Nerve growth factor derivative NGF61/100 promotes outgrowth of primary sensory neurons with reduced signs of nociceptive sensitization.

Nerve Growth Factor (NGF) is being considered as a therapeutic candidate for Alzheimer's disease. However, the development of an NGF-based therapy is limited by its potent pain activity. We have developed a "painless" derivative form of human NGF (NGF61/100), characterized by identical neurotrophic properties but a reduced nociceptive sensitization activity in vivo. Here we characterized the response of rat dorsal root ganglia neurons (DRG) to the NGF derivative NGF61/100, in comparison to that of control NGF (NGF61), analyzing the expression of noxious pro-nociceptive mediators. NGF61/100 displays a neurotrophic activity on DRG neurons comparable to that of control NGF61, despite a reduced activation of PLCγ, Akt and Erk1/2. NGF61/100 does not differ from NGF61 in its ability to up-regulate Substance P (SP) and Calcitonin Gene Related Peptide (CGRP) expression. However, upon Bradykinin (BK) stimulation, NGF61/100-treated DRG neurons release a much lower amount of SP and CGRP, compared to control NGF61 pre-treated neurons. This effect of painless NGF is explained by the reduced up-regulation of BK receptor 2 (B2R), respect to control NGF61. As a consequence, BK treatment reduced phosphorylation of the transient receptor channel subfamily V member 1 (TRPV1) in NGF61/100-treated cultures and induced a significantly lower intracellular Ca2+ mobilization, responsible for the lower release of noxious mediators. Transcriptomic analysis of DRG neurons treated with NGF61/100 or control NGF allowed identifying a small number of nociceptive-related genes that constitute an "NGF pain fingerprint", whose differential regulation by NGF61/100 provides a strong mechanistic basis for its selective reduced pain sensitizing actions.

Colonization by Legionella spp. of water networks in residential buildings of the Province of Pisa, Italy.

BACKGROUND: Despite the increase of community acquired cases of legionellosis in Italy over the last years, the Italian guidelines do not give indications for prevention and control of Legionella in the hot water networks (or centralized conditioning systems) of residential buildings. We performed a survey on eight medium sized apartment buildings in the Pisa district to assess the prevalence of Legionella spp. in the water network and the respondance to drinking water requisites at the point of use, according to the Italian norms. METHODS: For each building two hot water and three cold water samples (located at water entrance from the aqueduct network into the building pipework, at the exit from pressure autoclave, and at a remote tap) were collected. RESULTS: Legionella was detected in 20% of residential buildings, mostly in those with a central hot water production system. CONCLUSIONS: The study highlights a condition of potential risk for susceptible population subgroups and supports the need for measures of risk assessment and control.

[Size distribution of amphibole fibres from lung and pleural tissues sampled from mesothelioma cases due to environmental exposure]. / Caratterizzazione dimensionale di fibre anfiboliche nel polmone e nella pleura di casi di mesotelioma da esposizione ambientale.

BACKGROUND: It has been suggested that malignant mesothelioma might be mainly or only connected with the action of short and ultrathin fibres. On the basis of this hypothesis fibres less than 5 microm long and 0.2-0.1 microm thick would enter the pulmonary-pleura barrier and reach the parietal pleura thus inducing mesothelioma. The hypothesis raised a stimulating scientific discussion. OBJECTIVES: The aim of this communication is to report the initial results obtained comparing the size of amphibole fibres from healthy lung tissue with those from pleural tissue sampled from subjects whose death cause of death was mesothelioma. METHODS: Four mesothelioma cases due to environmental exposure were studied; the fibres were categorized by scanning electron microscopy; for every fibre, length and diameter were measured and the mineral type was defined by its chemical composition determined by X-ray microanalysis. RESULTS: The most important characteristics of the detected fibres were: the average length offibres from the lung and pleural tissues taken from the same subject did not difer, in all cases, by more than 10-12%; 95% offibres found in the lung tissues of all subjects had a length greater than 5 microm; 98% of fibres found in the pleural tissues had a length greater than 5 microm; the average diameter of the fibres found in the pleural tissues was 70% of the diameter of the fibres from the lung tissues. CONCLUSIONS: The experimental data obtained in this study confirm the correlation between malignant mesothelioma and the presence in the lung and pleural tissues of fibres with a length greater, even much greater, than 4-5 microm; thus the hypothesis that the chief factors inducing mesothelioma are the "ultrashort" and "ultrathin" fibres appears rather weak.

Erionite and asbestos differently cause transformation of human mesothelial cells.

Malignant mesothelioma (MM) is an aggressive tumor associated with environmental or occupational exposure to asbestos fibers. Erionite is a fibrous zeolite, morphologically similar to asbestos and it is assumed to be even more carcinogenic. Onset and progression of MM has been suggested as the result of the cooperation between asbestos and other cofactors, such as SV40 virus infection. Nevertheless, several cases of MM were associated with environmental exposure to erionite in Turkey, where SV40 was never isolated in MM specimens. We show here that erionite is poorly cytotoxic, induces proliferating signals and high growth rate in human mesothelial cells (HMC). Long term exposure to erionite, but not to asbestos fibers, transforms HMC in vitro, regardless of the presence of SV40 sequences, leading to foci formation in cultured monolayers. Cells derived from foci display constitutive activation of Akt, NF-kappaB and Erk1/2, show prolonged survival and a deregulated cell cycle, involving cyclin D1 and E overexpression. Our results reveal that erionite is able per se to turn HMC into transformed highly proliferating cells and disclose the carcinogenic properties of erionite, prompting for a careful evaluation of environmental exposure to these fibers. The genetic predisposition to the effect of erionite is a separate subject for investigation.

Skin prick-test reactivity to aeroallergens and allergic symptoms in an urban population of central Italy: a longitudinal study.

BACKGROUND: Cross-sectional studies report an increasing prevalence of allergic diseases, such as rhinitis and asthma. Not thoroughly known, instead, is the natural history of allergic sensitization and the progress of the allergic disease-related symptoms. AIM: The purpose of this study was to evaluate longitudinally the skin reactivity for the most common aeroallergens and the allergic symptoms in an urban population living in Perugia, a town of central Italy with a low-level of air pollution exposure. METHODS: In the 1998-1999 period 788 subjects were tested for skin reactivity to a panel of aeroallergens and underwent the administration of a questionnaire. These same subjects were part of a cohort of 1200 subjects who participated in a previous epidemiological study performed in 1984-1985 using the same tools. Subjects were aged between 14 and 64 years at the time of the first survey. RESULTS: In the present survey 196 subjects (24.9%) had skin reactivity to at least one aeroallergen, while in the previous survey 143 subjects (18.1%) had skin prick-test reactivity. The increase of the skin reactivity between the two observations was highly significant (P<0.001) and was mainly observed in subjects <40-years old. The greatest increment in skin reactivity was seen to Dermatophagoides pteronyssinus (house dust mite) allergen. Data obtained from questionnaires showed that subjects who declared allergic symptoms increased from 341 (43.3%) to 380 (48.2%). However, the increase was significant (P<0.01) only in subjects who had a positive association between allergic symptoms and prick-test reactivity and was greater for rhino-conjunctivitis than for asthma-related symptoms. CONCLUSIONS: In a cohort of urban population of the centre of Italy, exposed to a low and stable level of air pollution, the sensitization to common aeroallergens increased with time, mostly in people <40-years of age. The greatest increment was found for indoor allergens such as Dermatophagoides pteronysimus. A significant increase in allergic symptoms, mainly related to rhino-conjunctivitis, was observed only in the presence of positive prick test.

Nature and extent of the exposure to fibrous amphiboles in Biancavilla.

An epidemiological and environmental study in the Biancavilla area (Sicily, Italy) was recently prompted by an impressively high incidence of malignant pleural mesothelioma. Epidemiology suggested an environmental contamination by amphibole fibres rather than risks related to a specific occupational activity. The aim of this study is to describe the diffusion of fibrous amphiboles in the area and identify their source. Fibrous amphiboles were found in the products from the local quarries, which had been used for years to build houses. After sampling all around Biancavilla, three sites were detected and they were characterized by an abundant presence of mineral fibres. Fibrous amphiboles were also recovered from building materials (mortar and plasters) and airborne particulates sampled in urban sites with high dust emissions due mainly to unpaved roads. Moreover, amphibole fibres were detected in the lung tissue of a woman who died of pleural mesothelioma. The results of this study suggest that the amphibole fibre diffusion in the Biancavilla environment lasted for many years and had been maximum during the sixties and the seventies with the uncontrolled development of the local building industry. Today, the environmental situation results to be changed following both the closing of the stone quarries and the urbanization works after 2001, above all the asphalting of dusty roads. Anyway sporadic mesothelioma cases have still to be expected in the next years.

Multinucleation and pro-inflammatory cytokine release promoted by fibrous fluoro-edenite in lung epithelial A549 cells.

An unusual cluster of malignant mesothelioma was evidenced in Biancavilla, a Sicily village where no inhabitant had been significantly and professionally exposed to asbestos. Mineralogical and environmental studies led to the identification of a new prismatic amphibole, named fluoro-edenite. We previously reported, by using the human lung epithelial A549 cells, that prismatic fluoro-edenite was unable to induce changes that could be somehow related to cellular transformation, and this was in accordance with studies carried out in vivo. More recently, a fibrous amphibole with a composition very similar to that of prismatic fluoro-edenite, was identified in Biancavilla. This fibrous fluoro-edenite was shown to induce mesothelioma in rats. In keeping with this effect in vivo, in the present work we observed multinucleation and spreading, common features of transformed cells, as well as pro-inflammatory cytokine release in A549 cells. Such cell changes occurred without interfering with the passage of the resulting multinucleated cells through the cell cycle and without condemning cells to death. Hence, in lung epithelial cells, fibrous fluoro-edenite behaved similarly to the unrelated asbestos type crocidolite, whose connection with severe inflammation and cancer of the lung is renowned.

Solid-state study of mepivacaine hydrochloride.

Different crystalline forms of the local anaesthetic mepivacaine hydrochloride (MH) were revealed by Fourier transform infrared spectroscopy (FT-IR), not by conventional differential scanning calorimetry (DSC). The existence of two polymorphic anhydrous modifications was discovered and further characterized by X-ray powder diffraction and thermal analysis: Form II, the commercial one, and the more stable Form I, obtained by re-crystallization from Form II. Two pseudopolymorphs were also obtained: Form III, a solvate crystallized from ethanol and Form IV, a solvate crystallized from methanol. Single crystal X-ray diffraction data for both solvates were collected and their structures were determined. Form II, metastable and monotropically related to Form I, generates through desolvation of Form III, very often present in industrial processing, where crystallization from ethanol solution is a common practice. For the sake of clarity, the presence of polymorphic forms should be reported in the drug master files of MH. However, since MH is readily water soluble, the observed polymorphism has no relevance to its typical clinical use as aqueous solutions.

[Results of an interlaboratory fibre count comparison program concerning the SEM technique]. / Risultati di un programma pilota per il controllo di qualità dei laboratori che effettuano analisi sull'amianto mediante microscopia elettronica a scansione (SEM).

BACKGROUND: The necessity of quality control for laboratories carrying out airborne asbestos fibre monitoring is recognized in Italian law concerning the worker and the environmental protection against asbestos. The scanning electron microscopy technique is prescribed to control the airborne fibre concentration after asbestos removal from buildings. OBJECTIVES: In 2002 the Italian laboratories carrying out SEM analysis on asbestos were requested by the Istituto Superiore di Sanità to take part in a fibre count comparison program. Thirty-nine agreed to participate. METHODS: Fifteen samples were exchanged among the laboratories participating in the program. Seven samples consisted of polycarbonate membranes and eight of cellulose ester membranes. The sample loads did not exceed 50 fibres/mm2. The fibre counting results were evaluated with reference to the mean value of each sample calculated from the results provided by all the participants. RESULTS: Only 19% of the fibre count results were considered "insufficient", and the results falling within the 95% confidence interval were the 65% of the total. University and public laboratories obtained on the whole the best results.

Long-term effects of losartan and enalapril, alone or with a diuretic, on ambulatory blood pressure and cardiac performance in hypertension: a case-control study.

BACKGROUND: The long-term effects of angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers on ambulatory blood pressure and cardiac performance have never been examined comparatively. OBJECTIVE: We compared losartan and enalapril in their long-term effects on office and ambulatory blood pressure, cardiac structure and function, and routine biochemical tests. DESIGN: In the setting of the Progetto Ipertensione Umbria Monitoraggio Ambulatoriale (PIUMA) study, 22 hypertensive subjects were studied with ambulatory blood pressure monitoring and echocardiography before and after an average of 3.3 years of treatment with losartan 50mg daily. These subjects were matched in a 1:3 ratio with a group of 66 subjects treated with enalapril 20mg daily. Case-control sampling was based on age (+/-5years), sex, pre-treatment office blood pressure (+/-5mmHg) and ambulatory blood pressure (+/-5mmHg), and duration of treatment (+/-6months). An additional group of subjects who interrupted their treatment with enalapril (n=18) or losartan (n =2) because of unwanted effects before execution of the follow-up study was not included in the analysis. RESULTS: Hydrochlorothiazide was added during follow-up in order to optimize blood pressure control (office blood pressure <140mmHg systolic and 90mmHg diastolic) in 10 subjects (45%) in the losartan group and 34 subjects (52%) in the enalapril group. Office and ambulatory blood pressures were lowered to a similar extent by losartan and enalapril. Left ventricular mass decreased from 98 to 87g/m(2) with losartan (P <0.01) and from 98 to 89 g/m(2) with enalapril (P <0.01). The change in left ventricular mass over time was more closely associated with the change in ambulatory blood pressure than with office blood pressure in both groups. Left ventricular internal diameter did not change with either drug. The endocardial shortening fraction, mid-wall shortening fraction and Doppler indexes of active diastolic relaxation did not change with either drug. None of the biochemical parameters showed a significant change. Serum uric acid showed a slight and non-significant reduction only in the losartan group. CONCLUSION: In this case-control study in uncomplicated subjects with essential hypertension, losartan and enalapril, alone or combined with a diuretic, effectively and equally lowered office and ambulatory blood pressure and induced a significant reduction in left ventricular mass during long-term treatment. Left ventricular systolic and diastolic function remained unchanged with either regimen.

Persistence of increased left ventricular mass despite optimal blood pressure control in hypertension.

BACKGROUND: Left ventricular hypertrophy is an adverse risk marker in essential hypertension and its regression has a favorable effect on prognosis. It is unclear whether blood pressure normalization induced by long-term therapy is able to normalize left ventricular mass completely. METHODS: In the setting of a prospective cohort study, 107 consecutive hypertensive patients who achieved blood pressure normalization (clinic blood pressure < 140/90 mmHg on > or = 3 consecutive visits) under long-term (1-10 years, average 2.9) drug treatment were individually matched with 107 healthy normotensive controls by gender, age (+/- 5 years), body mass index (+/- 3 kg/m2), and clinic systolic blood pressure (+/- 5 mmHg) in a case-control design. All subjects underwent 24-hour blood pressure monitoring and M-mode echocardiography. RESULTS: Treated hypertensive patients and normotensive controls did not differ by age, body mass index, clinic blood pressure (128/82 vs 128/81 mmHg), and 24-hour blood pressure (120/77 vs 120/76 mmHg). Left ventricular mass and relative wall thickness were greater in the hypertensive than in the normotensive group (97 +/- 24 vs 86 +/- 17 g/m2 and 0.40 +/- 0.08 vs 0.37 +/- 0.08, both p < 0.001). CONCLUSIONS: Left ventricular mass is greater in well-controlled hypertensive patients than in normotensive controls matched by age, obesity, gender, and clinic and 24-hour blood pressure. This finding is consistent with the lower than epidemiologically expected reduction in coronary heart disease risk during antihypertensive therapy and might reflect the persistent effect on left ventricular mass of hemodynamic and/or non-hemodynamic factors other than blood pressure in treated patients with essential hypertension.

Clinical relevance of office underestimation of usual blood pressure in treated hypertension.

Average 24-h blood pressure (BP) is more representative of usual BP than office BP. However, the clinical relevance of 24-h BP in treated hypertensive subjects is incompletely known. Thus, we studied 395 uncomplicated hypertensive subjects (209 men, 53+/-10 years) who were receiving antihypertensive drug therapy from >1 year. All subjects underwent 24-h ambulatory BP monitoring and M-mode echocardiography. Subjects were classified by tertile of the difference between observed and predicted 24-h systolic BP (the latter determined by regressing 24-h systolic BP on office systolic BP): higher-than-predicted (III tertile), around the regression line (II tertile), and lower-that-predicted (I tertile) 24-h BP. Despite similar office BP (144/89, 141/88, and 144/89 mm Hg in the III, II, and I tertile, P = not significant), age, body mass index, and duration of hypertension, left ventricular mass was greater in the subjects with higher-than-predicted 24-h systolic BP (50+/-14 g x m(-2.7)) than in the other two groups (46+/-13 g x m(-2.7) and 42+/-10 g x m(-2.7), both P < .05). The III tertile also showed a more concentric left ventricular geometric pattern (relative wall thickness was 0.42+/-0.08, 0.40+/-0.07, and 0.38+/-0.07 in the III, II, and I tertile, P < .001) and a reduced systolic function at the midwall level (16.8+/-3, 17.7+/-3, and 18.2+/-3, P < .001). In conclusion, treated hypertensive subjects whose 24-h BP is notably higher than one would predict from office BP are more likely to develop left ventricular hypertrophy, a strong adverse prognostic marker. In a sizable subset of treated hypertensive subjects, BP measured in the physician's office underestimates usual BP and its impact on left ventricular structure.

[Modification of the DNA spatial structure when complexed with cisplatin]. / Modifikatsiia prostranstvennoi struktury DNK v komplekse s tsis-platinoi.

The experimental and theoretical analyses of the conformational transitions of DNA-cis-platinum complexes have been carried out. It is shown that at low concentrations of the ligand, the thermodynamic parameters of the helix-coil transition of the complexes are not the result of the local B-->A transition.

Crystal structure of reduced bovine erythrocyte superoxide dismutase at 1.9 A resolution.

Cu,Zn superoxide dismutase was investigated crystallographically in the reduced form. Co-ordinate errors were estimated by comparing two independently refined models, based on two different data sets. This gave a detailed error estimation as opposed to the standard sigma A and Luzzati plots, which estimate only the overall error. The high quality of the final model, obtained after scaling together the two data sets, combined with the error estimates allowed a detailed analysis of the protein and solvent structures. An automatic procedure for building and refining solvent structure was tested and found to give reproducible results. Contrary to results obtained from spectroscopic studies, the co-ordination of the metal ions in the catalytic site is preserved in the crystal structure of the reduced enzyme, as compared with the crystal structure of the oxidised form. Analysis of the solvent reveals a well-defined chain of closely packed, hydrogen-bonded water molecules filling the active site groove. This structural feature could serve as a hydrogen bond relay for efficient delivery of protons to the active centre. Analysis of electron density suggests that Glu119 is covalently modified. The modification, if originated in vivo, could have a role in the catalytic mechanism and could affect the overall electrostatic field in the active site. There are significant differences between the active sites of the two crystallographically independent monomers. They are explained in terms of local differences in the crystal environment.

X-ray, NMR and molecular dynamics studies on reduced bovine superoxide dismutase: implications for the mechanism.

Single crystals of the reduced form of Cu, Zn superoxide dismutase (space group P2(1)2(1)2(1), one dimer per asymmetric unit) have been obtained and their X-ray structure refined at 1.9 A resolution. The structure shows that the imidazolate bridge is maintained in the present crystalline form. It is confirmed that in solution the bridge is broken and the involved histidine is protonated on the side of copper. Based on the NOE constraints, and with the aid of molecular dynamics calculations, a structural model is proposed for the molecule in solution. Both structures are considered significant as far as the enzymatic mechanism is concerned.

Acute respiratory effects of sublingual buprenorphine: comparison with intramuscular morphine.

In this randomized, double-blind, placebo study, the respiratory effects of a single dose of sublingual buprenorphine (0.4 mg) were examined and compared with those induced by one dose of intramuscular morphine (10 mg) in a population of women, aged 25-65 years, admitted at the Hospital for Elective Surgery because of uterine fibromyomatosis. Some indices of control of breathing (P0.1, VT/TI, VE, VA, TI, TE, TI/TTot, RR), gas exchange parameters (D[A-a]O2, VD/VT, PAO2) and blood gases (PaO2, PaCO2) were measured in basal condition and at 30, 60, 90, 180 and 360 min after the administration of the drugs. No significant changes of the respiratory function were observed in patients who have received sublingual buprenorphine. In the morphine-group, however, mild PaO2 decrease and PaCO2 increase were found at 60 and 90 min (p less than 0.05), without any reduction of the respiratory drive activity, as shown by P0.1, VT/TI and VE. The significant FRC reduction, observed in the morphine-group (p less than 0.05), could have induced both TE shortening and RR increase with larger dead space ventilation and consequent fall of VA (p less than 0.05). These results suggest that the administration of one dose of sublingual buprenorphine (0.4 mg) does not cause any detrimental respiratory effect; on the other hand, an appreciable, although clinically trivial, worsening of the respiratory function results from intramuscular morphine (10 mg), in the absence of any obvious respiratory depression.

Comparative evaluation of cardioselectivity of metoprolol OROS and atenolol: a double-blind, placebo-controlled crossover study.

Cardioselectivity of a single oral dose of metoprolol oral osmotic (OROS) (14/190 mg) and atenolol (100 mg) was compared in 12 patients with reversible obstructive airway disease by assessing the dose-response curve to increasing doses of inhaled salbutamol. The beta-blocking activity of the two drugs, which was determined by measuring heart rate, blood pressure, and derived indexes at peak plasma drug levels, was similar. Both metoprolol and atenolol significantly reduced forced vital capacity and peak expiratory flow, with no difference between drugs. Atenolol but not metoprolol also significantly reduced forced expiratory volume in 1 second and specific airway conductance. Both metoprolol and atenolol shifted the dose-response curve of specific airway conductance to the right. The results indicate that the new OROS delivery system for metoprolol, which produces a relatively constant plasma drug level, provides a cardioselectivity comparable to or greater than that of atenolol at maximum plasma levels.

[Pharmacologic control of breathing]. / Controllo farmacologico della ventilazione.

Recent advances in respiratory neuropharmacology and neurophysiology have allowed the assessment of the effects of different drugs on the control of the ventilation both qualitatively (alterations of ventilatory pattern) and quantitatively (size and duration of the ventilatory and haemogasometric alterations). In the control mechanism of ventilation, the pharmacological intervention can act both on the respiratory input (basal metabolism, peripheral chemo-receptors, pulmonary receptors, bulbar neurons, cortical nervous system) and on the respiratory output (respiratory muscles). Based on personal experience in this field and the recent literature, the Authors briefly discuss the seat and the mechanism of action of the drugs with stimulating effect (respiratory analeptics, almitrines, progesterone, acetazolamide, salicylates, protriptyline, theophylline) and depressing effect (narcotics and narcotic-antagonists, anaesthetics, barbiturates and benzodiazepines) on the ventilation, as well as the role of the neurotransmitters and modulators. The clinical (positive and negative) effects of these drugs, particularly related to the patients with chronic lung disease, are also illustrated.

[Giovanni Martinotti and experimental pancreatectomy, a century ago]. / Giovanni Martinotti e la pancreasectomia sperimentale, un secolo fa.

On July 13th, 1888, Giovanni Martinotti (1857-1928) announced in Torino the feasibility of a total pancreatectomy in the dog. The essential details for a successful outcome of the operation, as described by Martinotti, were employed by Oscar Minkowski (1859-1931) in Strassburg for the demonstration of diabetes after total removal of pancreas in the dog, on May 22nd, 1889. Martinotti's work deserves a reevaluation in the history of diabetology.

Sympathetic activation on effort in patients with chronic heart failure. Long term effects of captopril.

Ten patients with congestive heart failure (CHF) (NYHA II-IV) on adjusted doses of digitalis and diuretics underwent a careful clinical assessment including an evaluation of exertion dyspnoea and the usual echocardiographic indices of cardiac performance. A cardiopulmonary exercise test with an increment of 20W every 3 minutes was prolonged until exhaustion. Systemic arterial pressure, ECG, VO2, VCO2 and VE were monitored throughout. Gas tensions, plasma catecholamines and lactate were measured in blood samples taken at the first and third minute of each exercise stage. The above measurements were carried out before and after 3 months of treatment with Captopril, 50 mg b.i.d. or t.i.d. A highly significant correlation between arterial lactate and plasma norepinephrine (NE) was observed in each patient during both exercise tests (r = 0.77 to 0.99; p less than 0.05 at least). Left ventricular end-diastolic dimensions were reduced by Captopril (from 69.9 +/- 1.7 to 65.2 +/- 1.4 mm, p less than 0.01) along with a concomitant increase in percent fractional shortening. Most of the patients were reclassified at a lower NYHA class and a significant decrease in dyspnoea score was observed. The exercise time was significantly increased (from 11.2 +/- 1.8 to 12.9 +/- 1.9 min; p less than 0.05), but the peak values of NE, arterial lactate and VO2 were not affected by the treatment. The predicted value of VE at a VCO2 of 1 L/min, regarded as an index of dyspnoea, was significantly decreased by Captopril (from 41.4 +/- 2.9 to 38.9 +/- 2.7 L/min; p less than 0.05). The positive effects of long-term treatment with Captopril on cardiac performance in CHF are confirmed. Sympathetic activity is linked to anaerobic muscular metabolism during exercise and seems to be independent of pharmacological ACE inhibition. The discrepancy between the exercise tolerance and the peak VO2 might be explained by a better utilization of the available energy.