentation (/35%) of the ECFV. The normalization of CVP is likely to be a consequence of ECFV reduction, which itself is reduced by increased urinary excretion of water and sodium. Second, recovery from TS was studied. Resumption of the horizontal position was shown to be associated with a significant increase of heart rate (HR) and a slight reduction of blood pressure (BP); there was an apparent delay between increased HR and reduced BP. This imbalance between HR and BP is compatible with CVD. A model of simulated orthostatism (SO) was developed to further investigate the responses of HR and BP. Interestingly, SO (90 degrees rotation) in the normal rat was associated with significant tachycardia and a slight increase of BP. This pattern remained stable for at least 3 h. In rats that were tail suspended for 48 h, episodes of hypotension and bradycardia (5 +/- 1 in 3 h) suggested a defect in adaptation to increased hydrostatic pressure. In conclusion, TS appears to be an appropriate model of CVD. Reduction process. Return to horizontal position in TS rats induced a tachycardia with minimal effects on BP; this pattern is close to that observed in humans assuming upright posture. SO in previously TS rats disclosed episodes of hypotension and bradycardia that deserve further investigation.

Carotid arterial hemodynamics in response to LBNP in normal subjects: methodological aspects.

Pulsatile changes in blood pressure and arterial diameter were studied noninvasively with applanation tonometry and echo-tracking techniques at the sites of the common carotid artery (CCA) and the carotid arterial bulb (CAB) in 12 healthy volunteers. Determinations were performed before and during application of -10 and -40 mmHg lower body negative pressure (LBNP) to investigate noninvasively the tensile forces acting on the CAB. Together with significantly decreased mean arterial pressure, increased heart rate, forearm vascular resistance, and plasma norepinephrine, the -40 mmHg LBNP stimulus produced the following significant changes in CCA and CAB hemodynamics: 1) for the same decrease in mean arterial pressure, a greater decrease in carotid than in brachial pulse pressure was observed (P < 0.01) due to a significant change in pressure wave transmission and in the timing of the carotid backward pressure wave; and 2) a highly significant decrease in pulsatile changes in diameter and tangential tension occurred, with a greater decrease in systolic than in diastolic tangential tension. Subsequently, cyclic tangential tension decreased more substantially than mean tangential tension. The cyclic changes in tension were quite significant after -40 mmHg LBNP but were already observed for mild -10 mmHg LBNP in which mean systemic blood pressure and heart rate were not modified. During -10 and -40 mmHg LBNP, CCA and CAB compliance and distensibility were unchanged. This study provides evidence that the autonomic nervous system activation produced by the LBNP procedure is associated with significant changes in pressure-wave amplification and in cyclic tensile forces acting on the CAB. These changes, which may occur even for mild LBNP, should be taken into account when interpreting results of the LBNP procedure in humans.

Carotid artery pulsatility during parabolic flights.

In cardio-vascular hemodynamic, the arterial pulsatility, represented by the arterial pulse pressure (PP= systolic blood pressure-diastolic blood pressure), is different from one site to another, in opposite with the mean blood pressure almost identical in the whole body in supine position (or in microgravity). This is due to the arterial tree geometry and regional differences in the distensibility properties of the arterial wall. As the level of blood pressure opposed to the cardiac left ventricle work is the central pressure, on one hand and as the arterial pulsatility at the site of arterial baro-receptors (located on aortic arch and carotid arteries' bifurcation) regulates the sympathetic and vagal control of heart and peripheral resistances on the other hand, to determine the evolution of this central pulse pressure is of major importance in the knowledge of cardio-vascular hemodynamic during hyper or hypogravity as observed during parabolic flights. The aim of this study was to evaluate noninvasively the carotid artery pulsatility and mechanic properties during parabolic flights.

Neuronal metabolism of catecholamines in pithed and electrically stimulated rats.

The aim of the present study was to investigate a possible physiological equilibrium, assessed by statistically significant correlations, between pre-junctional mechanisms that regulate both release and reuptake of norepinephrine (NE) and post-junctional mechanisms that participate in the regulation of the smooth muscle cell and thus in the regulation of blood pressure. This study was carried out in pithed and electrically stimulated (2.5 Hz) rats to obtain an experimentally controlled release of NE. A radio-enzymatic assay was used to measure plasma concentrations of NE, index of NE release and levels of its deaminated metabolites 3,4-dihydroxyphenyl glycol (DHPG) and 3,4-dihydroxymandelic acid (DOMA). DHPG is known to be an index of NE reuptake and deamination while the physiological significance of DOMA remains unclear. Our results demonstrate a statistically significant correlation between plasma NE concentration and blood pressure on one hand, and between plasma NE and DHPG concentrations on the other. These correlations support our working hypothesis and suggest a physiological equilibrium between pre- and post-junctional phenomena in the control of blood pressure. During 2.5-Hz stimulation, plasma DHPG concentration was increased while plasma DOMA remained unchanged. This is consistent with activation of the reduction pathway and the consequent formation of DHPG by aldehyde reduction, while the oxidation pathway mediated by aldehyde dehydrogenase does not appear to play a major role in the presynaptic metabolism of reuptaken NE in the present experimental conditions. Further investigations are needed to investigate the apparent dissociation between the two enzymatic pathways involved in the second step of the deamination process.

Early disturbance of baroreflex control of heart rate after tail suspension in conscious rats.

Experiments were performed on conscious chronically instrumented rats maintained on tail suspension to determine the time course of changes in baroreceptor control of heart rate produced by this procedure. Pressor responses were elicited by bolus injections of graded doses of phenylephrine and sodium nitroprusside, permitting evaluation of the totality of the sigmoidal curve relating mean arterial pressure to heart rate. Compared with control rats maintained at 0 degrees, rats maintained at 20 degrees using tail suspension for 24 h showed a significant reduction in reflex gain (-3.9 +/- 0.1 vs. -5.8 +/- 0.3 beats/min; P < 0.001) together with a reduction in the upper (472 +/- 11 vs. 512 +/- 5 beats/min; P < 0.01) and lower (270 +/- 3 vs. 284 +/- 2 beats/min; P < 0.01) plateaus of the sigmoidal curve. In three groups of rats, the sigmoidal curve was studied successively after returning for 1, 24, and 48 h at 0 degrees. The observed change in the gain of the reflex returned toward control values after 48 h, whereas the other parameters characterizing the sigmoidal curve did not change significantly. Transient but significant modifications of heart rate (tachycardic response) after the immediate return to the horizontal position were observed. The study provides evidence that 1) a significant change of the totality of the sigmoidal curve characterizing baroreceptor control of heart rate occurs very early after tail suspension in rats and 2) the gain of the reflex is restored during the 48 h after release of tail suspension, whereas the other parameters characterizing the curve, particularly the plateaus, remain altered.

Cardiac hypertrophy, aortic compliance, peripheral resistance, and wave reflection in end-stage renal disease. Comparative effects of ACE inhibition and calcium channel blockade.

BACKGROUND: We wished to assess the respective roles of the antihypertensive and blood pressure (BP)-independent effects of antihypertensive drugs on arterial hemodynamics and left ventricular hypertrophy (LVH) in end-stage renal disease (ESRD) patients. METHODS AND RESULTS: In a double-blind study, 24 ESRD patients with LVH were randomized to 12 months' administration of either the angiotensin-converting enzyme (ACE) inhibitor perindopril (n = 14) or the calcium channel blocker nitrendipine (n = 10). Repeated measurements of the following parameters were performed: BP (mercury sphygmomanometry), left ventricular mass (LVM, echocardiography), cardiac output (aortic cross-section and velocity integral), total peripheral resistance (cardiac output and mean BP), aortic and large-artery compliance (pulse wave velocity, Doppler flowmeter), and arterial wave reflections (augmentation index, applanation tonometry). Radioimmunoassay was used to determine plasma renin activity, aldosterone, and plasma catecholamine levels. Two-way (time-treatment) ANOVA for repeated measures was used for statistical analysis. Perindopril and nitrendipine induced significant and similar decreases in BP, total peripheral resistance (P < .001), aortic and arterial pulse wave velocities (P < .001), and arterial wave reflections (P < .01). At baseline, the two groups had LVH mostly due to increased LV end-diastolic diameter (LVEDD) (perindopril, 54.3 +/- 1.4 and nitrendipine, 54.3 +/ 2.4 mm) with near-normal mean LV wall thickness (perindopril, 11.4 +/- 0.3 and nitrendipine, 11.2 +/- 0.4 mm). A decrease in LVM was observed only in patients receiving perindopril (from 317 +/- 18 to 247 +/- 21 g) (time-treatment interaction, P = .036). Nitrendipine had no significant effect on LVM (314 +/- 29 versus 286 +/- 32 g). The decrease in LVM observed with perindopril was associated with a reduction in LVEDD (49.9 +/- 1.6 versus 54.3 +/- 1.4 mm after 12 months) (time-treatment interaction, P = .04), while the mean LV wall thickness was unchanged (11.4 +/- 0.3 versus 10.5 +/- 0.5 mm). Cardiac alterations were not correlated with changes in BP or with alterations in plasma renin activity or aldosterone or catecholamine levels. CONCLUSIONS: In ESRD patients with LVH, ACE inhibition decreases LVM independently of its antihypertensive effect and of associated alterations in arterial hemodynamics. The decrease in LVM was due primarily to a decrease in LV volume, which may have resulted in these patients from chronic volume overload.

[Pressure-independent improvement of aortic distensibility in hypertensive hemodialysed patients]. / Amélioration pression-indépendante de la distensibilité aortique chez l'hémodialysé hypertendu.

Hypertensive patients undergoing hemodialysis (HPH) have a marked impairment of their large artery distensibility and an increased cardiovascular morbidity. We investigated twelve HPH (8 males, 4 females, 53 +/- 12 years of age, +/- SD) following a single dose of an ACE inhibitor (quinapril 20 mg) comparatively to a placebo in a randomised cross over study over a week (H0 to H172). We measured repeatedly blood pressure and aortic distensibility (carotid-femoral pulse wave velocity, PWV). Statistical analysis was made through repeated measure ANOVA and repeated measure analysis of covariance because of the tight link between pressure and arterial function. Blood pressure decreased (SAP: p < 0.01, DAP: p < 0.001), and PWV was significantly improved independently of the pressure decrease. ACE inhibitor reduces blood pressure in these patients and improves large arterial function independently of the blood pressure changes.

Plasma erythrocyte relationship of catecholamines in human blood.

The equilibrating process of catecholamines (CAs) between plasma and red blood cells (RBC) was studied by measuring their erythrocyte/plasma concentration gradient (E/P ratio); ratio of E/P > 1 for a given amine was considered the consequence of its accumulation in or on RBC. We studied in vitro human blood obtained from 9 polycythemic patients from whom blood was drawn in control condition and in response to loading with exogenous CAs. Preliminary study showed a lack of difference in results obtained in these patients from those in 9 healthy volunteers and confirmed that RBC accumulate dopamine (DA) and epinephrine (EPI) but not norepinephrine (NE). When a moderate amount of exogenous CAs was added, plasma and RBC concentrations were increased, with a delay between the two compartments indicated by a decrease in the E/P ratio of DA and EPI. When a large amount of exogenous CAs was added, their RBC concentrations were in direct proportion to their plasma concentrations. Thus, the kinetics of CA equilibration between plasma and RBC appears to be dependent on their chemical structure (DA is more easily accumulated than NE) and their plasma concentrations. Physiologically, the E/P ratio of DA was significantly greater than 1, suggesting that RBC maintained their capacity to accumulate DA even when DA plasma concentration was very high. Additional studies demonstrated that accumulation of CAs in or on RBC is a reversible process, inhibited by cold temperature and increased when blood pO2 is drastically reduced.(ABSTRACT TRUNCATED AT 250 WORDS)

Neuronal metabolism of catecholamines: plasma DHPG, DOMA and DOPAC.

Pre-synaptic endings of the sympathetic nervous fibers control the metabolism of catecholamines, particularly inactivating norepinephrine after its neuronal recapture. The present study was carried out to investigate this segment of the metabolism of catecholamines through measurements of DHPG, DOMA and DOPAC concentrations in plasma. A sensitive and specific radio-enzymatic assay was developed of which the major characteristic is to include the plasma sample in the incubation mixture without initial extraction of the deaminated metabolites. In the rat, there was a statistically significant correlation between norepinephrine and DHPG in both anesthetized and conscious conditions and after clonidine or guanethidine induced reduction of sympathetic activity; thus it can be suggested that plasma DHPG is a good index of neuronal metabolism of norepinephrine in this animal. In humans, our data indicate an interesting correlation between norepinephrine and DOMA concentrations in plasma in resting conditions and within three hours after clonidine. Further studies need to be carried out to establish whether DOMA is a better index of neuronal metabolism of norepinephrine than DHPG.

Effects of clonidine on plasma catecholamines and neuropeptide Y in hypertensive patients at rest and during stress.

Neuropeptide Y (NPY), a potent vasoconstrictor agent reported to be released, in addition to norepinephrine (NE), by sympathetic nerve endings during stress, may contribute to the pressor response to various stimuli. The objectives of this study were to determine (a) whether plasma NPY concentrations are altered during different types of stress (cold pressor test, mental stress, and active orthostatism) and (b) whether clonidine, via its central sympatholytic effect, affects the stress-induced blood pressure, NPY, and/or catecholamine changes. Eighteen untreated patients with mild essential or borderline hypertension participated in an acute randomized, double-blind, parallel study. The blood pressure and heart rate were recorded during three control periods, each followed by either a cold pressor test (CPT), a mental stress test (MS: mental arithmetic), or active orthostatism (AO), performed in a random order. Venous blood samples for catecholamines and NPY determination were taken at the end of each control and test period. This entire procedure was repeated after oral clonidine (150 micrograms) or placebo. Before treatment, a CPT, MS, or AO increased the blood pressure to the same extent. The stress-induced increase in plasma NE was greater during AO (+99 +/- 23%) than during CPT (+35 +/- 8%) and MS (+55 +/- 12%). The stress-induced increase in plasma epinephrine was only significant during MS (+142 +/- 69%). A small but significant increase in NPY (p < 0.05) was observed during AO only (+10 +/- 7%). Compared to placebo, clonidine significantly decreased the basal blood pressure and the pressor response to CPT, but did not change the pressor response to MS and AO.(ABSTRACT TRUNCATED AT 250 WORDS)