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The Sleep Hormone Melatonin Can Aggravate Asthma and Undermine the Therapeutic Effect of Bronchodilators

Melatonin MT2 receptor blockers could be used to reverse the negative effects of melatonin-enhanced bronchial constriction.

Asthma symptoms such as chest tightness, difficulty breathing, and wheezing can worsen at night and disrupt sleep. Known as “nocturnal asthma,” this condition is widely observed amongst patients with continuous asthma and is becoming an increasingly important area of research as studies have reported that more than 50 per cent of asthma deaths occur at night. While several risk factors of nocturnal asthma including but not limited to allergic rhinitis, obesity, and regular smoking, have been identified, the pathogenesis of nocturnal asthma remains unclear.

Recently, a group of researchers led by Kentaro Mizuta from Tohoku University Graduate School of Dentistry has discovered that a sleep hormone called melatonin, which is often prescribed for insomnia, can worsen asthma by favouring bronchoconstriction and undermining the relaxing effect of bronchodilators. Melatonin induces its effects by activating the melatonin MT2 receptor. Bronchodilators are normally taken to widen the bronchus and ease the contraction of smooth muscles of the bronchus.

At around 4.00 a.m., scientists have found that both serum melatonin concentration and asthma attacks tend to peak. To clarify the precise mechanisms of melatonin on the airways, the team closely investigated how the physiological effects of melatonin are mediated and whether the melatonin receptors are expressed on airway smooth muscle. They also examined whether melatonin receptors play a role in regulating intracellular cyclic AMP (cAMP) and calcium concentrations, which modulate airway smooth muscle tone, and whether they promote airway smooth muscle cell proliferation.

By analysing mRNA and protein expression in human and guinea pig airway smooth muscles, the researchers found that the melatonin MT2 receptor is expressed in the airways, whereas the MT1 receptor is not. They also observed that activating the melatonin MT2 receptor using higher doses of melatonin or the melatonin receptor agonist, ramelteon, significantly inhibited the accumulation of cAMP in human airway smooth muscle cells and greatly potentiated bronchoconstriction, verifying the hormone’s asthma-aggravating effect. Although melatonin, on its own, did not result in an increase in intracellular calcium concentration, melatonin significantly heightened acetylcholine-stimulated increases of intracellular calcium concentration and weakened the relaxant effects of the bronchodilator β-adrenoceptor agonist, isoproterenol, in guinea pigs.

“Although serum concentration of melatonin did not significantly induce the airway constriction, greater doses of melatonin, which is clinically used to treat insomnia, jet lag, or cancer, worsened asthma symptoms and impaired the therapeutic effect of bronchodilators,” said Mizuta.

By identifying the roles of the melatonin and the MT2 receptor in modulating airway smooth muscle tone, the findings of their study are expected to advance the development of safer and more effective asthma therapeutics.

“The pharmacological therapy that blocks the melatonin MT2 receptor could inhibit the detrimental effects of melatonin on airways,” added Sasaki. [APBN]

Source: Sasaki et al. (2021). Melatonin MT2 receptor is expressed and potentiates contraction in human airway smooth muscle. American Journal of Physiology-Lung Cellular and Molecular Physiology, 321(6), L991-L1005.