Antonino Mistretta

Randomised double-blind placebo-controlled study of the effect of inhibition of nitric oxide synthesis in bradykinin-induced asthma

BACKGROUND Bronchoconstriction induced by bradykinin is reduced by the release of nitric oxide (NO) in the airways of guinea pigs. Inhaled NO is known to cause bronchodilatation in asthmatic patients. To find out the role of endogenous NO in airway response to bradykinin in asthma, we examined the effect of the NO synthase inhibitor NG-monomethyl-L-arginine (L-NMMA) on broncho-constriction after bradykinin challenge in ten patients with mild asthma. METHODS The study had a randomised, double-blind, placebo-controlled, cross-over design. Participants were studied during two phases, each consisting of 2 study days. After baseline measurements of forced expiratory volume in 1 s (FEV1) participants inhaled an aerosol of L-NMMA or saline (placebo). After 5 min, saline and doubling doses of bradykinin (from 0.25 nmol) were inhaled until FEV1 fell by at least 20% of the post-saline value. The effect of L-NMMA and placebo on airway response to doubling concentrations of methacholine (from 0.03 mg/mL) was then examined. We also assessed the effect of the inactive enantiomer of L-NMMA, D-NMMA, and placebo on bronchoconstriction after bradykinin or methacholine challenge in six of the participants. FINDINGS The geometric mean of the provocative dose producing a 20% fall in FEV1 to bradykinin was 138.0 nmol (range 48.2-475.2 nmol) after placebo and 11.2 nmol (range 0.9-51.3 nmol) after L-NMMA (p < 0.01). L-NMMA also caused a decrease in the provocative concentration of methacholine producing a 20% fall in FEV1 from 0.93 mg/mL (range 0.12-2.55 mg/mL) to 0.38 mg/mL (range 0.06-0.92 mg/mL; p < 0.01). In contrast, D-NMMA did not affect airway response to bradykinin or methacholine. INTERPRETATION The results suggest that bronchoconstriction after bradykinin inhalation is greatly inhibited by the formation of NO in airways of asthmatic patients and that NO could have a bronchoprotective role in asthma.

Increased prevalence of cardiac arrhythmias and transient episodes of myocardial ischemia in hypertensives with left ventricular hypertrophy but without clinical history of coronary heart disease.

To evaluate the behavior of cardiac arrhythmias (CA) and transient episodes of myocardial ischemia (TEMI), in relation to the circadian pattern of blood pressure in patients suffering from arterial hypertension, with or without echocardiographically ascertained left ventricular hypertrophy (LVH), we studied 128 patients, 87 men (M) and 41 women (F), aging from 21 to 76 years, subdivided into two groups: Group I, including 66 patients with LVH (45 M and 21 F; mean age of 53.7 +/- 9.1 years; Group II, including 62 patients without LVH (42 M and 20 F; mean age of 49.7 +/- 9.5 years). Office blood pressure (OBP) as well as nighttime ambulatory blood pressure (ABP) were higher in patients with LVH (P < .05 and P < .01). CA were present in a higher number of patients of Group I (P < .001): premature supraventricular beats (PSVB) 22.7 v 4.8%, supraventricular couplets (SVC) 36.4 v 16.1%, supraventricular tachycardia runs (SVT runs) 27.3 v 12.9%, ventricular ectopic beats (VEB) 25.6 v 8.0%, ventricular couplets (VC) 30.3 v 12.9%, ventricular tachycardia runs (VT runs) 12.1 v 3.2%. The absolute number of ectopic beats was also significantly higher in patients of Group I. Ventricular arrhythmias were significantly related to ASBP (r = 0.83, P < .01), to ADBP (r = 0.74, P < .01) and to heart rate (r = 0.87, P < .01) in patients of Group I. TEMI were more frequent in patients of Group I (73 v 41 episodes, 39.39% v 25.8% of patients, P < .01) and were related to ABP peaks. In fact, in both groups of patients all TEMI without heart rate increase and most TEMI with heart rate increase were registered between 6:00 and midnight, hours in which ABP values were higher. We conclude that hypertensives with LVH, but without clinical history of coronary heart disease, have a higher prevalence of ventricular arrhythmias and of transient episodes of myocardial ischemia in relation to the circadian pattern of ABP.

Purine derivatives in the study of allergic inflammation in respiratory diseases

Adenosine, a naturally occurring purine nucleoside, elicits dose‐related bronchoconstriction in asthmatic subjects when administered by inhalation and it is recovered in increased amounts from the bronchial lavage fluid of subjects with active asthma when compared to normal controls. Although the mechanism by which adenosine mediates bronchoconstriction in asthmatic subjects is not clear, recent data indicate an important role for mast cell mediator release. We have recently shown that local airway challenge with adenosine in subjects with asthma and rhinitis provokes an increase in the levels of PGD2, histamine and tryptase. However, airway responsiveness and atopic status are the most important determinants of adenosine‐induced responses, regardless of any increases in mast cell mediators in airway fluids. New discoveries suggest that the airway response to adenosine may be an index of mast cell priming and therefore may provide a useful tool to further explore the inflammatory processes in allergic asthma and rhinitis. Therefore adenosine provocation may gain increasing acceptance as an additional measure of disease activity in asthma and rhinitis.

Effect of a Calcium Antagonist, Nifedipine, in Exercise-Induced Asthma

The nifedipine effect was studied in 8 extrinsic asthmatic subjects with exercise-induced asthma. Before the exercise the patients received, in a randomized double-blind manner, either 20 mg nifedipine, sublingually or sodium cromoglycate by inhalation on 2 separate days. Nifedipine and sodium cromoglycate in all patients inhibited the exercise fall in FEV1. No differences were found between the two drugs. Nifedipine is a potent antagonist of calcium ion influx in smooth muscle and secretory cells, and these studies suggest that it may inhibit release of mast cell mediators and reduce bronchial smooth muscle contractility in asthma.

Relationship of Serum Theophylline Concentrations to Histamine-Induced Bronchospasm

This study was performed in a randomized double-blind manner on 6 separate days in 10 asthmatic patients to investigate the effect of a sustained theophylline on baseline bronchial hyperreactivity to histamine in relation to the theophylline serum levels and the degree of bronchodilatation produced. No significant bronchodilatation was seen after theophylline administration at every time of evaluation. An improvement of PD20 values of histamine was observed after 4 h (p less than 0.05), 8 h (p less than 0.01) and 12 h (p less than 0.05) from theophylline administration versus respective PD20 values obtained with placebo at the same times. No significant correlation was found between serum theophylline levels and percentage change of PD20 values after drug administration (r = 0.250). We observed an improvement of PD20 mean values in relation to the maximal serum theophylline concentration but our study failed to correlate the degree of protection with serum concentration.

Effect of Duovent (Ipratropium Bromide and Fenoterol) on Non-Specific Bronchial Hyperreactivity

Beta 2-adrenergic and anticholinergic drugs have shown an action in modulating bronchial hyperreactivity to various stimuli (chemical, physical, immunological, pharmacological). The aim of our study was to compare the efficacy of a combination of ipratropium bromide and fenoterol (Duovent) with the activity of single drugs in the prevention of histamine-induced bronchospasm. Twenty-six atopic asthmatic subjects were examined in a double-blind trial, during an asymptomatic period, with a FEV1 value not lower than 20% of the predicted normal value. During 4 consecutive days all patients received 2 puffs, respectively, of Duovent (200 micrograms fenoterol + 40 micrograms ipratropium bromide), fenoterol (400 micrograms), ipratropium bromide (80 micrograms) and placebo in a randomized order. PD20 values were evaluated after each drug administration: after 2 h in 16 patients and after 5 h in the other 10 patients. The data were modified to log values, and statistical analysis was performed by two-way analysis of variance. This study showed that Duovent and fenoterol have a protective effect against histamine-induced bronchospasm with a significant increase in the PD20 values 2 h (p less than 0.01) and 5 h (p less than 0.05) after treatment when compared to placebo. Duovent inhalation determined a more protective effect than other drugs but not significantly when compared to fenoterol. Some advantages in the modulation of bronchial reactivity could be seen from using Duovent because with the lower dose of the beta 2-adrenergic drug the same results could be obtained without side-effects.