Carbon dioxide enhances substance P-induced epithelium-dependent bronchial smooth muscle relaxation in Sprague–Dawley rats

Abstract

Hypocapnia and hypercapnia constrict and relax airway smooth muscle, respectively, through pH- and calcium (Ca(2+))-mediated mechanisms. In this study we explore a potential role for the airway epithelium in these responses to carbon dioxide (CO(2)). Contractile and relaxant responses of isolated rat bronchial rings were measured under hypocapnic, eucapnic, and hypercapnic conditions. Substance P was added to methacholine precontracted bronchial rings with and without epithelium. The role of Ca(2+) was assessed using Ca(2+)-free solutions and a Ca(2+) channel blocker, nifedipine. The effects of pH were assessed in solutions with HEPES buffer. Hypocapnic challenge increased the organ bath's pH and increased bronchial smooth muscle resting tension. This effect was abolished with HEPES buffer and partially inhibited by nifedipine. Hypocapnic conditions suppressed substance P-induced epithelium-dependent relaxation, whereas hypercapnia augmented the response. The epithelial hypocapnic effect was pH dependent, whereas the hypercapnic effect was pH independent. CO(2) had no effect on the epithelial independent smooth muscle agonists methacholine and isoproterenol. In conclusion our data indicate that, in addition to the effects of pH and Ca(2+), CO(2) affects airway smooth muscle by a pH-independent, epithelium-mediated mechanism. These findings could potentially lead to new treatments for asthma involving CO(2)-sensing receptors in the airways.

Nebulized perflubron and carbon dioxide rapidly dilate constricted airways in an ovine model of allergic asthma

“…They showed that low airway PCO 2 combined with high arterial PCO 2 resulted in a large increase in airway resistance [47]. These findings indicate that CO 2 may have unique properties when delivered through the airways and supports the previously cited in vitro work that airway epithelium plays a part in the relaxant response [22]. Finally the rapidity of the response as seen in the sheep video indicates that neural mechanisms are involved.…”

“…The bronchodilatory effect of CO 2 has been demonstrated in many mammalian species including cats, rats dogs [19,22] as well as sheep and humans However, the literature indicates that it might operate through several distinct mechanisms.…”

“…The first mechanism is through a direct physiologic relaxant effect of CO 2 on airway smooth muscle [20–22]. The way(s) in which CO 2 regulates bronchial smooth muscle tone is not fully understood.…”

“…The way(s) in which CO 2 regulates bronchial smooth muscle tone is not fully understood. Recent in vitro data indicates that part of this effect is mediated by pH dependent and part by pH independent but epithelium dependent mechanisms [22]. Studies in vivo indicate the response (in rats) to inhaled CO 2 does not require adrenergic pathways [46].…”

“…Hypercapnia has long been known to relax airway smooth muscle in vitro [20,21], whereas hypocapnia causes airway smooth muscle contraction [22]. Hyperventilation is a well known trigger of asthma [23].…”