Adenosine-mediated Cyclic AMP-dependent Inhibition of Ciliary Activity in Rabbit Tracheal Epithelium

Abstract

We wished to determine whether adenosine, a purine nucleotide, modulates activity of respiratory cilia and, to this end, we studied cultured rabbit tracheal epithelium in response to adenosine and related substances in vitro. Ciliary beat frequency (CBF) as determined by a photoelectric method was depressed by adenosine (10(-3) M), the maximal decrease from the baseline value (965 +/- 29 beats/min, mean +/- SE) being 31.6 +/- 5.0% (p less than 0.001). The adenosine A2-receptor agonist N-ethylcarboxamide adenosine had only a small effect on ciliary activity, whereas other adenosine analogs elicited decreases in CBF in a dose-dependent fashion. The order of potency of cilia-inhibitory action was N-cyclohexyladenosine (an agonist for adenosine A1-receptor) greater than phenylisopropyladenosine greater than adenosine greater than N-ethylcarboxamide adenosine. Intracellular cyclic AMP (cAMP) levels were decreased by 10(-3) M adenosine from 39.2 +/- 6.5 to 25.3 +/- 4.8 pM/mg protein (p less than 0.05). The effect of adenosine on CBF was enhanced by dipyridamole, an adenosine uptake inhibitor, and by deoxycoformycin, an adenosine deaminase inhibitor. The adenosine-induced decreases in CBF and cAMP content were reversed by 8-phenyltheophylline, an adenosine receptor antagonist. These results suggest that there is an adenosine A1-receptor on rabbit tracheal epithelium that inhibits adenylate cyclase, which may result in the impairment of respiratory ciliary activity, and that adenosine-induced ciliary inhibition may be modulated by adenosine uptake and its catabolism by airway epithelial cells.

Real-time analysis of cAMP-mediated regulation of ciliary motility in single primary human airway epithelial cells

“…Adrenergic drugs, known to increase CBF (Sanderson and Dirksen, 1989;Wyatt et al, 1998;Yang et al, 1996), also increase intracellular cAMP levels. Even though adenosine may inhibit CBF through A1 receptor activation and subsequent adenylyl cyclase inhibition in rabbit epithelia (Tamaoki et al, 1989a), adenosine has been reported to stimulate human airway CBF via A2b receptors through cAMP production (Morse et al, 2001).…”

Purinergic Signaling in the Airways

“…Mucosal adenosine also stimulated Cl Ϫ secretion in canine tracheal epithelium (Pratt et al, 1986). Adenosine induced cAMP-dependent inhibition of ciliary activity in rabbit tracheal epithelium (Tamaoki et al, 1989). Adenosine inhibits endothelin-1 production and secretion in guinea pig tracheal epithelial cells via A 2B receptors and cAMP formation (Pelletier et al, 2000).…”

Adenosine activation of A2Breceptor(s) is essential for stimulated epithelial ciliary motility and clearance

“…The differential effects of adenosine to stimulate and/or inhibit ciliary motility and clearance have been investigated in numerous models (34,35,55,57), yet the net effects of adenosine receptor activation on ciliary function remain unclear. We chose an ex vivo model using both pharmacological and genetic manipulations to provide further clarity into the complex roles of adenosine in the regulation of mammalian ciliary beating.…”

“…Earlier studies established that adenosine could modulate ciliary activity (57,59). However, since these early findings, there have been several studies that revealed that the varied response of adenosine in modulating mucociliary velocity depends on its specific interaction with its cell-surface receptors and its ability to activate cAMP (30,34,35,55).…”