Isolated Bronchi from Asthmatics Are Hyperresponsive to Adenosine, which Apparently Acts Indirectly by Liberation of Leukotrienes and Histamine

Abstract

Bronchial hyperresponsiveness can be demonstrated in asthmatic subjects by inhalation of adenosine, but the action of adenosine at the level of the human airway smooth muscle has received comparatively little attention. We have previously observed that bronchi isolated from one asthmatic patient contracted in response to adenosine. We have therefore, during the course of a 3-yr study, further characterized the effects of adenosine in bronchi prepared from surgical specimens of lung tissue of asthmatics and of nonasthmatics. Contraction responses were always studied in vitro the same day the tissues were obtained. Bronchi from asthmatics (19 strips from six patients) were more sensitive to adenosine than were bronchi from nonasthmatics (21 strips, seven patients). In contrast, there was no difference in sensitivity to histamine or leukotriene C4 between the two groups, nor was the maximal tissue contractility different. The contractile effect of adenosine was inhibited by the adenosine A1-antagonist 2-thio-[(1,3-dipropyl)-8-cyclopentyl]-xanthine as well as by the dual A1 and A2 antagonists 8-(p-sulfo)-phenyltheophylline and theophylline. The combination of leukotriene antagonism (receptor-antagonist ICI 198,615 or biosynthesis inhibitor MK-886) and histamine antagonism (antihistamines mepyramine and metiamide) blocked the contractile effects of adenosine, suggesting that adenosine acts indirectly by liberation of leukotrienes and histamine, possibly from mast cells. The findings of increased sensitivity to adenosine in bronchi from asthmatics to our knowledge represents the first evidence of increased bronchial reactivity in vitro in asthmatics.

A Selective Agonist Affinity Label for A3 Adenosine Receptors

“…Thus, we have introduced a new tool for the study of A 3 receptors, their molecular structure, regulation, and physiological role in the inflammatory (1-3), pulmonary (8,9), cardiovascular (21), and central nervous systems (10,11). It will be necessary to examine the functional effects (3-5) of this isothiocyanate derivative as a function of time in order to establish whether it acts as a full agonist in functional assays and whether this action is maintained or rapid desensitization occurs.…”

A role for mast cells in adenosine A3 receptor‐mediated hypotension in the rat

“…The reason for this difference remains to be clarified. Nevertheless, there are several examples of mast cell-dependent functional responses to adenosine receptor ligands apparently acting independently of a second activating stimulus, including bronchoconstriction in rats (Pauwels & Van Der Straeten, 1987) and contraction of human bronchi (Bjork et al, 1992) and constriction of arterioles from the hamster cheek pouch (Doyle et al, 1994) in vitro. General similarity between responses to APNEA and compound 48/80…”

The Association of Cortactin with Profilin-1 Is Critical for Smooth Muscle Contraction

“…Peptide-Asthma is characterized by airway hyperresponsiveness, which is largely attributed to hyperreactivity of airway smooth muscle (41)(42)(43)(44). However, the molecular mechanisms that control airway hyperresponsiveness and smooth muscle hyperreactivity are not fully understood.…”