Alain Saadjian

Role of Endogenous Adenosine as a Modulator of Syncope Induced During Tilt Testing

Background—Previous reports that used head-up tilt testing and adenosine administration have suggested that adenosine may be an important endogenous mediator that may trigger a vasovagal response in susceptible patients. However, little is known regarding endogenous adenosine plasma levels (APLs) during vasovagal syncope provoked by tilt testing. The aim of this study was to determine whether APLs differ in patients with a positive head-up tilt test compared with those with a negative test and whether APLs are modified during tilt-induced vasovagal syncope. Methods and Results—APLs (mean±SEM) were measured during head-up tilt test in 26 patients who presented with unexplained syncope. In the 15 patients with a negative test, APLs were 0.39±0.03 &mgr;mol/L at baseline, 0.22±0.03 &mgr;mol/L immediately after tilting, and 0.44±0.03 &mgr;mol/L after 45 minutes. APLs were significantly higher in the 11 patients with a positive test (2.66±0.67 &mgr;mol/L at baseline and 3.22±0.85 &mgr;mol/L immediately after tilting) than in those with a negative test. During tilt testing–induced syncope, APLs increased to reach 4.03±0.66 &mgr;mol/L (ie, a 52% increase compared with baseline levels;P <0.02). Furthermore, we observed that the higher the APL during syncope, the shorter the time to appearance of symptoms. Conclusions—This study showed that APLs were higher in patients with a positive tilt test than in patients with a negative test and that they increased during tilt testing–induced syncope. These observations suggest that adenosine release may be involved in the triggering mechanism of syncope induced during tilt testing.

Hemodynamic Effects of Bilevel Nasal Positive Airway Pressure Ventilation in Patients with Heart Failure

Aims: Benefits of nasal continuous positive airway pressure (CPAP) in patients presenting with chronic heart failure (CHF) are controversial. The purpose of this study was to compare the hemodynamic effects of CPAP and bilevel positive airway pressure (BiPAP) in patients with or without CHF. Methods and Results: Twenty patients with CHF and 7 with normal left ventricular function underwent cardiac catheterization. Measurements were made before and after three 20-min periods of BiPAP: expiratory positive airway pressure (EPAP) = 8 cm H2O and inspiratory positive airway pressure (IPAP) = 12 cm H2O, EPAP = 10 cm H2O and IPAP = 15 cm H2O, and CPAP = EPAP = IPAP = 10 cm H2O administered in random order. Positive pressure ventilation decreased cardiac output (CO) and stroke volume. No change was observed in either pulmonary or systemic arterial pressure. There was no difference in the hemodynamic effects of the three ventilation settings. Only mean pulmonary wedge pressure (MPWP) and heart rate were lower with CPAP than with BiPAP. CO decreased only in patients with low MPWP (≤12 mm Hg). BiPAP ventilation increased PaO2 and decreased PaCO2 more than CPAP. Conclusions: In patients with cardiac failure, a decrease in CO occurs both during CPAP and BiPAP, when pulmonary wedge pressure is low (≤12 mm Hg).

Long-term effects of cicletanine on secondary pulmonary hypertension

Cicletanine, a furopyridine-derivative drug, was shown to enhance the production of endogenous prostacyclin. The potent vasodilating properties of prostacyclin are used to treat severe primary pulmonary hypertension. Prostacyclin has a short half-life and can be administered only as an i.v. infusion. The aim of this study was to evaluate the effects of cicletanine on pulmonary artery hypertension (PAH) resulting from chronic obstructive lung disease (COLD). In a double-blind controlled study, we evaluated the effects of short- and long-term administration of cicletanine (50 mg daily, orally) on hemodynamics and blood gases of patients with PAH resulting from COLD. The initial dose of 50 mg of cicletanine had no effect. A significant decrease in the mean pulmonary artery pressure (15%) and in total pulmonary resistance (20%) was observed after 3 or 12 months of treatment in the cicletanine group (11 patients), when compared with placebo (12 patients). PaO 2 decreased slightly in the cicletanine group, but the difference from the control group was not significant. These results suggest that long-term treatment with cicletanine can induce effective pulmonary vasodilation in patients with PAH caused by COLD and that this is probably responsible for a small venous admixture. Chronic obstructive lung disease.

Adenosine plasma concentration in pulmonary hypertension

OBJECTIVE In this study, we sought to appreciate the role of adenosine in the regulation of pulmonary vascular tone, especially in the case of clinical pulmonary hypertension, by investigating the relationship between endogenous plasma adenosine levels and pulmonary artery vasoconstriction. METHODS Adenosine plasma concentrations, were measured simultaneously in the distal right pulmonary artery and in the femoral artery, both at steady state (room air) and during pure oxygen inhalation. Three clinical situations were considered: (1) normal hemodynamics [7 control subjects, mean pulmonary artery pressure (MPAP) = 18.5 +/- 1 mm Hg], (2) moderate pulmonary hypertension secondary to chronic obstructive pulmonary disease (COPD), (8 patients, MPAP = 31 +/- 3 mm Hg), (3) severe primary pulmonary hypertension (PPH), (8 patients, MPAP = 70 +/- 5 mm Hg). RESULTS In every instance, adenosine evaluated by HPLC was higher in the pulmonary than in the systemic circulation. For room air, adenosine plasma concentrations were significantly lower in COPD (0.49 +/- 0.16 mumol l-1) and PPH patients (0.45 +/- 0.14 mumol l-1) than in controls (1.26 +/- 0.12 mumol l-1). During O2 administration, adenosine plasma concentrations all decreased but more so in COPD and PPH patients. The significant correlations between adenosine plasma concentrations and both pulmonary vascular resistance and PvO2, in controls, were not found in COPD or PPH patients. CONCLUSION The adenosine plasma concentrations in the pulmonary circulation of PPH and COPD patients are low, and may contribute to pulmonary artery hypertension.

Head-up tilt induced syncope and adenosine A2A receptor gene polymorphism

AIMS High adenosine plasma levels and high expression of adenosine A(2A) receptors are observed in patients with unexplained syncope and a positive head-up tilt test (HUT). This study aimed to evaluate the single nucleotide polymorphism (SNP) (c.1364 T>C) which is the most commonly found polymorphism in the A(2A) receptor gene, in patients with unexplained syncope undergoing HUT. METHODS AND RESULTS One hundred and five patients with unexplained syncope who underwent HUT were included. Fifty-two had a positive test. Receptor genotype determinations were performed in patients and in 121 healthy subjects. Genotype (TT, CC, TC) was determined from DNA leucocytes. The distribution of the polymorphism showed significant (P < 0.0001) difference when the results of HUT were analysed. Fifty-two per cent of patients with a positive HUT had a CC genotype and 34.6% a TC genotype, whereas 13.2% of the patients with a negative HUT had a CC genotype and 71.7% a TC genotype. Patients with a CC genotype had a higher incidence of spontaneous syncopal episodes. CONCLUSION In patients with unexplained syncope, a significant association between high incidence of syncopal episodes, positive HUT, and the presence of the CC variant in the adenosine A(2A) receptor gene was elicited.

Peripheral plasma adenosine release in patients with chronic heart failure

Objective: Chronic heart failure (CHF) is accompanied by increased adenosine plasma levels (APLs). It is unknown whether adenosine release occurs at the peripheral level or whether the myocardium itself is the source of adenosine release. To answer this question, we evaluated APLs in the coronary sinus of CHF patients during a resynchronisation procedure and compared the values with those at the peripheral level. We also investigated a possible correlation between APLs and ischaemia-modified albumin (IMA) levels, a useful marker of tissue ischaemia. Methods: 19 men and seven women were prospectively included. Blood samples for APLs were collected simultaneously from a brachial vein (peripheral) and from the coronary sinus. Blood samples for brain natriutretic peptide (BNP) and IMA were collected from a brachial vein. Results: APLs from the brachial vein were higher than those from the coronary sinus (1.69 vs 0.75 μM p<0.01). IMA levels were correlated with APLs from the brachial vein (r = 0.59, p<0.01). BNP concentrations were correlated with APLs from the brachial vein (r = 0.73, p<0.001) but not with APLs from the coronary sinus (r = 0.38, p>0.05). BNP concentrations and IMA levels were correlated (r = 0.71, p<0.001). Conclusions: In CHF patients, adenosine release occurs at a peripheral level and not at the myocardium level.

Plasma beta-endorphin and adenosine concentration in pulmonary hypertension

To determine whether beta-endorphin plays a role in the regulation of pulmonary vascular tone in patients with pulmonary hypertension, we investigated the relations between hemodynamics and beta-endorphin and adenosine concentrations in 3 clinical situations: (1) normal hemodynamics (7 subjects, mean pulmonary artery [PA] pressure 18.5 +/- 1 mm Hg); (2) moderate pulmonary hypertension secondary to chronic obstructive pulmonary disease (COPD) (8 patients, mean PA pressure 31 +/- 3 mm Hg); and (3) severe primary pulmonary hypertension (PPH) (8 patients, mean PA pressure 70 +/-5 mm Hg). Plasma beta-endorphin and adenosine were measured in a distal PA and in the femoral artery in room air and during oxygen inhalation. Beta-endorphin levels were similar in the pulmonary and systemic circulations. No difference was observed between patients with COPD and PPH, but relative to controls, both had significantly higher beta-endorphin levels. Pulmonary adenosine was significantly lower in patients with pulmonary hypertension than in controls (-60% in COPD [p <0.005] and -70% in PPH [p <0.001]). Pure oxygen administration significantly decreased adenosine and beta-endorphin levels, much more so in patients with COPD and PPH. We found a negative correlation between beta-endorphin and adenosine concentrations (r = -0.751, p <0.001): the higher the adenosine, the lower the beta-endorphin level. These observations suggest that because adenosine release by pulmonary vascular endothelium is reduced in pulmonary hypertension, the resulting worsened hypoperfusion and tissue oxygenation may cause increased beta-endorphin release.

Effects of nicardipine on pulmonary and systemic vascular reactivity to oxygen in patients with pulmonary hypertension secondary to chronic obstructive lung disease.

Summary: We compared the acute effects of nicardipine and a placebo on the response of pulmonary and systemic circulation to different inspiratory fractional concentrations of O2 (FiO2) in 10 patients with pulmonary hypertension secondary to chronic obstructive lung disease. After catheterization of the pulmonary and femoral arteries, gas mixtures containing 15, 21, and 30% O2 were randomly administered for 20 min each during infusion of saline and then nicardipine (0.06 mg/kg/min). Plasma nicardipine level was maintained at 30 ng/ml. During nicardipine infusion, cardiac index (CI) was significantly higher (+20%, p < 0.05) than during placebo infusion, with no change in mean pulmonary artery pressure (MPAP). Pulmonary resistances also decreased significantly (– 20%) during nicardipine. No change in arterial or mixed venous O2 contents was noted. Mean arterial pressure (MAP) and systemic resistances decreased significantly with nicardipine. Inhaling a hyperoxic mixture was followed by a significant decrease in arterial pressure during placebo infusion; this was not observed during nicardipine. In contrast with systemic circulation, the response of the pulmonary circulation to different FiO, levels was unaffected by nicardipine.

Hemodynamic and oxygen delivery responses to nifedipine in pulmonary hypertension secondary to chronic obstructive lung disease

The effects of a single dose of nifedipine (20 mg sublingually) on hemodynamics and tissue oxygenation were evaluated in 24 patients suffering from pulmonary hypertension secondary to severe chronic obstructive lung disease. A significant improvement in pulmonary circulation and right ventricular pump function occurred. An increase in the oxygen delivery to the tissue was also demonstrated. A complementary study in 10 patients showed that the effects observed after a single dose were still apparent after oral intake (30 mg/day) for 15 days. For these reasons nifedipine may contribute in the treatment of cor pulmonale.

Supraspinal Antinociceptive Effects of μ and δ Agonists Involve Modulation of Adenosine Uptake

BackgroundThe modulation of extracellular adenosine concentration by opioids provides evidence that the antinociceptive effects of these compounds involve endogenous adenosine. The aim of this study was to determine whether there is a relation between the inhibition of brain synaptosome adenosine up