BNP has an important role in several other activities in the lung, such as bronchodilatation, pulmonary permeability and surfactant production.35 Therefore, it might be that high circulating levels of BNP released from the heart in states such as HF could have a modulating function on airway smooth muscle (ASM). In effect, BNP relaxes guinea pig tracheal smooth muscle in vitro36
and is effective in preventing ovalbumin-induced
bronchoconstriction and microvascular leakage in guinea pigs in vivo.37 Moreover, recently it has been shown that human recombinant BNP (nesiritide) is a potent bronchodilator in patients with asthma.38
Recently, we documented the relaxant effect of BNP on isolated human bronchi, particularly after passive sensitisation,39
incubation of human bronchial smooth muscle with BNP inhibited constriction induced by cholinergic and histaminergic stimulation.40
and also showed that The
bronchial relaxation induced by BNP appears to be associated with the activation of natriuretic peptide receptor (NPR)1 localised on the bronchial epithelium.40
guanylate cyclase (pGC) domain and this catalyses the formation of cGMP, the downstream second messenger involved in most BNP signalling.41
in vivo and relax ASM in vitro.42
It is well known that agents that activate GCs bronchodilate BNP is able to induce a time- and
concentration-dependent increase of cGMP levels in human ASM cells.43
Although we cannot exclude a role of inflammatory cells based on our results, the removal of the bronchial epithelium completely abolished the bronchial relaxant effects of BNP, suggesting a BNP-related, post-transductional control of bronchial contractility involving bronchial epithelium.40
Intriguingly, bronchial NPR1 immunoreactivity
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NPR1 contains an intracellular particulate
was detected in epithelium and inflammatory cells, but was faint or absent in ASM cells.40
Methoctramine, an antagonist of M2 muscarinic
receptors, and quinine, an inhibitor of organic cation transporters that reduces acetylcholine (ACh) release, abolished BNP-induced relaxant activity.40
The latter was associated with increased bronchial messenger (m)RNA for nitric oxide synthase (NOS) and NO release, inhibited by L-NAME, a NOS inhibitor, and aminoguanidine, an inhibitor of inducible NOS.40
In vitro, BNP increased ACh release from bronchial epithelial cells, whereas NO release was unchanged.40
Our results suggest that bronchial epithelial cells regulate the BNP-induced relaxant activity in human isolated bronchi by an autocrine loop involving BNP-induced low-dose ACh release from airway epithelium that stimulates NO release from underlying non-epithelial bronchial tissues. We speculate that BNP binding elicits the vesicular release of ACh from bronchial epithelial cells, including neuroendocrine and brush cells. Although there is less ACh released from the airway epithelium compared with that from neurons, it seems to be sufficient to activate postsynaptic M2 muscarinic receptors on the surface of ASM cells, which in turn increases NO and cGMP production.40
These findings support a teleological role for elevated BNP concentrations, at least in patients with COPD, in whom BNP might be part of a response aimed at mitigating the effects of the disease. They add important information to current understanding of the local reciprocal interactions of BNP with bronchial tone control and suggest alternative pharmacological options for chronic airway disease therapy, including bronchial asthma or COPD.44
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