Frontiers reviewTheory of gastric CO2 ventilation and its control during respiratory acidosis: Implications for central chemosensitivity, pH regulation, and diseases causing chronic CO2 retention
Introduction
Carbon dioxide is produced in the mitochondria during aerobic metabolism and quickly hydrated to form carbonic acid, which dissociates into H+ and HCO3−. Currently, the only recognized mechanism for rapid removal of CO2 produced from aerobic metabolism is brain stem-controlled cardiopulmonary reflexes that increase pulmonary blood flow and alveolar ventilation () for optimal CO2 uptake and removal by the lungs. For example, an increase in arterial (); i.e. respiratory acidosis that is caused by alveolar hypoventilation is “sensed” by peripheral and central (intracranial) CO2/H+-chemoreceptors. Stimulation of peripheral and central chemoreceptors leads to an increase in and perfusion resulting in exhalation of excess CO2 to correct respiratory acidosis and restore pH balance (Forster and Smith, 2010, Guyenet et al., 2010, Nattie, 1999, Nattie and Li, 2010).
The goal of this Frontiers Review is to summarize the large body of evidence supporting the new theory that alveolar CO2 ventilation and perfusion are supplemented during respiratory acidosis by gastric CO2 uptake from blood, CO2 reconstitution and concentration in the stomach lumen in excess of venous , and “ventilation” of CO2 out of the body through coordinated vagovagal-mediated neuromuscular reflexes within the gastroesophagopharyngeal system. The entire seven-step mechanism of gastroesophagopharyngeal CO2 ventilation will be referred to from here on as simply “gastric ventilation ()”. The end result is that gastric CO2 is vented upwards through the esophagus and into the pharynx to be mixed with expired alveolar gas. The contribution of gastric CO2 raises mixed-expired () above that due to alveolar CO2 diffusion alone (Sections 2.1 Gastric CO, 2.2 Non-deglutitive gastric acid production and ventilation during respiratory acidosis: an explanation for the paradoxical negative). In the absence of food stimuli, a significant amount of CO2 is generated in the stomach from the reaction between gastric acid and HCO3− (Section 2.1), which are transported into the lumen in response to systemic respiratory acidosis; this reflex will be referred to as “non-deglutitive” production of gastric acid, HCO3−, and CO2 and it is key to the theory presented here (Sections 4.4.1 Acute respiratory acidosis stimulates gastric acid secretion, 4.5 Step 5—transport of intracellular HCO, 4.6 Step 6—regeneration of CO).
The conception of the theory of gastric ventilation and its evolution grew out of the author's desire to understand the possible functional significance of data from electrophysiological studies of chemosensitive cSC neurons (in vitro) in the context of an integrated physiological system that participates in CO2 regulation and pH homeostasis. Based on the electrophysiological studies of Dean, Putnam and their colleagues (Section 1.1.1) and several key observations reported in the gastric and respiratory physiology literature (Sections 1.1.2 Arterial CO, 1.1.3 The stomach acts as a “lung” during CO, 1.1.4 Hypercapnic acidosis and orexin both stimulate pulmonary ventilation and gastric acid secretion, 1.1.5 Gastroesophageal diseases and pulmonary diseases occur together), in some instances several decades removed, the idea emerged that there is a non-alveolar mechanism for CO2 removal that involves the digestive system. A critical aspect in developing this new theory was reevaluating a large body of older gastric physiology literature in the context that the gastroesophagopharyngeal system, in the absence of food stimuli, also functioned as a gas exchanging organ for CO2 removal during respiratory acidosis and, possibly, metabolic acidosis. The following discussion lists these key observations that provided the foundation for this new theory. Further details and additional evidence are provided in Section 4.
Prior electrophysiology studies of cSC neurons in rat brain stem tissue slices (Dean et al., 1990, Huang et al., 1997, Mulkey et al., 2003, Nichols et al., 2009a, Nichols et al., 2009b) indicated that CO2/H+-sensitive neurons are as prevalent in the cDMV (motor nucleus) as the cNTS (sensory nucleus). This raised the following question: what is the functional significance of putative CO2/H+-chemoreceptor neurons being concentrated in both a “motor” nucleus (cDMV) and a “sensory” nucleus (cNTS)? In addition, neurons at the very same level of the cNTS and cDMV make extensive afferent and efferent connections with various components of the cardiopulmonary system (Dean and Putnam, 2010) and digestive system (Travagli et al., 2006) (Fig. 1). Why would seemingly unrelated organ systems—respiration and digestion—share identical CNS locations and, presumably, local synaptic circuits and neurons (and stimuli, Section 1.1.4)?
Respiratory acidosis stimulates gastric mucosal blood flow (GMBF) and gastric acid secretion and gastric acid production in turn removes CO2 from arterialized blood (Section 4.1.1). CO2 consumed in the production of gastric acid and HCO3− in the gastric epithelium is reconstituted in the gastric lumen from the reaction between luminal H+ and HCO3− (Section 4.6). Accumulation of gastric luminal results in increased esophageal () to levels that exceed of blood (Section 4.6). Is there a gastroesophagopharyngeal muscular “pump” for venting gastric CO2 into the esophagus and pharynx that supplements the diaphragmatic-intercostal–abdominal muscular respiratory pump? Presumably there is such a pump (Section 4.7) given that eating induces a postprandial elevation in expired (Section 2.1) and a rise in in excess of blood during periods of CO2 rebreathing and increased dead space ventilation (Section 2.2).
The acid secreting stomach behaves exactly as the lung with regard to CO2 gas exchange (Section 4.1.1): CO2 diffuses out of arterialized blood into the gastric epithelium as epithelial CO2 is consumed to form HCO3− and H+ for gastric acid. With continued CO2 removal from arterial blood and gastric acid and HCO3− production, venous drops significantly below in gastric circulation (Eichenholz et al., 1967, McQuarrie et al., 1967) and establishes an anomalous Cl−/HCO3− shift similar to that in the pulmonary circulation (Sanders et al., 1973).
Cardiorespiratory and digestive reflexes regulated by cSC neurons are activated concurrently by the same stimuli, most notably, hypercapnic acidosis and orexin. For example, hypercapnic acidosis increases breathing and blood pressure (Forster and Smith, 2010, Guyenet et al., 2010, Nattie and Li, 2010) as well as increases gastric acid secretion (Section 4.4.1), disrupts gastric motility (Section 5.3), and reduces lower esophageal sphincter (LES) tension (LiCalzi et al., 1980). Similarly, orexin stimulates ventilation (Young et al., 2005), gastric acid secretion (Okumura and Takakusaki, 2008, Takahashi et al., 1999) and, conversely, increases gastric motility (Krowicki et al., 2002). Orexin also has been proposed to function in maintaining the ventilatory response to CO2 during wakefulness (Deng et al., 2007, Nakamura et al., 2007, Nattie and Li, 2010). Orexin-containing neurons in the lateral hypothalamus are stimulated during hypercapnic acidosis (Williams et al., 2007) and, recently, the lateral hypothalamus was identified as another site of functional CO2 chemosensitivity (Li et al., in press). Orexinergic afferents project to several CO2-chemosensitive areas downstream, including the cNTS and cDMV (Date et al., 1999, Harrison et al., 1999, Peyron et al., 1998), suggesting that orexin has wide-ranging stimulatory effects on intracranial chemoreceptors during respiratory acidosis.
It has long been recognized that pulmonary diseases causing CO2 retention often occur with diseases of the gastroesophageal system. Is coexistence of CO2 retention and gastric dysfunction related to the fact that chronic respiratory acidosis causes hyper-stimulation of CO2-chemosensitive networks in the cSC that activate vagovagal reflexes leading to excess gastric acid secretion (Section 5.1), abnormally low tension in the LES (Section 5.2.1), and disruption of gastrointestinal motility (Section 5.3)?
Neurons in the cDMV control gastric acid secretion through vagal innervation of gastric neurons that in turn control parietal cell acid output (Travagli et al., 2006). Dean and Putnam (2010) have postulated that these gastroesophageal reflexes are controlled by CO2/H+-chemosensitive neurons located in the cNTS and cDMV, which is one of the several sites of CO2 chemoreception in the brain stem.1 Their hypothesis states that during respiratory acidosis the cSC senses its own local CO2/H+ status and integrates this information with chemo-afferent inputs from all other sites of intracranial chemoreception in the CNS as well as peripheral CO2 chemoreception (Fig. 1). In response, at least two efferent outputs are co-activated for CO2 removal under control of the cSC (Dean and Putnam, 2010). (1) Systemic hypercapnic acidosis increases and perfusion for the removal of CO2 from pulmonary blood so it can be eliminated from the lungs during expiration. This is the classical reflex by which pH balance is restored in response to respiratory acidosis (Section 1). The cSC is thought to contribute a portion of this drive to breathe in conjunction with the output of chemosensitive neurons in other areas through various reciprocal intrabulbar connections and bulbospinal efferent connections with spinal nuclei controlling respiratory rhythmogenesis, pattern formation, and cardiovascular output. Direct connections from the cNTS to the retrotrapezoid nucleus (RTN) and caudal ventrolateral medulla are believed to be particularly important in the formation of the cardiopulmonary efferent signals (Dean and Putnam, 2010). The cSC is unique, however, among the other sites of intracranial chemosensitivity in that it is only one to receive direct peripheral chemoreceptor input, which is then relayed via the cNTS to other sites of CO2 chemosensitivity such as the RTN (Dean and Putnam, 2010).
(2) The above hypothesis also predicts that a gastroesophageal reflex is activated concurrently with the cardiopulmonary reflex (Dean and Putnam, 2010). It begins with a CO2-activated increase in GMBF and increased CO2 removal from gastric arterialized blood for use in the production of gastric acid and HCO3− by parietal cells of the gastric epithelium. CO2 is regenerated in the stomach lumen from the reaction between gastric H+ and HCO3− and vented out of the stomach through increased (Section 4). It is these CO2-activated gastroesophageal reflexes whereby the cSC further distinguishes itself again from all other sites of intracranial CO2 chemosensitivity: the cNTS and cDMV, through reciprocal local circuit interactions and vagovagal connections, exert primary control over the various gastroesophageal targets that control this supplemental non-alveolar form of CO2 elimination (Fig. 1). None of the other sites of central chemosensitivity, including the RTN, which has been proposed by some to be the primary site for CO2 chemoreception (Guyenet et al., 2008b, Guyenet et al., 2009), are known to make direct synaptic connections with the digestive system.
Thus, the traditional view that central CO2 chemosensitivity and pH regulation during respiratory acidosis is a function of the cardiopulmonary systems alone is expanded here to include coordinated control of cardiopulmonary and cardio-gastroesophagopharyngeal systems operating in parallel as follows: CO2 gas exchange occurs simultaneously across both the alveolar and gastric epithelia; CO2 accumulates in the alveoli and gastric lumen; gas mixture containing a high level of CO2 is propelled out of the alveoli and gastric lumen, driven along pressure gradients created concurrently by the coordinated contractions of respiratory muscles and esophagopharyngeal muscles, through parallel running tracheal and esophageal vents that merge together in the oropharyngeal cavity. This revised view of central chemosensitivity and acute pH regulation by CO2 elimination provides answers in part to two frequently asked questions in the field of central CO2 chemoreception (Nattie and Li, 2009, Nattie and Li, 2010); that is, why do we need chemoreceptors at so many sites in the brain?; and do all chemoreceptors serve the same purpose?
According to the foregoing scenario, it can be postulated that chemoreceptors are at different sites because central chemosensitivity and pH regulation require multiple organ systems; specifically, the cardiopulmonary systems (Forster and Smith, 2010, Guyenet et al., 2010), gastroesophagopharyngeal systems (Section 4.7), the gastrointestinal system (Section 6), and the renal system (Schwartz et al., 1965). In this scenario, effecting pH regulation would require a chemosensitive network that is capable of controlling, integrating and coordinating multiple organ systems and their respective vascular supplies. Added to this fundamental level of complexity is the emerging realization that the CO2 chemoreceptor network is a dynamic neural network that is affected by arousal state (Dean and Nattie, 2010, Nattie and Li, 2001, Nattie and Li, 2002, Nattie and Li, 2010), neuropeptides that control gastrointestinal functions (Section 1.1.4), chronic hypoxia (Nichols et al., 2009b), chronic hypercapnia (Schaefer, 1979, Schaefer et al., 1963, Sherman et al., 1980), acute hyperoxia (Matott et al., 2010, Mulkey et al., 2003, Pilla et al., 2011), and other sources of redox and nitrosative stresses (Dean, 2010, Mulkey et al., 2004). Given this level of complexity and neural plasticity, it is not surprising, therefore, that central CO2 chemosensitivity and pH regulation would require a distributed network of chemosensors, local circuits, and parallel efferent outputs. This new idea, however, does not resolve the ongoing debate of whether there is a hierarchy of central chemoreceptors that controls overall pH balance (Guyenet, 2008, Guyenet et al., 2005, Guyenet et al., 2008a, Guyenet et al., 2008b, Nattie and Li, 2009, Nattie and Li, 2010, Richerson, 2005). Regardless, the theory of gastric CO2 ventilation explains in part why there may be so many sites of CO2 chemosensitivity and provides evidence that not all chemosensitive areas necessarily serve the same aspects of pH regulation. Relative to the cSC, as presented in Fig. 1, the cNTS is postulated by Dean and Putnam to serve as an important “chemoreceptor hub” for neural integration of all chemo-afferent information (central chemoreception and peripheral chemoreception) with gastroesophagopharyngeal afferent information for directing coordinated efferent control of cardiopulmonary reflexes (in part) and gastroesophagopharyngeal reflexes, via the cDMV and other brain stem nuclei, that together eliminate CO2 during respiratory acidosis (Dean and Putnam, 2010).
Section snippets
Gastric CO2 production and ventilation at rest and after eating
CO2 diffuses from the gastric blood into the epithelium and is used by parietal cells for the production of HCO3− and H+, which are transported along with Cl− into the stomach lumen (Sections 4.1 Step 1—gastric gas exchange during respiratory acidosis: GMBF increases and CO, 4.2 Step 2—intracellular conversion of CO, 4.4 Step 4—transport of intracellular H). Exposure to the low pH environment of the gastric lumen causes HCO3− to react with H+ and regenerate CO2 and water (Section 4.6). One
Cardiopulmonary and gastroesophageal interactions: fish, turtles, and alligators
The notion that the digestive tract interacts with the lungs as a supplemental source of CO2 exchange is not that unusual if one considers the comparative physiology of animals whose pulmonary system and digestive system interact to achieve a significant level of intermittent gas exchange. Air-breathing fish (Lungfish) use the stomach and part of the small intestine as an accessory breathing organ during short land migrations, effectively maintaining gas exchange (Amin-Naves et al., 2007,
Seven steps of gastric CO2 ventilation and its regulation by the cSC
The theory of gastric ventilation for supplemental CO2 elimination during respiratory acidosis has seven main events (Fig. 2A): (1) gastric gas exchange whereby CO2 diffuses from gastric arterialized blood across the basolateral membrane into the gastric epithelium. As in the lung, CO2 off-loading in the stomach is facilitated by increased GMBF; (2) intracellular conversion of CO2 into carbonic acid followed by its dissociation into H+ and HCO3−; (3) transport of intracellular HCO3− across the
Peptic ulcers
Respiratory acidosis (Koo et al., 1989) and metabolic acidosis (Bushell and O’Brien, 1982) induce evidence of gastric ulceration after only 2–3 h, which raises the following question: does chronic systemic acidosis coexist with peptic ulcer disease? The answer is unequivocally “yes”. The vast majority of clinical research supports the conclusion that increased gastric acid secretion often occurs during chronic respiratory acidosis caused by hypoventilation disorders (Fedorova et al., 2003,
Net acid excretion via the gastrointestinal system
An additional mechanism for the removal of acid equivalents that will be mentioned briefly for the sake of completeness and because of the possible involvement of the cSC is net acid excretion (NAE) via the gastrointestinal system. NAE is determined by the (i) intrinsic buffering power of chyme/digesta (Bumm et al., 1987, van Herwaarden et al., 1999); (ii) the relative amount of HCO3− added to digesta fluids and solids in the duodenum by the pancreas and liver (Kaunitz and Akiba, 2006b); and
Implications and future studies
The celebrated physiologist, Walter B. Cannon, stated the following observation in his centenary review (Cannon, 1933) of William Beaumont's pioneering studies of gastric acid and digestion (Myer, 1939, Beaumont, 1833, Mumey, 1933, Widder, 2006).8
Acknowledgements
Thank you to my colleague, Dr. Rick Rogers, who asked me the key question many years ago that eventually lead to this new theory; that is, does the cSC regulate gastric acid secretion during systemic acidosis for purposes of whole body pH regulation? I must also acknowledge my other colleagues, including Drs. Donald Bolser, Michael Curley, Dominic D’Agostino, Paul Davenport, Edward Flynn, Bert Forster, Lynn Hartzler, Bruce Lindsey, Capt. John Murray (U.S.N.), Teresa Pitts, and Robert Putnam who
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