β-Adrenergic Responses in Lymphocytes
The lymphocytes were isolated from peripheral blood obtained under identical basal conditions in all subjects, allowing results from the two studies to be pooled. Unstimulated cAMP accumulation in lymphocyte incubates was similar in the three groups (Table 1). Isoprenaline enhanced cAMP accumulation approximately fivefold, the maximum response being reached at 10-5 M in most experiments (Table 1, Fig 1). The EC50 for isoprenaline varied considerably, but was about 5 to 10xl0“8 M, on the average (Table 1). IBMX enhanced basal and isoprenaline stimulated cAMP accumulation approximately fourfold in all three groups, without changing the EC^-values for isoprenaline. The cAMP-values for the prselective antagonist atenolol were similar in the three groups and four orders of magnitude higher than the cAMP-values for the nonselective (J-adrenoceptor antagonist propranolol (Table 1). Thus, lymphocytes from all three groups of subjects seemed to have a homogenous population of 02-adrenoceptors.
Asthma is a complex trait that is determined by both genetic and environmental factors. Evidence for genetic predisposition to asthma (and related phenotypes) is derived from family studies, twin studies, adoption studies, and segregation analyses (also see Burkart et al for a more recent review). There is also evidence that different genes influence asthma phenotypes of different racial/ethnic groups. Many candidate genes contributing to the development and expression of asthma have been proposed including gene variants associated with T-cell differentiation and related biological processes (eg, cytokine function and IgE production), genes related to drug response (eg, p-adrenergic receptor and glucocorticoid receptor), and genes important to the handling of environmental toxins (eg, cytochrome P450 and glutathione S-transferase genes). Genetic polymorphisms in the P2-adrenergic receptor have been linked to asthma severity, and the prevalence of functional polymorphisms in the p2-adrenergic receptor gene varies across race.
Double-blind Crossover Study of Five Bronchodilator Medications and Two Delivery Methods in Stable Asthma: Is There a Best Combination for Use in the Pulmonary Laboratory?
There have been many investigations examining the physiologic responses of subjects to single bron-chodilator drugs, the physiologic responses to one drug in comparison to another, and the method of inhalation. The majority of these studies have looked at the safety and relative efficacies of the medications in relation to the speed of onset of bronchodilation in the treatment of asthmatic subjects, the time of peak response, the duration of the response, and the degree of side effects. There is still debate as to whether there is a best drug or method of delivery for circumstances such as laboratory testing.
In our USAF Reference Cardiopulmonary Laboratory, nearly one third of our studies of pulmonary function involved bronchodilator agents in patients with reversible bronchospastic disease. It is obviously important to use the best medication and method of delivery to derive optimal changes on the tests of pulmonary function—within the twin restraints of cost and time available. In our laboratory, we had access to two different methods of delivery (compressed air-driven nebulizer and metered-dose inhalers) and medications from three major classes of autonomic active bronchodilator medications: (1) catecholamines (isoproterenol and isoetharine); (2) resorcinols (meta-proterenol and terbutaline); arid (3) saligenin (albuterol [salbutamol]).
We therefore designed this double-blind crossover study to determine whether any one medication, method of delivery, or combination of medication and method of delivery would be statistically superior in a busy laboratory for the demonstration of short-term reversibility in a group of subjects with stable asthma.
The efficacy of bronchodilator drugs administered by metered-dose inhalers depends on adherence to proper technique. Alternate devices for delivery, including spacers and ultrasonic and air-compressor nebulizers, have been proposed for use in ambulatory patients. These devices are being prescribed for patients who either have difficulty in using a metered-dose inhaler or have inadequate control by standard therapy, including bronchodilators administered by metered-dose inhaler.
In this study, we compared the bronchodilator response to albuterol (salbutamol) delivered by metered-dose inhaler and ultrasonic nebulizer in subjects with moderately severe stable obstructive pulmonary disease.
Materials and Methods
Nineteen outpatients (13 male and six female subjects; mean age, 61 years) with stable obstructive pulmonary disease were studied. Six were asthmatic, and 13 had chronic obstructive pulmonary disease (COPD) (criteria of American Thoracic Society). Twelve were taking theophylline, nine ipratropium, eight inhaled steroids, and seven oral steroids. All subjects had been taking oral or inhaled P-adrenergic agonists. The baseline value for forced vital capacity (FVC) was 1.58 + 0.11 L (± SE), for forced expiratory volume in one second (FEV,) was LOO + 0.10 L (45 percent of predicted), and for the mean forced expiratory flow over the middle half of the FVC (FEF25-75%) was 0.62 -I- 0.10 L/sec. No subject had previously used an ultrasonic or air-compressor nebulizer. Subjects abstained from bronchodilator therapy for eight hours prior to study. Oral steroids were administered as usual. Informed consent was obtained from each patient.
Hemodynamic Effect of Hydralazine in Advanced, Stable Chronic Obstructive Pulmonary Disease with Cor Pulmonale: Materials and Methods
Vasodilators have been used recendy for the treatment of primary pulmonary arterial hypertension. From the studies reported, it can be concluded that vasodilator therapy is effective for selected patients, namely, those with lower mean pulmonary arterial pressure and pulmonary arteriolar resistance. In these patients, vasodilator drugs might counteract the vasoconstriction of the pulmonary circulation that is considered a major factor responsible for the hypertensive state. Pulmonary hypertension