Central and peripheral mechanisms underlying gastric distention inhibitory reflex responses in hypercapnic-acidotic rats

Abstract

We have observed that in chloralose-anesthetized animals, gastric distension (GD) typically increases blood pressure (BP) under normoxic normocapnic conditions. However, we recently noted repeatable decreases in BP and heart rate (HR) in hypercapnic-acidotic rats in response to GD. The neural pathways, central processing, and autonomic effector mechanisms involved in this cardiovascular reflex response are unknown. We hypothesized that GD-induced decrease in BP and HR reflex responses are mediated during both withdrawal of sympathetic tone and increased parasympathetic activity, involving the rostral (rVLM) and caudal ventrolateral medulla (cVLM) and the nucleus ambiguus (NA). Rats anesthetized with ketamine and xylazine or α-chloralose were ventilated and monitored for HR and BP changes. The extent of cardiovascular inhibition was related to the extent of hypercapnia and acidosis. Repeated GD with both anesthetics induced consistent falls in BP and HR. The hemodynamic inhibitory response was reduced after blockade of the celiac ganglia or the intraabdominal vagal nerves with lidocaine, suggesting that the decreased BP and HR responses were mediated by both sympathetic and parasympathetic afferents. Blockade of the NA decreased the bradycardia response. Microinjection of kainic acid into the cVLM reduced the inhibitory BP response, whereas depolarization blockade of the rVLM decreased both BP and HR inhibitory responses. Blockade of GABA(A) receptors in the rVLM also reduced the BP and HR reflex responses. Atropine methyl bromide completely blocked the reflex bradycardia, and atenolol blocked the negative chronotropic response. Finally, α(1)-adrenergic blockade with prazosin reversed the depressor. Thus, in the setting of hypercapnic-acidosis, a sympathoinhibitory cardiovascular response is mediated, in part, by splanchnic nerves and is processed through the rVLM and cVLM. Additionally, a vagal excitatory reflex, which involves the NA, facilitates the GD-induced decreases in BP and HR responses. Efferent chronotropic responses involve both increased parasympathetic and reduced sympathetic activity, whereas the decrease in BP is mediated by reduced α-adrenergic tone.

Fig. 1.

Relationships among Pco₂, pH, mean arterial blood pressure (BP) changes (ΔMAP), or heart rate [HR; in beats/min (bpm)]. A: inverse relationship between Pco₂ and ΔMAP and HR in response to gastric distention. B: significant direct relationship between pH, BP, and HR. C: increase in baseline BP with increased CO₂. Pa_CO2, arterial Pco₂.

Fig. 2.

Relationships between Pco₂ and ΔMAP or HR in a single group of animals anesthetized with α-chloralose. Similar to xylazine-anesthethized animals, changes in BP and HR were inversely related to increases in Pco₂ during gastric distention.

Fig. 3.

Hypercapnic rats subjected to repeated gastric distention every 10 min. The stimulation of mechanosensitive receptors on the wall of the stomach resulted in consistent decreases in both BP (A) and HR (B) responses. Values above each bar indicate baseline MAP and HR (means ± SE) before gastric distention. Bars represent depressor and bradycardia reflex responses after distention of the stomach every 10–15 min.

Fig. 4.

MAP responses to gastric distension before and after chemical denervation of intra-abdominal celiac ganglion/sympathetic afferents (I) or vagal afferents (II) with 1% lidocaine. Lidocaine denervation transiently attenuated the cardiovascular depressor reflexes. Original data before (a and d), immediately after (b and e), and 30 min after (c and f) chemical denervation of the celiac ganglion (I) and abdominal vagus (II) of the inhibitory BP and HR responses are shown above the histograms. Values above each bar indicate baseline MAP and HR (means ± SE) before gastric distention. Bars represent depressor and bradycardia reflex responses after distention of the stomach every 10–15 min.*P < 0.05.

Fig. 5.

Cardiovascular responses of gastric distention after unilateral blockade of the rostral ventrolateral medulla (rVLM), caudal ventrolateral medulla (cVLM), and nucleus ambiguus (Nuc Amb). Blockade of the rVLM with either kainic acid (KA) or gabazine reduced both the inhibitory BP and HR responses (I and IV). Microinjection of KA into the cVLM attenuated the hypotensive response (II, A), whereas the bradycardia was unaffected (II, B). On the other hand, blockade of the nucleus ambiguus did not attenuate the hypotensive response (III, A) but did attenuate the chronotropic response (III, B). Values above each bar indicate baseline MAP and HR (means ± SE) before gastric distention. Bars represent depressor and bradycardia reflex responses after distention of the stomach every 10–15 min. *P < 0.05.

Fig. 6.

Role of the sympathetic adrenergic and parasympathetic cholinergic systems in gastric distention-induced reflex responses in hypercapnic rats. Cholinergic blockade with atropine methyl bromide attenuated the HR but not the BP reflex changes (I). β-Adrenergic blockade with atenolol also reduce the negative chronotropic response, whereas the depressor response was unaffected (II). Prazosin, an α-adrenergic antagonist, reduced the depressor but not HR responses (III). Original data are shown above the histograms and correspond to a–f in I–III. Values above each bar indicate baseline MAP and HR (means ± SE) before gastric distention. Bars represent depressor and bradycardia reflex responses after distention of the stomach every 10–15 min.*P < 0.05.

Fig. 7.

Composite map showing microinjection sites in the nucleus ambiguus (N. Amb), cVLM, and rVLM. O, outside the nucleus ambiguus; NTS, nucleus tractus solitarii; py, pyramidal tract; AP, area postrema; ●, KA microinjection site; *gabazine microinjection site.