Changes in vascular alpha 1- and alpha 2-adrenoceptor responsiveness by selegiline treatment.

Pharmacoepidemiological studies have reported an excess of mortality with selegiline, a MAO B inhibitor used in the treatment of Parkinson's disease. The mechanism of this putative adverse effect remains unknown but an interaction with the sympathetic nervous system was suggested. The aim of the present study was to investigate the influence of selegiline (10 mg/daily, orally during one week) on vascular alpha1- and alpha2-adrenoceptor responsiveness in conscious unrestrained dogs. Selegiline significantly increased resting values of both systolic and diastolic blood pressures and noradrenaline plasma levels (HPLC) without changing heart rate. Moreover, spectral analysis of systolic blood pressure (Fast Fourier Transformation) showed that selegiline increased the relative energy of a low frequency band without modifying the total spectrum. ED 50 calculated from dose-pressor response curves with phenylephrine (after beta-blockade by propranolol), an index of alpha1-adrenoceptor response or with noradrenaline (after alpha1- and beta blockade by prazosin plus propranolol), an index of alpha2-adrenoceptor response, were significantly higher after selegiline. Selegiline failed to modify the number of platelet alpha2-adrenoceptors measured by [(3)H] RX 821002 binding. Yohimbine-induced increase in noradrenaline release was significantly more marked after selegiline. These results support the evidence that selegiline induces a vascular alpha1- and alpha2-adrenoceptor-hyposensitivity that can be explained by the increase in noradrenaline release elicited by the drug.

Fluoxetine-induced pressor response in freely moving rats: a role for vasopressin and sympathetic tone.

The present study was performed in order to assess, in freely moving rats, the cardiovascular effects of central administration of fluoxetine, a serotonin reuptake inhibitor. Two kinds of experiments were performed: 1) acute central administration of fluoxetine. and 2) chronic intraperitoneal administration of fluoxetine plus selegiline, a monoamine oxidase B inhibitor. Intracerebroventricular (i.c.v.) administration of fluoxetine (5-50 microg) induced an increase in blood pressure. This fluoxetine-induced pressor response reached its maximal 1 hour after injection without any significant change in heart rate. At the dose of 10 microg i.c.v., fluoxetine significantly increased mean blood pressure by 16 +/- 4 mmHg. This pressor response was reduced by an intravenous (i.v.) pretreatment with the alpha1-adrenoceptor antagonist, prazosin (500 microg kg(-1)) (+ 7 +/- 4 mmHg, P <0.05) or with the V1A-vasopressin receptor antagonist (20 microg kg(-1)) (+5 +/- 3 mmHg, P < 0.05). The pressor response was completely abolished by a concomitant pretreatment with prazosin plus the V1A-vasopressin receptor antagonist. Pretreatment with the beta-adrenoceptor antagonist, propranolol (1 mg kg(-1) i.v.), or the 5-HT2 receptor antagonist, ketanserine (5 mg kg(-1) i.v.), did not modify the fluoxetine-induced pressor response. In freely moving rats receiving fluoxetine (10 microg i.c.v.), vasopressin plasma levels were significantly higher (39 +/- 5 pg mL(-1) than in rats receiving 10 microL i.c.v. saline (14 +/- 4 pg mL(-1)). A 30 day intraperitoneal (i.p.) administration of fluoxetine in association with selegiline induced an increase in noradrenaline plasma levels and locomotor activity without any significant change in blood pressure and heart rate. These data suggest that, the pressor response elicited by central acute administration of fluoxetine is mediated by both an increase in sympathetic tone and vasopressin release. This observation could suggest the putative interest of alpha1-adrenoceptor and or V1A-vasopressin receptor antagonists in the treatment of "Serotonin Syndrome".

Role of simian virus 40 Vp1 cysteines in virion infectivity.

We have developed a new nonoverlapping infectious viral genome (NO-SV40) in order to facilitate structure-based analysis of the simian virus 40 (SV40) life cycle. We first tested the role of cysteine residues in the formation of infectious virions by individually mutating the seven cysteines in the major capsid protein, Vp1. All seven cysteine mutants-C9A, C49A, C87A, C104A, C207S, C254A, and C267L-retained viability. In the crystal structure of SV40, disulfide bridges are formed between certain Cys104 residues on neighboring pentamers. However, our results show that none of these disulfide bonds are required for virion infectivity in culture. We also introduced five different mutations into Cys254, the most strictly conserved cysteine across the polyomavirus family. We found that C254L, C254S, C254G, C254Q, and C254R mutants all showed greatly reduced (around 100,000-fold) plaque-forming ability. These mutants had no apparent defect in viral DNA replication. Mutant Vp1's, as well as wild-type Vp2/3, were mostly localized in the nucleus. Further analysis of the C254L mutant revealed that the mutant Vp1 was able to form pentamers in vitro. DNase I-resistant virion-like particles were present in NO-SV40-C254L-transfected cell lysate, but at about 1/18 the amount in wild-type-transfected lysate. An examination of the three-dimensional structure reveals that Cys254 is buried near the surface of Vp1, so that it cannot form disulfide bonds, and is not involved in intrapentamer interactions, consistent with the normal pentamer formation by the C254L mutant. It is, however, located at a critical junction between three pentamers, on a conserved loop (G2H) that packs against the dual interpentamer Ca(2+)-binding sites and the invading C-terminal helix of an adjacent pentamer. The substitution by the larger side chains is predicted to cause a localized shift in the G2H loop, which may disrupt Ca(2+) ion coordination and the packing of the invading helix, consistent with the defect in virion assembly. Our experimental system thus allows dissection of structure-function relationships during the distinct steps of the SV40 life cycle.

[Reduction of the pressor effect of fluoxetine after V1A-vasopressin receptor blockade in the conscious rats]. / Réduction de l'effet presseur de la fluoxétine après blocage des récepteurs V1A de la vasopressine, chez le rat conscient.

Pharmacovigilance data have reported some cases of arterial hypertension in patients treated with serotonin reuptake inhibitors. This side effect is now called serotonin syndrome. Moreover, some authors have shown that these drugs could reduce, at least in part, the fall in blood pressure (BP) observed in experimental models or in human forms of orthostatic hypotension, suggesting a modulation of the autonomic nervous system by these drugs. These data led us to study in freely moving Wistar rats the mechanisms involved and the putative involvement of autonomic nervous system. Intracerebroventricular (i.c.v.) administration of fluoxetine (5-50 micrograms) induced an increase in BP similar to which was obtained following central administration of serotonin (5-HT) (0.5-5 micrograms). After 5-HT, the pressor effect was immediate (1 min following injection) and involved the baroreflex pathway (bradycardia). The fluoxetine-induced pressor response reached its maximal 1 hour after injection without any significant change in heart rate (HR). At the dose of 10 micrograms i.c.v., fluoxetine significantly increased mean BP by 16 +/- 4 mmHg. This pressor response was partially but significantly reduced by a pretreatment by the alpha 1-adrenoreceptor antagonist, prazosin (500 micrograms.kg-1 i.v.) (+7 +/- 4 mmHg, p < 0.05) or by a V1A-vasopressin receptor antagonist (20 micrograms.kg-1 i.v.) (+5 +/- 3 mmHg, p < 0.05). However, pretreatment by the beta-adrenoreceptor antagonist, propranolol (1 mg.kg-1 i.v.) and the antagonist 5-HT2, ketanserine (5 mg.kg-1 i.v.) did not modify the fluoxetine-induced pressor response. In freely moving rats receiving fluoxetine (10 micrograms i.c.v.), vasopressin plasma levels were significantly higher (+39 +/- 5 pg.mL-1) than in rats receiving saline (100 microL i.c.v.) (+14 +/- 4 pg.mL-1), thus confirming the involvement of vasopressinergic mechanisms in the fluoxetine-induced pressor response. These data suggest that in freely moving Wistar rats, central acute administration of fluoxetine induces a pressor response mediated by both an increase in sympathetic tone and a vasopressin release. This observation could suggest the putative use of alpha 1-adrenoreceptors antagonists and/or V1A-vasopressin receptor antagonists in the treatment of the serotonin syndrome.

Characterization of the central muscarinic cholinoceptors involved in the cholinergic pressor response in anesthetized dogs.

Previous reports have shown that an intracisternal (i.c.) injection of acetylcholine in the dog increases both arterial blood pressure and plasma levels of noradrenaline and vasopressin via central muscarinic receptors. The aim of the present study was to characterize the central muscarinic cholinoceptor subtypes involved in such central cholinergic responses in anesthetized male Beagle-Harrier dogs (n = 12). For this purpose, we studied the relative potency of various muscarinic receptor antagonists to block the acetylcholine-induced pressor responses (30 microg kg(-1) i.c.). The acetylcholine-induced pressor response was inhibited in a dose-dependent manner by the i.c. administration of the non-selective muscarinic receptor antagonist atropine (ID50 = 0.5 microg kg(-1)), the muscarinic M receptor antagonist pirenzepine (ID50 = 0.45 microg kg(-1)), the muscarinic M2 receptor antagonist methoctramine (ID50 = 8.5 microg kg(-1)) and the muscarinic M3 receptor antagonist para-fluoro-hexahydro-sila-difenidol (ID50) = 43.7 microg kg(-1)). The order of potency of these four muscarinic receptor antagonists was: atropine = pirenzepine > methoctramine >> para-fluoro-hexahydro-sila-difenidol. In order to confirm the selectivity for muscarinic M1 receptors of this dose of pirenzepine, we checked that 40- to 50-fold higher concentrations were necessary to block a typical muscarinic M2 receptor response (bradycardia) and a typical muscarinic M3 receptor response (endothelial vasodilation) compared with methoctramine and para-fluoro-hexahydro-sila-difenidol, respectively. These results suggest that the pressor response elicited by intracisternal injection of acetylcholine in anesthetized Beagle-Harrier dogs is mediated through the activation of the muscarinic M1 cholinoceptor subtype.

Spontaneously hypertensive rats cholinergic hyper-responsiveness: central and peripheral pharmacological mechanisms.

1. The mechanisms and the subtypes of muscarinic receptors implicated in the cardiovascular effects of physostigmine were investigated in conscious normotensive and spontaneously hypertensive rats. 2. Intravenous (i.v.) physostigmine (50 microg kg-1) induced in both strains a long pressor response, accompanied by a bradycardia. This pressor response was larger in spontaneously hypertensive (+41+/-6 mmHg) than in Wistar-Kyoto (+25+/-2 mmHg) rats (P<0.05). 3. Pretreatment with atropine sulphate (0.4 mg kg-1 i.v.), completely abolished the physostigmine-induced pressor response in both normotensive and hypertensive rats. In both strains, the physostigmine pressor response was significantly reduced by the systemic administration of either an alpha1-adrenoceptor antagonist (prazosin, 1 mg kg-1) or a V1A-vasopressin receptor antagonist (AVPX, 20 microg kg-1). This physostigmine pressor effect was completely abolished in both strains when both antagonists were administered concomitantly. 4. In WKY rats, the pressor response to physostigmine (50 microg kg-1 i.v.) was inhibited in a dose-dependent manner by i. c.v. administration of atropine (ID50=3.70 nmoles), the M1 receptor antagonist pirenzepine (ID50=10.71 nmoles), the M2 receptor antagonist methoctramine (ID50=4.31 nmoles), the M3 receptor antagonist p-F-HHSiD (ID50=60.52 nmoles) and the M4 receptor antagonist tropicamide (ID50=214.20 nmoles). In the hypertensive strain, the ID50 were found to be significantly higher for atropine (7.34 nmoles), pirenzepine (21.60 nmoles) and p-F-HHSiD (139.50 nmoles) (P<0.05). 5. The present results indicate that physostigmine acts in normotensive and spontaneously hypertensive rats, through stimulation of both central M2 and M1 cholinoceptors to induce a rise in blood pressure mediated by an increase in plasma vasopressin and sympathetic outflow. Moreover, our results suggest that some modifications of the M1 receptor subtypes in terms of expression or affinity could be responsible for the hyper-responsiveness of the hypertensive strain to cholinomimetic agents.

Pressor and bradycardic effects of tacrine and other acetylcholinesterase inhibitors in the rat.

The cardiovascular effects of three different acetylcholinesterase inhibitors: physostigmine, tacrine and rivastigmine injected by intravenous (i.v.) route were compared in freely moving Wistar rats. The three drugs significantly increased both systolic and diastolic blood pressure and decreased heart rate. Compared to physostigmine, a 20-fold higher dose of tacrine and a 40-fold higher dose of rivastigmine was necessary to induce a comparable pressor effect. Tacrine was chosen as a model to study the mechanisms underlying the cardiovascular effects of i.v. cholinesterase inhibitors. Atropine totally abolished while methylatropine did not affect tacrine pressor effects. Conversely, both drugs abolished tacrine-induced bradycardia. The alpha1-adrenoceptor antagonist prazosin or the vasopressin V1 receptor antagonist, [beta-mercapto-beta,beta-cyclopenta-methylenepropionyl1, O-Me-Tyr2, Arg8] vasopressin partially but significantly reduced tacrine pressor effect and mostly abolished it when administered concomitantly. The tacrine pressor response was inhibited in a dose-dependent manner by the i.c.v. administration of the non-selective muscarinic receptor antagonist atropine (ID50 = 1.45 microg), the muscarinic M1 receptor antagonist pirenzepine (ID50 = 4.33 microg), the muscarinic M2 receptor antagonist methoctramine (ID50 = 1.39 microg) and the muscarinic M3 receptor antagonist para-fluoro-hexahydro-sila-difenidol (ID50 = 31.19 microg). Central injection of such muscarinic receptor antagonists did not affect tacrine-induced bradycardia. Our results show that acetylcholinesterase inhibitors induce significant cardiovascular effects with a pressor response mediated mainly by the stimulation of central muscarinic M2 receptors inducing a secondary increase in sympathetic outflow and vasopressin release. Conversely, acetylcholinesterase inhibitor-induced bradycardia appears to be mediated by peripheral muscarinic mechanisms.

Endogenous central cholinergic systems and baroreflex modulation in the conscious dog.

Intracisternal atropine and mecamylamine failed to modify baroreflex sensitivity in dogs, suggesting a lack of cholinergic neurons integrated in baroreflex pathways. Conversely, neostigmine lowered baroreflex sensitivity suggesting a putative cholinergic modulation.

Effect of losartan on afferent nerve stimulation.

The present study was undertaken to investigate the effects of losartan, a non-peptide angiotensin II subtype 1 (AT1) receptor antagonist, on both the pressor responses elicited by stimulation of afferent vagal nociceptive fibres and the involvement of the sympathetic nervous system (evaluated by plasma levels of noradrenaline and its co-neurotransmitter neuropeptide Y) in dogs. Electrical stimulation of the afferent fibres of the vagus (1, 5, 10 and 20 Hz) elicited a frequency-dependent increase in blood pressure and heart rate. Plasma noradrenaline levels only increased after stimulation at frequencies of 10 and 20 Hz. Plasma neuropeptide Y levels did not change. Losartan (10 mg/kg i.v.) induced both a decrease in resting blood pressure and an increase in basal plasma levels of noradrenaline and neuropeptide Y. Losartan failed to modify the magnitude of the electrically-evoked pressor and positive chronotropic responses. The angiotensin AT1 receptor antagonist elicited a fall in plasma noradrenaline values after a 1 Hz stimulation and abolished the increase in plasma noradrenaline levels induced by the 10 (but not 20) Hz stimulation. The data suggest that angiotensin AT1 receptors are not directly involved in acute pressor responses induced by stimulation of afferent vagal fibres. Moreover, the results show that, besides its sympatho-inhibitory effect, losartan can exert a sympatho-excitatory action as shown by the increase in the plasma levels of both noradrenaline and its coneurotransmitter, neuropeptide Y.

[Functional decoupling of left ventricular beta-adrenoceptor in a canine model of obesity-hypertension]. / Découplage fonctionnel des récepteurs beta-adrénergiques ventriculaires gauches dans un modèle canin d'obésité-hypertension.

OBJECTIVE: To assess cardiac beta-adrenoceptors (beta-AR) in an obesity-hypertension model. METHODS: Six male beagle dogs (aged 35 +/- 5 months) receiving during 30 weeks a high-fat diet with 60% uncooked beef fat were compared to 6 normal beagle dogs. With right auricular and left ventricular samples we analysed cardiac beta-AR density through binding study using [125I]-cyanopindolol. beta 1 and beta 2 densities were obtained by competition with CGP 20712A. Affinity state of beta-AR was assessed by competition with isoproterenol. Noradrenaline plasma level was assayed by HPLC. Left ventricular mass (LV mass) was measured by echocardiography. Results are expressed as mean +/- SE. All comparisons were performed using a variance analysis (*: p < 0.05). RESULTS: Systolic blood pressure was significantly higher in obesses (245 +/- 8 vs 197 +/- 10 mmHg in controls). Diastolic blood pressure did not differed between both groups (93 +/- 3 vs 84 +/- 3 mmHg in controls). Noradrenaline plasma levels were similar in both groups (276 +/- 30 vs 235 +/- 50 pg/mL in controls). Obesses were characterized by higher LV mass (80 +/- 24 vs 67 +/- 15 g in controls*). Right auricular and left ventricular beta-AR densities were not different in obesses (57 +/- 6 and 67 +/- 4 fmoles/mg protein) and in controls (68 +/- 7 and 63 +/- 9 fmoles/mg protein). The beta 1-AR proportion was the same in obesses and controls in right auricule (63 +/- 4 vs 64 +/- 3% in controls) and left ventricule (59 +/- 3 vs 60 +/- 4% in controls). The proportion of beta-AR receptors in a high affinity state was similar in right auricular samples (69 +/- 4 vs 67 +/- 3%) in controls) but was significantly different in left ventricule (28 +/- 6 vs 74 +/- 6%) in controls). CONCLUSION: Left ventricular beta-adrenoceptors came under a specific desensibilisation independent of plasma noradrenaline levels. This functional decoupling of beta-adrenoceptors may account for the progressive systolic dysfunction of hypertensive cardiomyopathy.

Fluoxetine in orthostatic hypotension of Parkinson's disease: a clinical and experimental pilot study.

Recent clinical studies have reported a beneficial effect of fluoxetine, a serotonin reuptake inhibitor, in patients with severe refractory orthostatic hypotension. The present study was undertaken to investigate the effect of fluoxetine in orthostatic hypotension occurring during Parkinson's disease on both blood pressure values and number of clinical symptoms during orthostatic procedure evaluated using a validated clinical rating scale. In a pilot study performed in fourteen patients with idiopathic Parkinson's disease plus orthostatic hypotension, fluoxetine hydrochloride (20 mg orally daily during one month) significantly reduced the fall in systolic blood pressure [-33 +/- 21 (SD) mmHg before fluoxetine vs -22 +/- 19 mmHg after fluoxetine, P = 0.03] elicited by standing without modifying heart rate. The drug also significantly reduced the number of postural symptoms occurring during the orthostatic procedure [2.9 +/- 1.5 (SD) before fluoxetine vs 1.2 +/- 1.3 after fluoxetine, P = 0.006]. A similar pattern of response was obtained in an experimental model of neurogenic orthostatic hypotension obtained in chronically sino-aortic denervated dogs submitted to an 80 degrees head-up tilt test procedure under chloralose anaesthesia. Fluoxetine did not change plasma noradrenaline levels. This pilot study suggests a slight but clinically significant effect of fluoxetine on both hemodynamic parameters and clinical symptoms in parkinsonian patients suffering from orthostatic hypotension.

Central cardiovascular effects of tacrine in the conscious dog: a role for catecholamines and vasopressin release.

Centrally acting cholinergic agents are currently reported to increase blood pressure in various species through the stimulation of muscarinic cholinoceptors. Moreover, several cardiovascular adverse effects have been reported from clinical studies. The aim of this study was to investigate the effects of tacrine, an acetylcholinesterase inhibitor which has been reported to have therapeutic potential in Alzheimer's disease, on blood pressure and two vasopressor systems (sympathetic and vasopressinergic) in Beagle dogs. Intravenous (i.v.) tacrine (2 mg kg(-1)) induced, in conscious and anesthetized dogs, an increase in systolic and diastolic blood pressure, accompanied by bradycardia. This increase was dose-dependent with a peak effect at 1.5 min following administration. Tacrine also induced an increase in noradrenaline, adrenaline and vasopressin plasma levels. Pretreatment with the muscarinic receptor antagonist, atropine (2 mg kg(-1), i.v.), abolished the pressor response to i.v. injection of tacrine while pretreatment with the peripheral muscarinic receptor antagonist, methylscopolamine (0.2 mg kg(-1), i.v.), did not alter the increase in blood pressure. Similarly, noradrenaline and adrenaline changes in plasma levels were not modified by methylscopolamine but were abolished by atropine pretreatment. A similar tendency although not significant was observed for vasopressin plasma levels. The present results demonstrate that in dogs, tacrine (2 mg kg(-1), i.v.) stimulates central muscarinic cholinoceptors to increase blood pressure through activation of the two components of the sympathetic nervous system (i.e., neuroneuronal noradrenergic and the neurohormonal adrenergic pathways) as well as through increasing noradrenaline, adrenaline and vasopressin plasma levels.

[Autonomic nervous system abnormalities in the initial phase of insulin resistance syndrome. Value of the study of variability of cardiac rate and blood pressure on a model of nutritional obesity]. / Anomalies du système nerveux autonome à la phase initiale du syndrome d'insulinorésistance. Apport de l'étude de la variabilité de la fréquence cardiaque et de la pression artérielle sur un modèle d'obésité nutritionnelle.

Changes in the activity of the sympathetic activity are often involved in the development of human insulin-resistance syndrome. However, the nature of changes in both the parasympathetic and orthosympathetic components are still controversial. We have recently developed an experimental model reproducing in dog this morbid triptyque (obesity, hypertension and hyperinsulinism), obtained by hypercaloric hyperlipidic diet. The aim of the present study was to characterize the changes in autonomic nervous system and spontaneous baroreflex in the initial period of obesity-hypertension syndrome. Ten male Beagle-Harrier dogs were used in this study. We investigated before and during 20 weeks after the beginning of the hypercaloric diet, plasma insulin, noradrenaline levels, spontaneous baroreflex efficiency (using the sequence method), arterial blood pressure, heart rate and their spectral analysis (fast Fourier Transformation) in both low (LF: 50-150 mHz, reflecting sympathetic activity) and high (HF: respiratory rate +/- 50 mHz, reflecting parasympathetic activity) frequency bands. Body weight (+20%), systolic (SBP: +23%) and diastolic (+16%) blood pressure and heart rate (+19%) increased during 6 weeks and then remained stable. Concomitantly, high frequency of HR (22.01 +/- 1.9 vs 14.15 +/- 1.04% at 7th week) and BF of systolic blood pressure (15.6 +/- 1.1 vs 19.2 +/- 1.2% at 4th week); p < 0.07, showed a rapid decrease in parasympathetic tone and a early increase in sympathetic activity. Nevertheless, in steady state of this syndrome, parasympathetic tone returned to initial values (18.43 +/- 3.25% at 20th week). Insulinemia significantly increased from the 4th week (14.2 +/- 0.9 vs 25.3 +/- 2.2 microUI/mL at 20th week), but noradrenaline remained not modify (400 +/- 85 vs 312 +/- 45 pg/mL at 20th week). Spontaneous baroreflex efficiency also decreased from the 2nd week (35.5 +/- 5.5 vs 16.7 +/- 4.9 mmHg/ms at 20th week). This study shows that an hyperlipidic hypercaloric diet induces a decrease in both parasympathetic tone and spontaneous baroreflex efficiency, which could be the physiopathological link between obesity, hypertension and hyperinsulinism.

Effects of octreotide on experimental neurogenic orthostatic hypotension in anaesthetized dogs.

This paper investigates the effects of octreotide (0.1 mg/kg, subcutaneous) on cardiovascular adaptation during head-up tilt test in an experimental model of neurogenic orthostatic hypotension (OH) obtained by chronic sinoaortic denervation in anaesthetized dogs. Blood pressure (BP), heart rate (HR), spectral variability (Fast Fourier transformation on 512 consecutive points, delta t: 2 Hz) and plasma catecholamine levels were measured in a double blind cross-over randomized study versus placebo, in supine position and during a head-up tilt test (80 degrees, 10 min) in six sinoaortic denervated and six control (normal) dogs. In normal dogs, head-up tilt test significantly increased HR and diastolic blood pressure (DBP). Plasma noradrenaline levels and energy of the low frequency band (40-150 mHz) of systolic blood pressure (SBP) significantly increased whereas the energy of the low frequency band of HR significantly decreased. Placebo and octreotide failed to modify supine and head-up tilt values of the measured parameters (except the value of low frequency band of SBP, which increased after octreotide). In sinoaortic denervated dogs, supine values of BP, HR and plasma noradrenaline levels were significantly higher than in controls whereas the energy of the low frequency spectral band of HR and SBP was similar to controls. Head-up tilt test induced a dramatic decrease in BP. HR, plasma noradrenaline levels and energy of the low frequency band of SBP and HR remained unchanged during head-up tilt tests. Neither supine nor head-up tilt values of these parameters were modified 45 min after octreotide or placebo administration. These results show that sinoaortic denervation is a reproducible model of OH characterized by a lack of activation of sympathetic efferent pathways during head-up tilt tests. Octreotide at the dose used remains ineffective to prevent the fall in BP under these experimental conditions.

Effects of yohimbine, an alpha 2-adrenoceptor antagonist, on experimental neurogenic orthostatic hypotension.

Yohimbine has been proposed for the treatment of neurogenic orthostatic hypotension; however, no controlled trial has been performed in experimental models of orthostatic hypotension or in patients with autonomic failure. The aim of the present study was to compare the effects of yohimbine (0.05 mg/kg, intravenously [i.v.]) and placebo (saline) in a new model of neurogenic orthostatic hypotension obtained by sinoaortic denervation (SAD) in chloralose-anaesthetized dogs. Blood pressure, heart rate, noradrenaline plasma levels and systolic blood pressure and heart rate short-term variabilities (calculated on low frequency [40-50 MHz] and high frequency [390-490 MHz] bands) were measured in supine position and after a 10 min 80 degrees head-up tilting. The drugs were administered in a double-blind cross-over randomized fashion. The head-up tilting performed in normal animals increased diastolic blood pressure (+12 +/- 4 mmHg), heart rate (+39 +/- 12 beats per minute [bpm]), the low frequency band of systolic blood pressure and noradrenaline plasma level, without changing systolic blood pressure or heart rate variability. In SAD dogs, a marked fall in systolic (-80 +/- 11 mmHg) and diastolic (-43 +/- 4 mmHg) blood pressures was observed within 1 min after placebo, without modification in heart rate, systolic blood pressure and heart rate short-term variabilities and noradrenaline plasma levels. In SAD dogs, yohimbine (0.05 mg/kg, i.v.) delayed the blood pressure fall elicited by head-up tilting, but failed to modify its magnitude. These results show that, in the model of orthostatic hypotension obtained by SAD, yohimbine, at an alpha 2-adrenoceptor selective dose (0.05 mg/kg), delays the fall in blood pressure elicited by head-up tilting. The effect of yohimbine can be explained by an increase in sympathetic tone.

A study of dopaminergic sensitivity in Parkinson's disease: comparison in "de novo" and levodopa-treated patients.

The present study investigates dopaminergic sensitivity in Parkinson's disease (PD) through the measurement of neuroendocrine (growth hormone: GH, prolactin: PRL) and cardiovascular (blood pressure: BP, heart rate: HR) responses to low doses of apomorphine (5 micrograms/kg s.c.) in three groups of subjects: 13 normal volunteers (controls), 19 "de novo" never-treated PD patients, and 14 levodopa-treated PD patients. Apomorphine did not change BP and HR but significantly decreased PRL plasma levels in controls as well as in the two groups of PD patients. GH plasma levels significantly increased after apomorphine. There was no significant difference in the changes in neuroendocrine (GH, PRL) parameters in the two groups of PD patients in comparison with controls. However, "de novo" patients exhibited a significantly higher number of apomorphine-induced orthostatic symptoms (7 of 19) than did controls (0 of 13) or treated PD patients (2 of 14). These results show that hypothalamic dopaminergic sensitivity (studied through GH and PRL responses to apomorphine) is normal in PD. In contrast, because apomorphine-induced orthostatic hypotension is mainly due to the stimulation of peripheral dopaminergic receptors, our study suggests a peripheral dopaminergic hypersensitivity in some "de novo" never treated (but not in treated) PD patients.

[Effects of octreotide on experimental orthostatic neurogenic hypotension]. / Effets de l'octréotide sur l'hypotension orthostatique neurogène expérimentale.

The synthetic somatostatin analogue, octreotide, has recently been proposed for the treatment of both postprandial and orthostatic hypotension (OH) in humans with autonomic failure related to multiple system atrophy (MSA) or diabetes mellitus. However, pharmacodynamic data are not still available in experimental models of orthostatic hypotension. We investigated in a model of neurogenic orthostatic hypotension, obtained by chronic sinoaortic denervation (SAD) in chloralose-anaesthetized dogs, the effects of octreotide (0.1 mg/kg, subcutaneous route) during a double-blind cross-over study vs placebo. Blood pressure (BP) and heart rate (HR) average values, SBP and HR short-term variabilities (using fast Fourier transformation) in both low (LF: 50-150 mHz) and high frequency range (respiratory rate +/- 50 mHz) and plasma noradrenaline (NA) levels (HPLC) were measured in supine position and during head-up tilt test (HUT: 80 degrees, 10 min) before and 45 min after drug administration. In controls, as expected, head-up tilt test induced a significant increase in DBP (+14 +/- 8 mmHg), HR (+36 +/- 21 beat/min), NA (296 +/- 118 vs 141 +/- 63 pg/ml), SBP-LF (25 +/- 5 vs 14 +/- 3%) whereas HR-HF significantly decreased. The changes during head-up tilt test were not modified after placebo or octreotide administration. In SAD dogs, head-up tilt test elicited a dramatic fall in SBP (-74 +/- 39 mmHg), DBP (-20 +/- 15 mmHg) without any significant change in HR (-5 +/- 12 beat/min), NA (708 +/- 213 vs 606 +/- 331 pg/ml), SBP-LF (16 +/- 3 vs 16 +/- 3%), HR-HF (8 +/- 2 vs 7 +/- 1%). Octreotide or placebo failed to significantly modify any of the measured parameters during head-up tilt test performed 45 min after drug administration. At the dose used, octreotide elicited a 80% decrease in insulin plasma levels after 45 min in both normal and SAD dogs. These results suggest that 1) this experimental model of orthostatic hypotension in SAD dogs is reproductible and can be used to investigate the pharmacological effects of antihypotensive drugs, 2) cardiovascular and biochemical characteristics of the SAD model are similar to those observed in MSA and 3) octreotide, in these experimental conditions, is not able to correct the BP fall during head-up tilt test.