Decreasing asthma morbidity.

Apart from the optimal use of drugs, various supplementary methods have been tested to decrease asthma morbidity, usually in patients from relatively affluent socio-economic backgrounds. A study of additional measures taken in a group of moderate to severe adult asthmatics from very poor socio-economic backgrounds who had had on average only 5 years of schooling, is reported here. The additional methods were selection of patients who could successfully use a metered dose inhaler and prescription of other forms of administration for those who could not, with regular repeat checking of the techniques of aerosol use, use of theophylline blood level monitoring to improve the basis for discussing drug non-compliance with patients, and repeated explanation to patients why regular medication and clinic attendance are essential. These measures resulted in a significant improvement in morbidity, whereas no such improvement was found in a control group.

The dose-related hyper-and-hypokalaemic effects of salbutamol and its arrhythmogenic potential.

1. The hypokalaemic effect of salbutamol after more than 30 min of administration has been well described. A hyper-and-hypokalaemic effect for adrenaline has been reported, but no such hyperkalaemic effect for salbutamol. 2. The possible hyper-and-hypokalaemic effects of salbutamol with the concomitant potential for pro-arrhythmia were assessed in the baboon (Papio ursinus). 3. Male and female baboons were anaesthetized with ketamine (15 mg kg-1) and maintained with 6% pentobarbitone as spontaneously breathing animals. Six baboons in each group received either 10, 100 or 500 micrograms kg-1 salbutamol i.v. Lead II of the ECG and femoral i.a. blood pressure were recorded continuously for 10 min. Arterial blood samples were collected at 0 min and then after 3 and 10 min of salbutamol administration. 4. All the animals developed sinus tachycardia (above 200 beats min-1) within 30 s of each dose of salbutamol administration and the high heart rate persisted throughout the experiment. All the animals were hyperkalaemic after 3 min and hypokalaemic after 10 min for each dose of salbutamol. Left ventricular conduction defects were seen in 3 animals during the hyperkalaemic phase. No arrhythmia was seen during the hypokalaemic phase. 5. Salbutamol has a transient hyperkalaemic and a more prolonged hypokalaemic effect in the baboon. The hypokalaemia could not be associated with arrhythmia although conduction defects were associated with the hyperkalaemia. 6. Since salbutamol is used as a bronchodilator in asthmatic patients and to treat acute hyperkalaemia, it is suggested that caution should be exercised when using salbutamol in high doses to treat acute asthma especially during the first few minutes of administration. The finding of hyperkalaemia with salbutamol questions its use in the treatment of hyperkalaemia.

The assessment of mucociliary clearance using monodisperse 99mTc-tagged red blood cells.

To assess mucociliary clearance rates of the lungs using a monodisperse particle of constant volume, we investigated the possibility of using a patient's own red blood cells. The cells are tagged with 99mTechnetium. The procedure was performed on two groups of volunteers. The test was found to be very reliable (98%). A second group was studied with the administration of a placebo or 400 mg Aminophylline during the acquisition of the data. The expected response could be seen in 81% of the cases studied.

Apparent racial difference in response to angiotensin I infusion.

Angiotensin I was infused into 16 healthy volunteers, 8 blacks and 8 whites with diastolic blood pressures below 75 mm Hg and the infusion rate increased at 3 min intervals until a diastolic blood pressure of equal to or greater than 95 mm Hg was achieved. Blacks exhibited a significantly greater angiotensin I sensitivity needing 1.8 micrograms/min as opposed to 3.9 micrograms/min in whites to achieve the target blood pressure. Plasma renin activities were similar in the two groups, but blacks had significantly higher urinary sodium values than whites, 223 mmol per 24 h as compared to 121 mmol per 24 h. It is concluded that the differences in response could be largely due to differences in dietary sodium intake. These factors need to be carefully considered when using angiotensin I infusion as a pharmacodynamic model for studying the effects of ACE inhibitors.

Apparent affinity values of beta-adrenergic blockers in a tissue with a mixture of beta-adrenergic receptor subtypes.

The affinity (pA2 or pKB) values of 3 different beta-adrenoceptor blocking drugs were determined using the isolated guinea-pig tracheal chain preparation. The pA2 values for each of the beta-adrenoceptor blocking drugs were determined, using respectively isoprenaline and salbutamol as agonists. Neuronal and extraneuronal uptake of agonist were blocked with phenoxybenzamine. With isoprenaline, a nonselective beta-adrenoceptor agonist, the pA2 values for the blocking drugs were unacceptable. Using the beta 2-selective beta-adrenoceptor agonist, salbutamol, under the same conditions, resulted in consistent pA2 values for the nonselective beta-adrenoceptor blocking drug propranolol and some concentrations of the beta 2-selective blocking drug ICI 118.551. pA2 Values for the beta1-selective antagonist atenolol were not consistent for the concentrations used. It is suggested that this is due to the guinea-pig trachea having a mixed beta-adrenoceptor population. A mathematical model is presented that shows the influence of a mixed receptor subpopulation on the shift of theoretical agonist concentration-effect curves in the presence of a competitive antagonist. It can be shown that the affinity values of antagonists for a specific receptor subtype are to a greater or lesser degree unreliable, depending upon the selectivity-ratios of both the agonist and the antagonist used.

[Cholinergic systems in bronchospasm]. / Cholinerge stelsels in brongospasma.

A neuronal cholinergic system is widely distributed in larger airways, particularly around bifurcations. These neurons form efferent pathways from the brainstem ending in the motor end-plate on smooth muscle, and ciliated and mucus-producing cells. Impulses originating in various sensory endings in the airways, from the central nervous system and from many sensory receptors throughout the body, influence the activity of the cholinergic system thereby controlling the patency of the airways and modulating the rate and depth of breathing. A non-neuronal cholinergic system present on mast cells facilitates their degranulation, resulting in the release of chemical mediators. These induce bronchospasm directly but also indirectly by activating the neuronal cholinergic system. Effective bonchodilator drugs are all antagonists of the cholinergic system. The most effective bronchodilators, however, are physiological antagonists of cholinergic and all other known bronchospasm-inducing agents. Such antagonists include beta-adrenergic stimulants and methyl xanthines. Competitive antagonists such as ipratropium which act on muscarinic receptors in the cholinergic motor end-plate are generally less effective. Drugs such as sodium cromoglycate act only prophylactically by reducing the degranulation of mast cells and/or minimizing irritation of airway sensory receptors.

Interaction of verapamil hydrochloride and atropine sulphate on histamine-induced bronchoconstriction.

Submaximal histamine dose-response curves were obtained on 34 dogs divided into six groups. These groups were: A (n = 6) untreated; B (n = 6) after atropine (1 mg/kg); C (n = 5) after verapamil inhalation (10 mg total dose); D (n = 5) after verapamil inhalation (100 mg total dose); E and F (n = 6) as for C and D but pre-treated with atropine (1 mg/kg). Total lung resistance (R1) was measured in each case at increasing delivered concentrations of inhaled histamine and expressed as a ratio of baseline valve. For each group a composite mean curve was obtained and the maximal recorded responses (mean maximal resistance ratios) for the various groups were compared. It appears that the combination of verapamil inhalation (low dose) and atropine reduced the anticholinergic effect of atropine causing marked bronchoconstriction. This unexpected result depends on the verapamil dose since it was not present at the higher dose (group F).

Different, dose-dependent effects of verapamil inhalation on histamine-induced bronchoconstriction in anaesthetized dogs.

Different, dose-dependent effects of verapamil inhalation on histamine-induced bronchoconstriction in anaesthetized dogs are reported. Cumulative histamine dose-response curves were obtained on three groups each consisting of six dogs. These groups were: A - after atropine sulphate (1 mg/kg); B - after atropine sulphate and verapamil (approximately 0.5 mg/kg); C - after atropine sulphate and verapamil (approximately 5.0 mg/kg). Total lung resistance (R1) was measured as the indicator of bronchoconstriction. The mean maximal response of R1 in B was significant greater (p less than 0.01) than in A and C, while no significant difference was observed between A and C. A possible mechanism is postulated.

Influence of vagus nerve on catecholamine production of dog lungs.

The effect of electrical stimulation of the cut cervical vagal nerves in dogs on airway resistance and circulating catecholamine concentrations was determined before and after propranolol. Airway resistance increased after 1 min of stimulation and decreased after 9 min of stimulation. The circulating catecholamine levels increased significantly in the pulmonary artery after 1 min of stimulation. After 9 min of stimulation the increase in the femoral artery was relatively more than in the pulmonary artery. This late increase most probably represents catecholamine supply from lung structures.

An alternative model for non-competitive antagonism.

An antagonist acting on its own receptor leading to a gradual decrease in the affinity between an agonistic drug and its own but different receptor, is a metaffinoid antagonist. The presently published models for metaffinoid antagonism predict a parallel shift in the concentration-effect curves of the agonist by the metaffinoid antagonist, due to a gradual change in the affinity between the agonist and its receptor. An alternative model is proposed where the presence of an antagonist changes the affinity of only a fraction of the agonistic receptors, leading, in contrast to the presently published model to: a) non-parallel shifts in concentration-effect curves and b) metaffinoid antagonistic curves that look like the curves obtained in metactoid antagonism. Experimental support for the alternative model is found in the interaction between various beta-adrenergic agonists and serotonin in the guinea-pig tracheal chain and rat stomach fundus strip preparations.