Dopaminergic Modulation of Human Bronchial Tone

Abstract

Background

Dopamine exerts inhibitory and excitatory effects on different systems. Its effect on human bronchial tone is controversial. It has been reported that dopamine has no acute effect on human airways from normal subjects or those with asthma background. However, inhaled or infused dopamine decreased histamine-induced bronchoconstriction in both normal and asthmatic subjects. We examined the possible modulating effect of dopamine on bronchial diameter by administering inhaled dopamine and the DA₂ dopaminergic blocker metoclopramide (MTC) to subjects with various degrees of bronchial tone.

Methods

We examined 50 volunteers. Arterial blood pressure and heart rate were determined in each subject. By means of spirometry, we measured forced vital capacity (FVC), forced expiratory volume in the first second (FEV₁), maximal forced expiratory flow (FEF_max), and forced expiratory flow at 50% of vital capacity (FEF₅₀), before and after each treatment. By inhalation with a nebulizer, we administered the following: a) dopamine (0.5 μg/kg/min) to 10 healthy subjects, 10 subjects with asthma without acute bronchospasm (AWAB), and nine subjects with acute asthma attack (AAA), and b) intravenous (i.v.) metoclopramide (7 μg/kg/min) was administered to 10 healthy subjects and 11 subjects with AWAB. For ethical reasons, MTC was not used in subjects with acute asthma attack. Non-parametric Wilcoxon test for paired samples, ANOVA test, and Bonferroni multiple comparison test were performed.

Results

Inhaled dopamine increased FEV₁ and FVC, FEF_max, and FEF₅₀ in the AAA group, but there were no modifications in the healthy group or in the AWAB group. Metoclopramide did not induce changes in respiratory parameters in healthy individuals or in those with AWAB.

Conclusions

Inhaled dopamine is able to induce bronchodilatation when the bronchial tone is already increased by acute asthma attack but did not modify the resting bronchial tone in normal subjects or in asthmatics without acute bronchospasm. Additionally, DA₂ blockade with metoclopramide did not modify resting bronchial tone. Dopamine exerts a modulatory effect on the bronchial tone of human airways depending on the degree of preexisting tone.

Introduction

Neural control of human airways is very complex (1). In addition to the involved function of afferent nerves, cholinergic and adrenergic pathways, and the influence of circulating catecholamines, nonadrenergic, noncholinergic nerves, both inhibitory and excitatory (iNANC/eNANC) are present 2, 3, 4. Adrenergic control of airways is performed by both sympathetic nerves, which release norepinephrine, and by the adrenal medulla, which releases epinephrine. The adrenergic system elicits bronchodilatation through β₂ adrenoceptor acti-vation (5) and constriction through α adrenoceptors only when the airways are altered, but not under normal conditions (1).

Dopamine exerts its action in peripheral tissues through adrenergic receptors, but also through DA₁, DA₂, DA₃, and DA₄ receptors (6). To our knowledge, peripheral dopaminergic receptors in human airways have not yet been identified. However, Bonnert et al. (7) have recently reported that a dopamine-like compound (AR-C68397AAA) induced bronchodilating effects through DA₂ dopaminergic receptors in guinea pigs and dogs. The authors suggested that this compound could be a potential agent for the treatment of bronchial asthma.

The effect of dopamine on the human bronchial tree is subject to controversy. Thomson et al. (8) did not see changes in airway conductance when administering dopamine to healthy subjects and to those with asthma but without acute attack. Later, Michoud et al. (9) found that inhaled or i.v. dopamine inhibited the constriction induced by administration of successive histamine doses in healthy subjects and in subjects with asthma background. These experiments suggested that dopamine could exert a modulating effect on airway diameter, which occurs only when bronchial tone is previously increased.

In regard to experiments in vitro, Michoud (10) observed that dopamine elicited relaxation of guinea pig trachea rings and that this relaxation was blocked by the beta adrenergic blocker propranolol. However, in human and dog trachea rings, dopamine produced contraction that was abolished by α adrenergic receptor blockers. Kamikawa et al. (11) reported that dopamine inhibited the cholinergic and non-cholinergic contraction induced by electric field stimulation in isolated guinea pig trachea and that dopaminergic inhibition was not blocked by either propranolol or the α₂ adrenergic blocker yohimbine, or by the DA₂ dopaminergic blocker haloperidol.

In addition, Chen (12) found that, in isolated dog trachea, dopamine elicited contraction and that this contraction was accompanied by tachyphylaxis. The contraction could be restored by adding histamine to the tissue. This effect of histamine was partially blocked by a DA₂ receptors blocker, domperidone, as well as by yohimbine, but was potentiated by atenolol, a β₁ adrenergic blocker.

Thus, it appears that dopamine exerts a bronchial motor tone effect that is independent from the other catecholamine actions. There are species differences in the actions of dopamine; additionally, in human airways in vitro dopaminergic responses are different from in vivo responses.