Effects of Systemic Hypercapnia and Orexin on Gastric Motility and Respiration in Rats

Abstract

The theory of pneumogastric ventilation predicts that systemic hypercapnia causes a primary pulmonary hypercapnic ventilatory response (HCVR) that is supplemented by a secondary gastric ventilatory response that work together to remove excess CO2 from the body. Gastric ventilation consumes arterialized CO2 during increased production and secretion of gastric acid. In the stomach lumen, CO2 is reconstituted and “ventilated” out through the esophagus, mixed in the oropharynx with pulmonary gas and “exhaled”. Activation of gastric ventilation occurs during CO2 retention in a hypercapnic environment or with alveolar hypoventilation such as COPD. Both pulmonary and gastric ventilatory responses are integrated and coordinated at the level of the caudal solitary complex (cSC), mediated in large part by the vagus nerve (Dean, 2011, Resp Physiol Neurobiol 175(2): 189–209). Central chemoreceptors in the cSC or stimulated by both CO2/H+ and orexin. Likewise, CO2/H+ and orexin stimulate pulmonary ventilation and gastric acid secretion. In fact, hypercapnia causes an increase in production of orexin, which helps maintain the HCVR during wakefulness (Nattie et al, 2010, J Appl Physiol 89: 153–162). Consistent with the theory of pneumogastric ventilation, we found that hypercapnia causes an acute decrease in gastric pH. We do not know, however, how hypercapnia affects gastric motility. Accordingly, we implanted male Sprague‐Dawley rats with the DSI 4‐ET Telemetry unit to measure ECG, respiratory rate via diaphragmatic EMG (dEMG), and gastric EMG (gEMG) to measure gastric motility. Following recovery from surgery, we then subjected them to step‐wise increases in ambient CO2 (30 min/step) starting with air, 5% CO2 in air, 10% CO2 in air, and recovery in air. We also tested the effects of orexin on gastric motility during normocapnia using a lateral tail vein IV injection of orexin‐A. Histamine was used as a positive control for gastric motility. Our findings show that in air, gEMG activity occurs roughly every 15 seconds with bursts lasting 3–4 seconds. Graded hypercapnia caused a graded decrease in the amplitude of periodic gEMG bursts (5% CO2) that stopped completely in 10% CO2. Recovery in air rapidly returns gEMG activity to normal. As expected, dEMG increased with increasing CO2. Similarly, orexin‐A causes an immediate decrease in gEMG activity. We postulate that CO2 activates cSC neurons causing vagally‐mediated relaxation of gastric smooth muscle and increase in gastric acid production to ventilate gastric CO2 during systemic hypercapnia.Support or Funding InformationONR N000141310405 & N000141612537