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Integration of Central and Peripheral Respiratory Chemoreflexes

Richard J.A. Wilson, Luc J. Teppema

10.1002/cphy.c140040

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Published online: March 2016

Full Article on Wiley Online Library



ABSTRACT

A debate has raged since the discovery of central and peripheral respiratory chemoreceptors as to whether the reflexes they mediate combine in an additive (i.e., no interaction), hypoadditive or hyperadditive manner. Here we critically review pertinent literature related to O2 and CO2 sensing from the perspective of system integration and summarize many of the studies on which these seemingly opposing views are based. Despite the intensity and quality of this debate, we have yet to reach consensus, either within or between species. In reviewing this literature, we are struck by the merits of the approaches and preparations that have been brought to bear on this question. This suggests that either the nature of combination is not important to system responses, contrary to what has long been supposed, or that the nature of the combination is more malleable than previously assumed, changing depending on physiological state and/or respiratory requirement. © 2016 American Physiological Society. Compr Physiol 6:1005‐1041, 2016.

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Figure 1. Figure 1. Types of chemoreceptor integration. Integration of chemoreflexes has long been a source of controversy and has yet to be resolved. Three forms of integration are traditionally considered: additive (no interaction; (A)); hypoadditive (B); and hyperadditive (C). Recently, a hybrid system has been proposed in which the type of interaction depends critically on physiological state (D). Blue and Red bars representing one chemoreflex with the other inactive, and vice versa; green bars represent concurrent activation of both chemoreflexes. In upper panels, size of bars shows response of a ventilatory parameter (e.g., V T, frequency of V E). In lower panels, ventilatory activity is plotted versus variable activation of one chemoreflex with the other at two fixed levels of activation (high green, low blue).
Figure 2. Figure 2. Recent preparations used to tease apart the nature of central and peripheral chemoreflex interaction. (A) Dog donor‐perfused, bilateral carotid sinus preparation; both carotid bodies intact and perfused independently of systemic circulation. Donor dog breathed hypoxic mixtures; the recipient received hypercapnic mixtures (from Adams et al. 1978). (B) Extracorporeal‐perfused carotid body in conscious dogs; one carotid body resected, CBX, the other carotid bodies perfused independently of systemic circulation (from Blain et al. 2010). (C) Decerebrate rat, dual perfused preparation; both carotid bodies intact and perfused independently of brainstem with artificial saline (from Day and Wilson, 2005).
Figure 3. Figure 3. Data from conscious dogs with an extracorporeal perfused carotid body suggesting hyperadditive inter‐action in v e between central and peripheral chemoreflexes. Each graph shows data from a different conscious dog with one carotid body extracorporeally perfused and the other denervated. Systemic (inspired) CO2 was varied against three different backgrounds of carotid body stimulation: normoxic‐normocapnia (filled squares), hyperoxic‐hypocapnia (“inhibited”; open squares), and hypoxic‐normocapnia blood (“stimulated”; shaded triangles). Note how the lines splay apart, indicative of a hyperadditive interaction. From Blain et al. 2010.
Figure 4. Figure 4. Additive interactions in one respiratory variable requires hypoadditivity in another. Primary respiratory variables are plotted against variable activation of one chemoreflex with the other at two fixed levels of activation (high green, low blue). In (A), addition (no interaction) between chemoreflexes in V T and frequency results in a hyperadditive interaction in V E. In (B), a hypoadditive interaction in either freq or V T (shown) results in a hypoadditive interaction in V E, or stated in another way, an additive interaction in V E necessitates a hypoadditive interaction in either freq or V T (64,200). Adapted from (206).
Figure 5. Figure 5. Order of stimuli has no effect on nature of interaction in dog extracorporeal‐perfused carotid body preparation. Ventilatory response to carotid body stimulation and systemic CO2 challenges in an extracorporeally perfused carotid body preparation. Animals were anesthetized with pentobarbital. Top panels, tidal volume (V T); bottom panels, frequency (f). Left panels show response to changes in inspired PO2 against a background in which the carotid body was perfused with normoxia or constantly stimulated with hypoxic‐hypercapnia. Right panels show the reverse order; carotid bodies either normoxic or stimulated against a constant background of different inspired PCO2. Regardless of the order in which brainstem and carotid bodies where stimulated, the magnitude of responses were the same. Data from this preparation supports a hypoadditive interaction. From Adams and Severns, 1982.
Figure 6. Figure 6. Data from dual perfused in situ rat preparation suggesting a hypoadditive interaction in v e between central and peripheral chemoreflexes. The dual perfused preparation allows the carotid bodies and brainstem to be perfused independently with defined medium. In this preparation, there are no descending inputs to the brainstem; vagotomy removes possible influences of lung stretch, irritant and neuroepithelial body activation; and hormonal or sympathetic influences on the carotid body are eliminated. The brainstem was held constant at one of three levels of PCO2 (25, 35, and 50 Torr; circles, triangle, and square symbols, respectively) while the response of the preparation to changes in PO2 at the carotid body was changed. Phrenic activity was used as a surrogate measure of ventilation; phrenic burst amplitude, nVT, was assumed to be proportional to tidal volume and multiplied by burst frequency to yield neural minute ventilation, nV E). Note how the lines converge indicative of a hypoadditive interaction. From Day and Wilson, 2009.
Figure 7. Figure 7. Data from humans suggesting a hyperadditive interaction between central and peripheral chemoreflexes. Effect of bicarbonate infusion (open symbols) on the ventilatory O2 ‐[H+] response relationship. A bicarbonate infusion reduces arterial [H+] and shifts the ventilatory O2 ‐[H+] response relationship to the left, whether pre‐treated with placebo or acetazolamide. Defining hypoxic sensitivity as the ratio of delta ventilation over delta log PaO2, for placebo the hypoxic sensitivity = 8.73 × [H+] − 304 and 9.06 × [H+] − 316 before and after bicarbonate, respectively. For acetazolamide, hypoxic sensitivity = 9.05 × [H+] − 432 and 6.07 × [H+] − 235 before and after bicarbonate, respectively. Numbers added to data points are mean arterial PCO2 values in Torr. At points d' and f, arterial [H +] is about equal, but at d' with a PaCO2. 7.1 Torr higher than at D, hypoxic sensitivity is doubled. Data are means ± SE from eight subjects. From: Teppema et al. 2010.
Figure 8. Figure 8. The hybrid model. Day and Wilson propose a hybrid model to reconcile their observation of a strong hypoadditive interaction in rats with observations of a hyperadditive interaction in the Smith‐Dempsey dog model (329). Carotid body activation can maintain breathing when the brainstem is extremely hypocapnic as shown in cats and rats (9,100) suggesting ventilatory responses to increasing chemoreceptor activity converge below eupnea (red dotted lines), indicative of a hypoadditive interaction. Above eupnea in wake dogs, ventilatory response slopes diverge (blue dashed line) indicative of a hyperadditive interaction. Transition between hypoadditive and hyperadditive interaction (i.e., the hybrid transition point; yellow star) may occur at a single point of convergence (right panel) or multiple points (left panel), and depend on metabolism and/or other factors determining physiological state. Left panel adapted from Wilson and Day, 2013.


Figure 1. Types of chemoreceptor integration. Integration of chemoreflexes has long been a source of controversy and has yet to be resolved. Three forms of integration are traditionally considered: additive (no interaction; (A)); hypoadditive (B); and hyperadditive (C). Recently, a hybrid system has been proposed in which the type of interaction depends critically on physiological state (D). Blue and Red bars representing one chemoreflex with the other inactive, and vice versa; green bars represent concurrent activation of both chemoreflexes. In upper panels, size of bars shows response of a ventilatory parameter (e.g., V T, frequency of V E). In lower panels, ventilatory activity is plotted versus variable activation of one chemoreflex with the other at two fixed levels of activation (high green, low blue).


Figure 2. Recent preparations used to tease apart the nature of central and peripheral chemoreflex interaction. (A) Dog donor‐perfused, bilateral carotid sinus preparation; both carotid bodies intact and perfused independently of systemic circulation. Donor dog breathed hypoxic mixtures; the recipient received hypercapnic mixtures (from Adams et al. 1978). (B) Extracorporeal‐perfused carotid body in conscious dogs; one carotid body resected, CBX, the other carotid bodies perfused independently of systemic circulation (from Blain et al. 2010). (C) Decerebrate rat, dual perfused preparation; both carotid bodies intact and perfused independently of brainstem with artificial saline (from Day and Wilson, 2005).


Figure 3. Data from conscious dogs with an extracorporeal perfused carotid body suggesting hyperadditive inter‐action in v e between central and peripheral chemoreflexes. Each graph shows data from a different conscious dog with one carotid body extracorporeally perfused and the other denervated. Systemic (inspired) CO2 was varied against three different backgrounds of carotid body stimulation: normoxic‐normocapnia (filled squares), hyperoxic‐hypocapnia (“inhibited”; open squares), and hypoxic‐normocapnia blood (“stimulated”; shaded triangles). Note how the lines splay apart, indicative of a hyperadditive interaction. From Blain et al. 2010.


Figure 4. Additive interactions in one respiratory variable requires hypoadditivity in another. Primary respiratory variables are plotted against variable activation of one chemoreflex with the other at two fixed levels of activation (high green, low blue). In (A), addition (no interaction) between chemoreflexes in V T and frequency results in a hyperadditive interaction in V E. In (B), a hypoadditive interaction in either freq or V T (shown) results in a hypoadditive interaction in V E, or stated in another way, an additive interaction in V E necessitates a hypoadditive interaction in either freq or V T (64,200). Adapted from (206).


Figure 5. Order of stimuli has no effect on nature of interaction in dog extracorporeal‐perfused carotid body preparation. Ventilatory response to carotid body stimulation and systemic CO2 challenges in an extracorporeally perfused carotid body preparation. Animals were anesthetized with pentobarbital. Top panels, tidal volume (V T); bottom panels, frequency (f). Left panels show response to changes in inspired PO2 against a background in which the carotid body was perfused with normoxia or constantly stimulated with hypoxic‐hypercapnia. Right panels show the reverse order; carotid bodies either normoxic or stimulated against a constant background of different inspired PCO2. Regardless of the order in which brainstem and carotid bodies where stimulated, the magnitude of responses were the same. Data from this preparation supports a hypoadditive interaction. From Adams and Severns, 1982.


Figure 6. Data from dual perfused in situ rat preparation suggesting a hypoadditive interaction in v e between central and peripheral chemoreflexes. The dual perfused preparation allows the carotid bodies and brainstem to be perfused independently with defined medium. In this preparation, there are no descending inputs to the brainstem; vagotomy removes possible influences of lung stretch, irritant and neuroepithelial body activation; and hormonal or sympathetic influences on the carotid body are eliminated. The brainstem was held constant at one of three levels of PCO2 (25, 35, and 50 Torr; circles, triangle, and square symbols, respectively) while the response of the preparation to changes in PO2 at the carotid body was changed. Phrenic activity was used as a surrogate measure of ventilation; phrenic burst amplitude, nVT, was assumed to be proportional to tidal volume and multiplied by burst frequency to yield neural minute ventilation, nV E). Note how the lines converge indicative of a hypoadditive interaction. From Day and Wilson, 2009.


Figure 7. Data from humans suggesting a hyperadditive interaction between central and peripheral chemoreflexes. Effect of bicarbonate infusion (open symbols) on the ventilatory O2 ‐[H+] response relationship. A bicarbonate infusion reduces arterial [H+] and shifts the ventilatory O2 ‐[H+] response relationship to the left, whether pre‐treated with placebo or acetazolamide. Defining hypoxic sensitivity as the ratio of delta ventilation over delta log PaO2, for placebo the hypoxic sensitivity = 8.73 × [H+] − 304 and 9.06 × [H+] − 316 before and after bicarbonate, respectively. For acetazolamide, hypoxic sensitivity = 9.05 × [H+] − 432 and 6.07 × [H+] − 235 before and after bicarbonate, respectively. Numbers added to data points are mean arterial PCO2 values in Torr. At points d' and f, arterial [H +] is about equal, but at d' with a PaCO2. 7.1 Torr higher than at D, hypoxic sensitivity is doubled. Data are means ± SE from eight subjects. From: Teppema et al. 2010.


Figure 8. The hybrid model. Day and Wilson propose a hybrid model to reconcile their observation of a strong hypoadditive interaction in rats with observations of a hyperadditive interaction in the Smith‐Dempsey dog model (329). Carotid body activation can maintain breathing when the brainstem is extremely hypocapnic as shown in cats and rats (9,100) suggesting ventilatory responses to increasing chemoreceptor activity converge below eupnea (red dotted lines), indicative of a hypoadditive interaction. Above eupnea in wake dogs, ventilatory response slopes diverge (blue dashed line) indicative of a hyperadditive interaction. Transition between hypoadditive and hyperadditive interaction (i.e., the hybrid transition point; yellow star) may occur at a single point of convergence (right panel) or multiple points (left panel), and depend on metabolism and/or other factors determining physiological state. Left panel adapted from Wilson and Day, 2013.
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Article Title: Integration of Central and Peripheral Respiratory Chemoreflexes
 

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Richard J.A. Wilson, Luc J. Teppema. Integration of Central and Peripheral Respiratory Chemoreflexes. Compr Physiol 2016, null: 1005-1041. doi: 10.1002/cphy.c140040