The Asthma Impact Record (AIR) index: a rating scale to evaluate the quality of life of asthmatic patients in France.

Asthma is a chronic disease, which affects patients' daily lives. The goal of this study was the development of a disease-specific scale to evaluate quality of life in asthmatic patients in France: The Asthma Impact Record Index (AIR Index). The study was conducted with the participation of 486 asthmatic patients using the following steps: 1) selection of dichotomous items; 2) reduction of the number of items; 3) study of reproducibility of the questionnaire; 4) weighting of items; 5) study of the reliability and validity of the final version of the AIR Index. The final version of the AIR Index contains 63 unweighted items. The items were classified into subscales representing the main dimensions of quality of life: 1) physical, which was itself split into two subscales: a) physical activities; and b) symptoms; 2) psychological; and 3) social or relational. The internal consistency, measured by Cronbach's alpha coefficients, was found to be high, for the global scale and all subscales (range 0.79-0.94). The concurrent validity, evaluated by studying the relationship between the score values on the global scale and the subscales, and the parameters reflecting disease severity, was also high. We conclude that the AIR Index might represent a useful evaluative and discriminant instrument in studying quality of life in asthma in French populations.

Role of 1,2-sn diacylglycerol in airway smooth muscle stimulated by carbachol.

Activation of muscarinic receptors in airway smooth muscle leads to breakdown of membrane polyphosphoinositides. In agreement with others, we show here that muscarinic stimulation elicits inositol-1,4,5-triphosphate formation. In addition, we show that carbachol also elicits total diacylglycerol and 1,2-sn diacylglycerol accumulation in a specific and dose-dependent manner (EC50 values: 2.1 x 10(-8) M for 1,2-sn diacylglycerol). The time-course of inositol-1,4,5-triphosphate accumulation is compatible with that of the clonic phase of muscle contraction. Since this derivative can mobilize intracellular Ca2+ stores, it may play a second-messenger role in the initial phase of contraction. The time-course of diacylglycerol accumulation is compatible with the muscarinic-induced tonic phase of smooth-muscle contraction. Carbachol induces similar dose-dependent reductions in isoproterenol-induced muscle relaxation (EC50 values for relaxation concentration-response curves to isoproterenol: 3 x 10(-6) M and 2.1 x 10(-5) M, with carbachol at 10(-7) M and 10(-4) M, respectively), and increases in adenylate cyclase activity (EC50 values for the concentration-response to isoproterenol: 1.2 x 10(-6) M and 1.5 x 10(-5) M, with carbachol at 10(-7) M and 10(-4) M, respectively). Since it is known that carbachol-induced uncoupling of beta 2-adrenergic receptors is proportional to the breakdown of polyphosphoinositides, and that 1,2-sn diacylglycerol is a potent activator of protein kinase C, 1,2-sn diacylglycerol could be mediating the uncoupling of beta 2-adrenergic receptors, via activation of alpha-protein kinase C and subsequent phosphorylation of receptor, and/or cyclase, and/or G proteins.(ABSTRACT TRUNCATED AT 250 WORDS)

The effect of intravenous phenylephrine on airway calibre in asthma.

Tracheobronchial vasoconstriction and subsequent reduction of airway wall thickness due to the alpha 1-agonist methoxamine, might be responsible for prevention of exercise-induced asthma, and reduction of bronchial hyperresponsiveness to methacholine increase in exercise performance in patients with impaired left ventricular function. Since bronchial wall oedema plays an important role in asthma, we have now investigated the bronchial response to the intravenously administered alpha 1-agonist, phenylephrine, in asthma of various severity. Increasing noncumulative intravenous phenylephrine doses (100 to 600 micrograms) were injected in 18 asthmatic subjects (three groups: mild asthma, mild asthma with recent acute attack, severe obstructive asthma) and in 11 control subjects. Changes in specific airways resistance (sRaw) on phenylephrine were linearly related to the dose administered in 16 out of 18 asthmatic subjects, and in only 3 out of 11 control subjects. In the asthmatic subjects, sRaw increased in 10 patients whose asthma was mild, or bronchial obstruction mild to moderate, and decreased in the remaining 8 asthmatic subjects with more severe disease or with a higher degree of bronchial obstruction. Changes in forced expiratory volume in one second (FEV1) were consistent with those of sRaw. In the five asthmatic subjects who underwent the protocol twice, results were reproducible. There was no difference in the responses of heart rate between the three groups of asthmatic subjects. It is likely that phenylephrine acts both via airway smooth muscle contraction, an effect which might predominate in mild asthma, and via mucosal vasoconstriction, which might overcome the effect on smooth muscle in more severe asthma with bronchial wall oedema.(ABSTRACT TRUNCATED AT 250 WORDS)

Modulation of airway smooth muscle beta-adrenoceptor function by a muscarinic agonist.

We have investigated the effect of a muscarinic agonist and protein kinase C (PKC) activation on beta-adrenoceptors and their coupling to adenylyl cyclase in bovine tracheal smooth muscle. There was a significant reduction in maximum binding capacity of [125I]iodocyanopindolol ([125I]ICYP) after exposure to carbachol and 4 beta-phorbol 12 beta-myristate 13 alpha-acetate (PMA). Similarly both carbachol and PMA inhibited the 5'-guanylylimidodiphosphate-induced shift in [125I]ICYP binding by isoproterenol and significantly decreased isoproterenol-induced cyclic AMP accumulation. A phorbol ester, 4 alpha-phorbol 12,13-didecanoate which does not activate PKC had no effect on beta-receptor binding or coupling. These results suggest that PKC activation directly via a phorbol ester and indirectly via muscarinic receptor stimulation may lead to reduction and uncoupling of beta-receptors in airway smooth muscle. We suggest that this mechanism may be relevant to the reduction in beta-receptor coupling in asthmatic airways as an effect of PKC activation by inflammatory mediators and neurotransmitters.

Lipoxin A4 inhibits phosphoinositide hydrolysis in human neutrophils.

Lipoxins (LX) are trihydroxytetraene metabolites derived from arachidonic acid via an interaction between the 5- and 15-lipoxygenases. Preincubation of [3H] myo-inositol labeled PMN with 10-7M and 10-5M LXA4 for 1 minute at 37 degrees C resulted in a concentration dependent inhibition of the generation of [3H] IP3 and [3H] IP in cells subsequently stimulated by increasing doses of LTB4 or FMLP for 1 minute at 37 degrees C. Preincubation of PMN with LXA4 did not inhibit specific binding of [3H] LTB4 to PMN. These results indicate that LXA4 inhibits chemotactic factor-induced phosphoinositide hydrolysis at a post-receptor level.

Cumulative dose-response curves for assessing combined effects of salbutamol and ipratropium bromide in chronic asthma.

We investigated whether salbutamol (S) and ipratropium bromide (IB) exerted a true additive bronchodilator effect in asthma. In fifteen selected chronic asthmatics, individual cumulative dose-response curves to S and IB were performed on two separate days (linear regression of bronchodilator response (delta FEV1) between 20 and 80% of maximal response, versus log dose), and the dose of S equipotent to the IB dose giving the maximal bronchodilator effect (IBopt) was calculated by interpolation of each S curve. On two other days, each patient received IBopt or the equipotent S dose followed by an additional 400 micrograms S. On day 1 or 2, FEV1 reached 220 +/- 410 ml and 2410 +/- 380 ml (p less than 0.05) after the maximal dose of IB and S respectively. On day 3 or 4 after pretreatment by IB or S an additional 400 micrograms S gave a further increase, which was similar in both series (315 and 320 ml, respectively). FEV1 after combination treatment reached 238 +/- 350 ml and was not significantly different from the maximal effect of S (2440 +/- 290 ml). We conclude that S and IB exert a true pharmacological additive effect, since the combination effect is as great as the maximal effect of the most potent drug (S) and greater than the maximal effect of IB, and that the same additional dose of S gives the same increase after equipotent doses of S and IB.

Tachykinin-induced phosphoinositide breakdown in airway smooth muscle and epithelium: relationship to contraction.

We have studied the contractile response and phosphoinositide hydrolysis induced by substance P (SP), neurokinin A (NKA), neurokinin B (NKB), and Alp-Phe-Phe(R)-Gly[ANC-2]-Leu-Met-NH2 (L 363851), a selective NK2-receptor agonist, in guinea pig tracheal smooth muscle. The four tachykinins elicited a concentration-dependent contraction in tracheal smooth muscle devoid of epithelium, with the following order of potency: NKA greater than L 363851 greater than NKB greater than SP, (EC50 1.0 x 10(-9) M, 3.2 x 10(-9) M, 7.5 x 10(-9) M and 1.2 x 10(-7) M, respectively), which suggests that NK2 receptors predominate in airway smooth muscle. In the presence of epithelium, the sensitivity of airway smooth muscle to tachykinins was decreased, and the concentration response curves to tachykinins were shifted rightward by 30-fold for SP, 9-fold for NKA, and 5-fold for NKB. The concentration response curve to L 363851 was not significantly shifted in the presence of epithelium. This suggests that epithelium may release a relaxant factor in response to tachykinins via an NK1 receptor. In airway smooth muscle, we found that tachykinins elicited phosphoinositide breakdown with an order of potency similar to that for contractile response (EC50 2.2 x 10(-5) M, 3.6 x 10(-5) M, 4.4 x 10(-5) M, and 5.9 x 10(-5) M). In epithelium, SP alone elicited a significant phosphoinositide breakdown, suggesting that epithelial receptors to tachykinins may be of the NK1 subtype. Since it is established that phosphoinositide derivatives can elicit mobilization of intracellular calcium, our results suggest that phosphoinositide breakdown is the coupling mechanism for tachykinin-induced contraction of airway smooth muscle.

Breakdown of phosphoinositides in airway smooth muscle: lack of influence of anti-asthmatic drugs.

Hydrolysis of membrane inositol phospholipids during agonist-induced contraction in bronchial smooth muscle leads to formation of inositol phosphates. Inositol phosphates are associated with intracellular Ca++ mobilization, which in smooth muscle leads to contraction. We have investigated the effects of inhibitors of the contraction, theophylline, isoproterenol (isoprenaline), and verapamil, on contraction due to carbachol and histamine in bovine airway smooth muscle, and on the formation of inositol phosphates in the same preparation. Since phospholipase C and A2 are involved in the formation of inositol phosphates, we have also studied the effect of inhibitors of phospholipases, dexamethasone and mepacrine, on the accumulation of inositol phosphates. Theophylline, isoproterenol and verapamil elicited a concentration-dependent relaxation of pre-contracted smooth muscle, with the following order of potency: Isoproterenol greater than verapamil greater than theophylline. The relaxant effect was more effective on histamine than on carbachol-induced contraction and depended on the initial airway tone. However, neither theophylline, isoproterenol or verapamil, nor dexamethasone or mepacrine changed the basal level of inositol phosphates or affected the rise due to agonists. We conclude that the smooth muscle effects of theophylline, isoproterenol, verapamil, dexamethasone and mepacrine are not mediated by interference with membrane phosphoinositide breakdown.

The effect of platelet activating factor on pulmonary beta-adrenoceptors.

An intravenous infusion of platelet activating factor (Paf) in the guinea-pig elicits an increase in bronchial responsiveness to the spasmogens, histamine and bombesin. Airways obstruction induced by bombesin in Paf-treated animals is poorly reversed by isoprenaline compared to comparable airways obstruction induced by bombesin in vehicle-treated animals. Isoprenaline induced a comparable dose-related relaxation in vitro of tracheal smooth muscle isolated from Paf- and vehicle-treated animals. No change in beta-adrenoceptor numbers or binding affinity was observed in lungs removed from Paf-treated animals in comparison with those from vehicle-treated animals, or after direct incubation with Paf in vitro. The reduced bronchodilator responsiveness to isoprenaline in Paf-treated animals is not related to changes in pulmonary beta-adrenoceptor function. These results suggest that non-spasmogenic elements may contribute to airways obstruction induced in hyper-responsive animals.

Phosphatidylinositol response to cholinergic agonists in airway smooth muscle: relationship to contraction and muscarinic receptor occupancy.

Hydrolysis of membrane phosphatidylinositol (PI) and polyphosphonoinositides (PPI) may be the coupling mechanism between receptor stimulation and the rise in intracellular calcium concentration that leads to smooth muscle contraction. In bovine tracheal smooth muscle, we correlated PI/PPI turnover, contraction and muscarinic receptor occupancy by carbamoylcholine (10(-9) to 10(-2) M). Inositol monophosphate formation after agonist stimulation, in the presence of lithium, provided a direct measurement of PI/PPI breakdown, and receptor occupancy was determined by [3H]quinuclidinyl benzylate binding. Carbamoylcholine caused a concentration-dependent contraction (EC50 = 7.4 X 10(-8) M), PI/PPI response (EC50 = 3.8 X 10(-5) M) and [3H]quinuclidinyl benzylate displacement (with high and low affinity binding sites have dissociation constants (Kd) of 3 X 10(-7) and 6 X 10(-4) M, respectively). This indicates the presence of spare receptors as maximal contraction is obtained when less than 20% of receptors are occupied. The concentration of carbamoylcholine inhibiting 50% of the PI/PPI response and 50% of maximal receptor occupancy (IC50) were similar for atropine (IC50 = 1 X 10(-9) and 5.3 X 10(-9) M, respectively), and for pirenzepine (IC50 = 3 X 10(-6) and 2.3 X 10(-6) M, respectively); the pA2 of the contraction was 8.3 +/- 0.12 for atropine and 7.2 +/- 0.08 for pirenzepine, indicating that M2 receptors may be largely predominant among bovine tracheal smooth muscle muscarinic receptors. Bovine tracheal smooth muscle may be a useful model to study the effects of other spasmogens, as it allows comparison of functional effects, PI breakdown and receptor occupancy in the same preparation.