Effect of Carbon Dioxide on Pulmonary Vascular Tone at Various Pulmonary Arterial Pressure Levels Induced by Endothelin-1

Abstract

There have been contradictory reports suggesting that CO(2) may constrict, dilate, or have no effect on pulmonary vessels. Permissive hypercapnia has become a widely adopted ventilatory technique used to avoid ventilator-induced lung injury, particularly in patients with acute respiratory distress syndrome (ARDS). On the other hand, respiratory alkalosis produced by mechanically induced hyperventilation is the mainstay of treatment for newborn infants with persistent pulmonary hypertension. It is important to clarify the vasomotor effect of CO(2) on pulmonary circulation in order to better evaluate the strategies of mechanical ventilation in intensive care. In the present study, pulmonary vascular responses to CO(2) were observed in isolated rat lungs (n = 32) under different levels of pulmonary arterial pressure (PAP) induced by various doses of endothelin-1 (ET-1). The purposes of this study were to investigate (1) the vasodilatory effect of 5% CO(2) in either N(2) (hypoxic-hypercapnia) or air (normoxic-hypercapnia) at different PAP levels induced by various doses of endothelin-1, and (2) the role of nitric oxide (NO) in mediating the pulmonary vascular response to hypercapnia, hypoxia, and ET-1. The results indicated that (1) CO(2) produces pulmonary vasodilatation at high PAP under ET-1 and hypoxic vasoconstriction; (2) the vasodilatory effect of CO(2) at different pressure levels varies in accordance with the levels of PAP, the dilatory effect tends to be more evident at higher PAP; and (3) endogenous NO attenuates ET-1 and hypoxic pulmonary vasoconstriction but does not augment the CO(2)-induced vasodilatation.

Sustained therapeutic hypercapnia attenuates pulmonary arterial Rho-kinase activity and ameliorates chronic hypoxic pulmonary hypertension in juvenile rats

“…Therefore, a more precise understanding of the contribution of enhanced endogenous NO production toward pulmonary vasorelaxation, augmented PKG signaling, and attenuated smooth muscle ROCK activity secondary to CO 2 will require further study. However, work by others has suggested that pulmonary vasodilatory effects of CO 2 may be independent of NO (11). Other likely upstream mechanisms by which CO 2 may have limited RhoA/ROCK activity, not explored in this study, include attenuated oxidative and nitrative stress in the lung (33,39,49) and downregulated expression of endothelium-derived GPCR ligands, such as endothelin-1 (33,74).…”

“…A possible implication of these observations is that benefits of CO 2 on PHT were related to the dose of CO 2 itself, rather than the degree of acidosis induced, in keeping with several ex vivo studies (11,67). Alternatively, recent evidence suggests that arterial ROCK activity is highly pH-sensitive, being decreased at both low and high intracellular pH (6).…”

“…Hypercapnia is thought to prevent pulmonary vascular injury via multiple pathways, among which include attenuated oxidative and nitrative stress (10,33,39,49) and downregulated expression of critical G proteincoupled receptor (GPCR) ligands, such as endothelin-1 (33), all of which have potential to activate ROCK in pulmonary arterial smooth muscle. Additionally, vasodilatory effects of CO 2 on the ex vivo pulmonary vasculature have been shown to be most evident when vascular tone is high (11), to occur independent of changes in pH (11,67), and to persist in the absence of endothelium-derived NO (11), suggesting a direct effect of CO 2 on smooth muscle.…”

Tolerance to acute hypoxia maximally increases in case of joint effect of normobaric hypoxia and permissive hypercapnia in rats

“…However, carbon dioxide was found to produce a cerebral protective effect in case of hypoxic/ischemic damage [23]. Some studies have examined the positive effect of hypercapnia on the potassium channel [11], antioxidant system [27], and blood circulation in the lungs [5]. In addition, there are also data indicating that apoptosis inhibition is affected by permissive hypercapnia [30].…”

“…The main mechanisms of these hypoxia effects are probably the increase in mRNA expression in early gene families [6], the activation of the K + channel by proteinkinase C [17], the activation of succinatoxidase oxidation [7], and genome reprogramming by HIF-1 redox-sensitive protein [12]. However, toxic effects of hypercapnia should be kept in mind; it consists of an acid-base balance shift toward acidosis development, metabolism depression, intracellular homeostasis, and mineral metabolism disorder, as well as in respiratory center work depression [1,5,10,23]. The negative effects of carbon dioxide described above manifest themselves at PCO 2 above 100 mmHg (30).…”