Pharmacology of levosimendan: inotropic, vasodilatory and cardioprotective effects.

WHAT IS KNOWN AND OBJECTIVE: Positive inotropic agents are frequently used in acute decompensated heart failure (ADHF) due to left ventricular systolic dysfunction. These agents are known to improve cardiac performance and peripheral perfusion in the short-term treatment. However, several preclinical and clinical studies emphasized detrimental effects of these drugs on myocardial oxygen demand and on sympathetic tone entailing arrhythmogenesis. Levosimendan is an inotropic agent with an original mechanism of action. This review focuses on major data available for levosimendan. METHODS: A literature search was conducted in the PubMed database by including studies published in English using combinations of the following key words, levosimendan, inotropic drugs and acute heart failure. Furthermore, bibliographies of selected references were also evaluated for relevant articles. The collection for this review was limited to the most recently available human and animal data. RESULTS AND DISCUSSION: Levosimendan's vasodilatory and cardioprotective effects are mediated by calcium sensitization of contractile proteins and opening of adenosine triphosphate (ATP)-dependent K+ channels in vascular smooth muscle cells and on mitochondrial ATP-sensitive potassium [mito.K(ATP)] channels. This inotropic agent has mild PDE inhibitory action. Unlike other inotropic agents, levosimendan improves cardiac performance without activating the sympathetic nervous system. Moreover, there are evidences that levosimendan has additional anti-inflammatory and anti-apoptotic properties that prevent cardiac toxicity and contributes to positive hemodynamic response of the drug. Four randomized trials evaluated the effects of levosimendan on mortality in patients with acute decompensated chronic heart failure; nevertheless, a clear benefit has not been demonstrated so far. Although levosimendan is indicated for the treatment of ADHF (class of recommendation IIa, level of evidence B), it is has not been approved in all countries. WHAT IS NEW AND CONCLUSION: This review summarizes the characteristics and the current knowledge of the literature on levosimendan and its active metabolite OR-1896.

DBH deficiency in an elderly patient: efficacy and safety of chronic droxidopa.

We describe the effects of chronic droxidopa in a patient with Dopamine beta-hydroxylase deficiency diagnosed at the age of 73. Investigations were performed to assess sympathetic activity (MIBG scintigraphy, catecholamines) and cardiovascular droxidopa safety.

Neurogenic orthostatic hypotension of Parkinson's disease: what exploration for what treatment?

The aim of this short review is to illustrate, using orthostatic hypotension as an example, the clinical problems related to autonomic features in Parkinson's disease. Orthostatic hypotension is frequently encountered in Parkinson's disease and its diagnosis remains manometric (a fall of at least 20 and/or 10 mmHg in standing blood pressure). It is often associated with supine hypertension to be taken into account before prescribing. To distinguish between the role of disease and of drugs (not only antiparkinsonian drugs), a simple clinical test of autonomic nervous system activity (deep breathing test and standing test with measurement of 30/15 ratio) can be used. When diagnosis with multisystem atrophy is discussed, cardiac [¹²³I]-metaiodobenzylguanidine (MIBG) scintigraphy is of value showing in Parkinson's disease a decreased uptake of the radiopharmaceutical indicating postganglionic sympathetic denervation. Concerning treatment, nonpharmacological methods have to be systematically used since no drug has been specifically evaluated for the treatment of orthostatic hypotension of Parkinson's disease.

Nanoscale structural mapping as a measure of maturation in the murine frontal cortex.

Atomic force microscopy (AFM) is emerging as an innovative tool to phenotype the brain. This study demonstrates the utility of AFM to determine nanomechanical and nanostructural features of the murine dorsolateral frontal cortex from weaning to adulthood. We found an increase in tissue stiffness of the primary somatosensory cortex with age, along with an increased cortical mechanical heterogeneity. To characterize the features potentially responsible for this heterogeneity, we applied AFM scan mode to directly image the topography of thin sections of the primary somatosensory cortical layers II/III, IV and V/VI. Topographical mapping of the cortical layers at successive ages showed progressive smoothing of the surface. Topographical images were also compared with histochemically derived morphological information, which demonstrated the deposition of perineuronal nets, important extracellular components and markers of maturity. Our work demonstrates that high-resolution AFM images can be used to determine the nanostructural properties of cortical maturation, well beyond embryonic and postnatal development. Furthermore, it may offer a new method for brain phenotyping and screening to uncover topographical changes in early stages of neurodegenerative diseases.

Predictors of Cardiovascular Autonomic Neuropathy Onset and Progression in a Cohort of Type 1 Diabetic Patients.

AIM: The prevalence of cardiovascular autonomic neuropathy (CAN) in diabetes mellitus is well documented. However, the rate and predictors of both the development and progression of CAN have been less studied. Hereby, we assessed the rate and the major risk factors for CAN initiation and progression in a cohort of type 1 diabetic patients followed over a three-year period. METHODS: 175 type 1 diabetic patients (mean age: 50 ± 11 years; female/male: 76/99) with positive bedside screening for CAN were included and underwent 2 standardized autonomic testings using 4 standardized tests (deep breathing, Valsalva maneuver, 30/15 ratio, and changes in blood pressure during standing), separated by 3 ± 1 years. CAN staging was achieved according to the Toronto Consensus Panel on Diabetic Autonomic Neuropathy into 4 categories: absent, possible, confirmed, or severe CAN. RESULTS: Out of the 175 patients included, 31.4% were free of CAN, 34.2% had possible CAN, 24.6% had confirmed CAN, and 9.7% exhibited severe CAN at the first assessment. Among the 103 patients with nonsevere CAN at inclusion, forty-one (39.8%) had an increase of at least one category when reassessed and 62 (60.2%) remained stable. A bivariate analysis indicated that only BMI and exposure to selective serotonin reuptake inhibitors (SSRIs) were significantly different in both groups. A multivariate analysis indicated that lower BMI (OR: 0.15, CI 95%: 0.05-0.48, p = 0.003) and SSRI exposure (OR: 4.18, CI 95%: 1.03-16.97, p = 0.04) were the sole predictors of CAN deterioration. In the 55 patients negative for CAN at the first laboratory assessment, 12 became positive at the second assessment. CONCLUSION: No clear predictive factor for CAN onset was identified. However, once present, CAN progression was related to low BMI and SSRI exposure.

Characterization and distribution of alpha 2-adrenergic receptors in the human intestinal mucosa.

The subtype and the expression of the alpha 2-adrenergic receptor were investigated in the normal mucosa from human intestine by means of radioligand binding, RNase mapping, and measurement of adenylate cyclase activity. The study of the binding of the alpha 2-adrenergic antagonist, [3H]RX821002, to epithelial cell membranes indicated the existence of a single class of noninteracting sites displaying a high affinity for the radioligand (Kd = 1.1 +/- 0.5 nM). The rank order of potency of antagonists to inhibit [3H]RX821002 binding (RX821002 > yohimbine = rauwolscine > phentolamine approximately idazoxan >> chlorpromazine > prazosin) suggested that the receptor is of the alpha 2A subtype. A conclusion which is confirmed by the fact that only alpha 2C10 transcripts were found in the human intestine mucosa. Competition curves with (-)-norepinephrine demonstrated that 60% of the receptor population exhibited high affinity for agonists. This high-affinity state was abolished by the addition of GTP plus Na+ or by prior treatment of the membranes with pertussis toxin indicating it corresponded to G protein-coupled receptors. [32P]ADP-ribosylation and immunoblotting experiments identified two pertussis toxin-sensitive G proteins corresponding to Gi2 and Gi3. The study of the distribution of the receptor indicated that (a) the proximal colon is the intestine segment exhibiting the highest receptor density and (b) the receptor is predominantly expressed in crypts and is preferentially located in the basolateral membrane of the polarized cell. The distribution of the receptor along the crypt-surface axis of the colon mucosa can be correlated with a higher level of alpha 2C10-specific mRNA and a higher efficiency of UK14304 to inhibit adenylate cyclase in crypt cells.

Limited beneficial effects of piceatannol supplementation on obesity complications in the obese Zucker rat: gut microbiota, metabolic, endocrine, and cardiac aspects.

Resveratrol is beneficial in obese and diabetic rodents. However, its low bioavailability raises questions about its therapeutic relevance for treating or preventing obesity complications. In this context, many related natural polyphenols are being tested for their putative antidiabetic and anti-obesity effects. This prompted us to study the influence of piceatannol, a polyhydroxylated stilbene, on the prevention of obesity complications in Zucker obese rats. A 6-week supplementation was followed by the determination of various markers in plasma, liver, adipose tissue and heart, together with a large-scale analysis of gut microbiota composition. When given in doses of 15 or 45 mg/kg body weight/day, piceatannol did not reduce either hyperphagia or fat accumulation. It did not modify the profusion of the most abundant phyla in gut, though slight changes were observed in the abundance of several Lactobacillus, Clostridium, and Bacteroides species belonging to Firmicutes and Bacteroidetes. This was accompanied by a tendency to reduce plasma lipopolysaccharides by 30 %, and by a decrease of circulating non-esterified fatty acids, LDL-cholesterol, and lactate. While piceatannol tended to improve lipid handling, it did not mitigate hyperinsulinemia and cardiac hypertrophy. However, it increased cardiac expression of ephrin-B1, a membrane protein that contributes to maintaining cardiomyocyte architecture. Lastly, ascorbyl radical plasma levels and hydrogen peroxide release by adipose tissue were similar in control and treated groups. Thus, piceatannol did not exhibit strong slimming capacities but did limit several obesity complications.

[Migraine in general practice. A French multicenter study]. / Prise en charge de la migraine en médecine générale. Une étude multi-centrique française.

INTRODUCTION: A national survey has been conducted with 349 general practitioners in order to analyze the management of concerned episodic headache in general practice. METHOD: This survey enabled collection of data from 2537 headache patients. The main data concered IHS diagnosis, severity of headache using the MIGSEV scale, management, practices and the impact on daily living (QVM and HIT-6 scales). RESULTS: Out of the 2537 included patients, 52 percent were migraine sufferers according to IHS criteria (code 1.1/1.2), 34 percent presented with migrainous disorders (code 1.7), and 14 percent were non-migraine headache patients. The distribution of management practices showed that 71 percent of them were given non-specific treatments, 46 percent of them specific treatments and 27 percent of them prophylactic treatments. Analysis of the impact of headache using the QVM or the HIT-6 demonstrated a relationship between diagnosis, migraine severity and disability. Analysis of the correlation between the severity of the last migraine attack as evaluated by the patient and that estimated by the doctor showed that the practitioner tended to underestimate the patient's pain. These results highlight the importance of communication between practitioners and migraine sufferers. CONCLUSION: Training of general practitioners in the use of simple tools such as the HIT-6 scale, should be helpful for a better evaluation of the impact of headache on daily living, and hence should lead to more optimal therapeutic management of headache patients.

Glutamate antagonists and Parkinson's disease: a review of clinical data.

Several lines of evidence demonstrate that glutamate antagonists can reverse experimental parkinsonism in animals. However, few clinical studies have been undertaken, principally because there is a shortage of glutamate antagonists which are considered safe for human use. This paper details the results of preliminary studies carried out on dextromethorphan, an anti-tussive agent and a weak open-channel blocker of the NMDA receptor; and the cerebral anti-ischaemic drug ifenprodil, a novel non-competitive inhibitor of the polyamine modulatory site on the NMDA receptor. Trials with these two compounds in small groups of parkinsonian volunteers have not demonstrated conclusive symptomatic improvement. These results do not exclude a possible role for NMDA receptor antagonists in the pharmacotherapy of Parkinson's disease, but rather point to the need for developing more potent and safe NMDA antagonists, with better pharmacodynamic and pharmacokinetic profiles.

Simulated microgravity increases beta-adrenergic lipolysis in human adipose tissue.

The effect of a sustained decrease in sympathetic nervous activity, achieved through 5-day head-down bed rest (HDBR), on the beta-adrenergic lipolytic activity of s.c. adipose tissue was studied in eight healthy men. The in situ beta-adrenoceptor (AR) sensitivity was studied using the microdialysis method. Local perfusion of increasing concentrations of isoprenaline showed an increased beta-AR sensitivity to lipolysis (assessed by extracellular glycerol concentration) and to vascular tone (assessed by the ethanol clearance). The adrenergic sensitivity of isolated adipocytes was studied in vitro. Basal lipolysis and the response to nonselective (isoprenaline) or selective (dobutamine, terbutaline, and CGP 12177) beta-AR agonists were increased after HDBR as was the lipolytic effect of dibutyryl cAMP. When data were expressed as a percentage of the dibutyryl cAMP effect to rule out the postreceptor events, basal and lipolytic responses to beta-AR agonists where similar before and during HDBR. The alpha 2-AR-mediated antilipolytic effects of adrenaline were not modified. Lymphocyte beta-AR number was unchanged during HDBR. Our results demonstrate that a sustained sympathoinhibition induces an increase in the lipolytic beta-adrenergic response in adipose tissue and suggest that this hypersensitization is linked to an increase in the postreceptor steps of the lipolytic cascade in the adipocyte rather than to changes in beta-adrenoceptors.

Decreased high affinity state in platelet alpha 2-adrenoceptors from diabetic patients with orthostatic hypotension.

Plasma catecholamine levels, total platelet alpha 2-adrenoceptor number and affinity state (using [3H]yohimbine binding) were investigated in insulin-dependent diabetic patients with (n = 12) or without (n = 10) orthostatic hypotension due to autonomic neuropathy as well as in normal control subjects (n = 6). Mean resting basal catecholamine values were similar in the three groups. One-minute standing elicited an increase in norepinephrine plasma level (but not in epinephrine plasma levels) in control group but not in diabetic patients (with or without orthostatic hypotension). The maximal number of platelet alpha 2-adrenoceptors (and KD) calculated by [3H]yohimbine saturation experiments was similar in the three groups. The percentage of platelet alpha 2-adrenoceptors in high affinity state (inhibition experiments of [3H]yohimbine by UK14,304, a specific alpha 2-adrenergic full agonist) was significantly lower in diabetic patients with orthostatic hypotension (29.2 +/- 5.3%) than in the other two groups. No significant difference was found between the control group (60.0 +/- 2.0%) and diabetic patients without orthostatic hypotension (64.3 +/- 3.1%). Since platelet alpha 2-adrenoceptors are thought to be a suitable index of vascular alpha-adrenoceptors, the decrease in platelet alpha 2-adrenoceptors in high affinity state could explain the occurrence of orthostatic hypotension in insulin-dependent diabetic patients. Multiple pathophysiological mechanisms underly orthostatic hypotension in insulin-dependent diabetic patients and include anomalies both in the sympathetic nervous system and in alpha 2-adrenoceptor coupling.

Two weeks of treatment with deprenyl (selegiline) does not prolong L-dopa effect in parkinsonian patients: a double-blind cross-over placebo-controlled trial.

We investigated the influence of 2 weeks of treatment with deprenyl on the acute effect of a single dose of 200 mg of L-dopa in a double-blind cross-over placebo-controlled trial in 16 parkinsonian patients with wearing-off phenomena. Deprenyl induced no significant benefit in the duration or the maximal improvement of L-dopa's effect. Moreover, deprenyl treatment did not improve the patient's motor status.

Eletriptan in acute migraine: a double-blind, placebo-controlled comparison to sumatriptan. Eletriptan Steering Committee.

OBJECTIVE: To compare the efficacy, safety, and tolerability of oral eletriptan (20 mg, 40 mg, and 80 mg) with that of oral sumatriptan (100 mg) and placebo for the acute treatment of migraine. BACKGROUND: Eletriptan is a potent and selective agonist at human recombinant 5HT1B/1D receptors, with efficacy in animal models that predict antimigraine activity. In healthy volunteers, the pharmacokinetics of eletriptan are characterized by linear and rapid oral absorption. METHODS: Randomized, double-blind, parallel-group study conducted in 857 outpatients with a diagnosis of migraine according to the International Headache Society (IHS) criteria. Of these, 692 took study medication for one acute migraine attack and provided on-drug efficacy data. Subjects received either placebo, 100 mg of sumatriptan or 20 mg, 40 mg, or 80 mg of eletriptan for the treatment of an acute migraine attack. The primary endpoint was the percentage of patients with a headache response (improvement in pain intensity from moderate or severe to mild or none) at 2 hours after treatment. RESULTS: At the primary endpoint (2 hours after dosing), headache response rates were 24% (30/126) for placebo; 55% (63/115) for sumatriptan, 100 mg; 54% (70/129) for eletriptan, 20 mg; 65% (76/117) for eletriptan, 40 mg; and 77% (91/118) for eletriptan, 80 mg. There was a difference compared with placebo (p<0.001) for all doses of eletriptan, and at 2 hours there was a difference between sumatriptan, 100 mg, and eletriptan, 80 mg (p<0.001). Headache-free rates at 2 hours were superior to placebo (6%; p<0.001) for both the 80-mg dose of eletriptan (37%) and the 40-mg dose (29%), with the 80-mg dose also being superior to 100 mg of sumatriptan (23%; p<0.05). Eletriptan and sumatriptan were well tolerated, and the majority of adverse events were mild or moderate in intensity and transient. CONCLUSION: In this placebo-controlled trial, eletriptan, at selected doses, demonstrated superior efficacy, onset of action and patient acceptability in the acute treatment of migraine when compared with oral sumatriptan and placebo.

Blood pressure and plasma catecholamines in never-treated parkinsonian patients: effect of a selective D1 agonist (CY 208-243).

We found blood pressure (BP), heart rate (HR), plasma norepinephrine (NE), and epinephrine (E) levels in the lying and the standing positions to be similar in never-treated parkinsonian patients (stages 1 and 2) and age-matched controls. CY 208-243, a new centrally active D1 agonist, significantly decreased BP, HR, and NE (but not E) values in the lying position; it elicited orthostatic hypotension and blunted the rise in NE elicited by standing up. These results indicate that the early stages of Parkinson's disease are not accompanied by major changes in autonomic cardiovascular function and suggest the involvement of central D1-receptors in the control of sympathetic tone.

Changes in short-term variability of blood pressure and heart rate during the development of obesity-associated hypertension in high-fat fed dogs.

OBJECTIVE: To investigate the nature and time course of autonomic nervous system changes elicited by a 21-week ad libitum high-fat diet (HFD) in dogs. RESULTS: The HFD increased body weight (+22.0+/-2.8% at week 21) with an abdominal circumference gain significantly more elevated than the thoracic one. The increases in insulin and free fatty acid plasma levels were correlated with body weight changes. Systolic and diastolic blood pressures and heart rate significantly increased (+23+/-6, +28+/-5 and 19+/-9% respectively). Arterial hypertension was characterized by an increase in cardiac output (+22.3+/-7.7%), in left ventricular mass (+18.1+/-5.0% at week 21) and a decrease in spontaneous baroreflex efficiency (-55+/-6%). The time course of autonomic changes (using spectral analysis of systolic blood pressure and heart rate) showed the existence of time-dependent modifications, which were linked with food intake. The initial rise in arterial blood pressure during body weight increment (observed between the 1st and 8th week of HFD) was associated with a transient increase in the low frequency band of systolic blood pressure variability and noradrenaline plasma levels associated with a long-lasting decrease in the high frequency band of heart rate variability. Early changes in short-term variability were significantly correlated with free fatty acid plasma levels. In contrast, the steady-state of obesity-related hypertension was associated with a decreased high frequency band of heart rate variability, without significant changes in noradrenaline plasma levels. CONCLUSIONS: This study shows that the HFD induces abdominal obesity, hyperinsulinaemia and arterial hypertension, with a left ventricular hypertrophy associated with a biphasic changes in autonomic activity: an early and long-lasting decrease in parasympathetic nervous system activity and an early but transient increase in sympathetic activity. The present data suggest that autonomic nervous system changes are dependent on the time course of obesity development.

A study of tolerance to apomorphine.

1. The present study was designed to investigate tolerance to several pharmacological effects of apomorphine. 2. Changes in blood pressure, heart rate, plasma noradrenaline levels, rectal temperature, respiratory rate and retching plus vomiting were compared after administration of apomorphine (200 micrograms kg-1, i.v. as a bolus) or saline at different time intervals (30, 120 and 720 min) in four groups of chloralose-anaesthetized dogs. 3. The first administration of apomorphine induced a significant decrease in blood pressure and rectal temperature, a marked rise in heart rate with no change in noradrenaline plasma levels or respiratory rate. Emesis occurred in 71% of the animals. 4. A second administration of apomorphine 30 min later failed to modify blood pressure or heart rate. In contrast, the magnitude of apomorphine-induced changes in blood pressure and heart rate was similar to that observed after the first administration when apomorphine was given 120 or 720 min later. 5. The apomorphine-induced decrease in rectal temperature evoked by a second dose of apomorphine was less marked when given 30 and 120 min after the first dose and unchanged when given 720 min later. 6. The number of animals exhibiting retching and vomiting was lower when apomorphine was reinjected after 30 min than when the time between two successive injections of apomorphine was 120 or 720 min. 7. These results show that tolerance to apomorphine involves its cardiovascular, hypothermic and emetic effects. The time course of tolerance to repeated injections of apomorphine is longer for its hypothermic than for its hypotensive or emetic effects. This suggests a tissue-specific regulation of D2 dopamine receptors to repeated injections of apomorphine.

Identification of human platelet alpha 2-adrenoceptors with a new antagonist [3H]-RX821002, a 2-methoxy derivative of idazoxan.

1. The binding of a new alpha 2-adrenoceptor antagonist, [3H]-RX821002 (2-(2-methoxy-1,4-benzodioxan-2-yl)-2-imidazoline), was investigated in human platelet membranes and compared with [3H]-yohimbine binding parameters. 2. Analysis of kinetic data revealed association and dissociation time courses consistent with a simple biomolecular reaction. Saturation isotherms showed that [3H]-RX821002 labelled a higher total number of alpha 2-binding sites (224 +/- 31 vs 168 +/- 24 fmol mg-1 protein) than [3H]-yohimbine and with higher affinity (Kd: 0.92 +/- 0.06 vs 1.51 +/- 0.08 nM). Moreover [3H]-RX821002 exhibited a lower percentage of nonspecific binding 3. The difference in total binding is due to a better labelling of the alpha 2-adrenoceptors in the low affinity state by [3H]-RX821002 since the labelled receptors number in high affinity state was identical with the two radioligands. 4. [3H]-RX821002 binding displayed a specificity similar to that obtained with [3H]-yohimbine. The potency of various compounds acting on adrenoceptors was: yohimbine greater than oxymetazoline greater than UK14304 greater than (-)-adrenaline greater than prazosin greater than or equal to (+)-adrenaline greater than isoprenaline. This order of potency is classical for an alpha 2A-adrenoceptor. 5. RX821002 is a more potent alpha 2-adrenoceptor antagonist than yohimbine on adrenaline-induced platelet aggregation. 6. These results indicate that [3H]-RX821002 is a suitable ligand for the identification of human platelet alpha 2-adrenoceptors.

Reserpine induces vascular alpha 2-adrenergic supersensitivity and platelet alpha 2-adrenoceptor up-regulation in dog.

1. The aim of the present study was to investigate the influence of catecholamine levels on the regulation of alpha 2-adrenoceptor sensitivity in dogs. 2. Blood pressure and heart rate values at rest, plasma catecholamine levels, platelet and adipocyte alpha 2-adrenoceptors as well as the alpha 2-mediated cardiovascular responses to clonidine (10 micrograms kg-1 i.v., after alpha 1-, beta-adrenoceptor plus muscarinic blockade) or noradrenaline (0.5, 1, 2 and 4 micrograms kg-1 i.v. after alpha 1- and beta-adrenoceptor blockade) were measured before and after reserpine treatment (0.1 mg kg-1 day-1 s.c. over 15 days). 3. Reserpine induced a significant decrease in resting systolic and diastolic blood pressures (213 +/- 2/87 +/- 6 mmHg before vs 158 +/- 5/59 +/- 3 mmHg after treatment) as well as in heart rate (91 +/- 2 beats min-1 before vs 76 +/- 3 beats min-1 after treatment). 4. A 5 min tilt test performed under chloralose anesthesia, failed to modify blood pressure before treatment whereas it induced a significant fall in the same animals after the 15 day treatment. Plasma levels of noradrenaline significantly decreased (262 +/- 58 vs 66 +/- 31 pg ml-1) whereas plasma adrenaline levels were unchanged. 5. The alpha 2-mediated pressor responses to noradrenaline were significantly increased after reserpine. Clonidine induced a marked pressor effect (+72 and +45% in systolic and diastolic blood pressures respectively) after reserpine treatment. This effect was suppressed by administration of RX-821002, a new specific alpha 2-adrenoceptor antagonist. 6. Reserpine treatment significantly increased platelet alpha 2-adrenoceptor number (identified with [3H]- yohimbine or [3H]-RX821002) with no change in Kd values. alpha 2-Adrenoceptor number remained unchanged in adipocytes (identified with [3H]-RX821002). 7. These results show that a 15 day treatment with reserpine induces a vascular alpha 2-adrenergic supersensitivity and an up-regulation in platelet alpha 2-adrenoceptors. In contrast, this phenomenon does not involve all the tissues since adipocyte alpha 2-adrenoceptors escape the effect of reserpine. We suggest that the levels of plasma noradrenaline play an important role in the regulation of the platelet and vascular alpha 2-adrenoceptors. In contrast, adipocyte alpha 2-adrenoceptors are not affected by changes in plasma noradrenaline levels.

Myocardial hypertrophy, cardiac beta-adrenoceptors and adenylate cyclase activity during sinoaortic denervation in dogs.

1. The long-term effects of sinoaortic denervation on the development of left ventricular hypertrophy (assessed by the measurement of the ratio (R): heart weight/total body weight and LVT: left ventricular thickness), myocardial beta-adrenergic receptivity (measured by [125I]-cyanopindolol binding and adenylate cyclase activity) and plasma catecholamine levels (measured by h.p.l.c.) were investigated in three groups of dogs: normotensive controls (group 1), dogs made hypertensive by sinoaortic denervation and evaluated 1 (group 2) and 18 months (group 3) later. 2. Noradrenaline (NA) and adrenaline (A) plasma levels were 461 +/- 54 and 85 +/- 45 pg ml-1 in controls, 861 +/- 185 and 191 +/- 23 pg ml-1 in group 2 (P less than 0.05). They were normal in group 3 (426 +/- 132 and 110 +/- 16 pg ml-1). 3. R and LVT values were significantly (P less than 0.05) higher in sinoaortic denervated dogs (R = 7.7 +/- 0.1 and 7.8 +/- 0.2; LVT = 13.6 +/- 1.3 and 14.2 +/- 0.9 mm in groups 2 and 3 respectively) than in normotensive dogs (group 1: R = 6.7 +/- 0.1, LVT = 9.3 +/- 0.8 mm). 4. In group 1, the total number of beta-adrenoceptors (Bmax) was 37 +/- 11 and 29 +/- 6 fmol mg-1 protein in the left ventricle (LV) and right auricle (RA) respectively. In group 2, Bmax was significantly lower (10 +/- 3 in LV and 13 +/- 2 fmol mg-1 protein in RA, P less than 0.05) than in group 1. There was no difference between group 1 and group 3 (37 +/- 3 fmol mg-1 prot in LV and 31 +/- 3 fmol mg-1 protein in RA). 5. The percentage of beta 1-adrenoceptors was 82 +/- 4 in LV and 75 +/- 5 in RA in group 1. It was significantly lower (P less than 0.05) in groups 2 (LV: 33 +/- 6 and RA: 33 +/- 5) and 3 (LV: 59 +/- 3 and RA: 55 +/- 4). 6. Basal values of adenylate cyclase activity in LV significantly decreased after sinoaortic denervation.7. These data show that sinoaortic denervation is associated with left ventricular hypertrophy which appears early (1 month) and persists until 18 months despite the normalization of plasma catecholamine levels. The total number of myocardial beta-adrenoceptors is closely related to catecholamine levels but a selective decrease in beta 1-adrenoceptors is observed during cardiac hypertrophy. The fall in basal adenylate cyclase activity suggests that cardiac hypertrophy is associated with an impairment of transmembrane signalling.

Effect of a 7-day treatment with idazoxan and its 2-methoxy derivative RX 821002 [correction of RX 821001] on alpha 2-adrenoceptors and non-adrenoceptor idazoxan binding sites in rabbits.

1. The present study investigates the influence of a 7-day treatment with 2 mg kg-1, s.c., twice daily of RX 821002 (an alpha 2-adrenoceptor antagonist which binds only to alpha 2-adrenoceptors) or idazoxan (alpha 2-antagonist which binds to alpha 2-adrenoceptors and also to non-adrenoceptor idazoxan binding sites: NAIBS) on alpha 2-adrenoceptor (labelled with [3H]-RX 821002) and NAIBS (labelled with [3H]-idazoxan) number in three tissues (adipocytes, colocytes and platelets) in the rabbit. 2. Acute administration of RX 821002 or idazoxan increased plasma non-esterified fatty acids (NEFA) and catecholamine levels with no change in plasma glucose levels. 3. The 7-day treatment with RX 821002 or idazoxan failed to influence food intake, total body weight or perirenal adipose tissue weight. 4. RX 821002 and idazoxan increased the number of [3H]-RX 821002 binding sites in adipose tissue with no change in colocytes or platelets. 5. RX 821002 and idazoxan failed to modify [3H]-idazoxan binding sites on adipocytes and colocytes. No significant [3H]-idazoxan binding was detected on rabbit platelets. 6. The results show that a 7-day treatment with alpha 2-antagonists induces an up-regulation in adipocyte alpha 2-adrenoceptors. In contrast, this phenomenon does not involve all the tissues since colocytes and platelets escape the effects of alpha 2-antagonists. The data suggest a differential regulation of alpha 2-adrenoceptors according to their location. 7. The fact that NAIBS did not vary suggests that alpha 2-adrenoceptors and NAIBS are two different entities. Finally, since RX 821002 and idazoxan exert similar effects after either acute or chronic treatment, it is suggested that NAIBS are not involved in the control of catecholamine release or in NEFA or glucose metabolism.