Brazilian Journal of Medical and Biological Research (1998) 31: 863-888 Chemoreceptors and systemic hypoxia 863 ISSN 0100-879X Chemoreceptors and cardiovascular control in acute and chronic systemic hypoxia J.M. Marshall Department of Physiology, The Medical School, Birmingham, UK Abstract Correspondence This review describes the ways in which the primary bradycardia and Key words J.M. Marshall peripheral vasoconstriction evoked by selective stimulation of periph- • Hypoxia Department of Physiology eral chemoreceptors can be modified by the secondary effects of a • Adenosine The Medical School chemoreceptor-induced increase in ventilation. The evidence that • Chemoreceptors Birmingham B15 2TT strong stimulation of peripheral chemoreceptors can evoke the behav- • Vasodilatation UK • Noradrenaline E-mail: [email protected] ioural and cardiovascular components of the alerting or defence response which is characteristically evoked by novel or noxious Presented at the XII Annual Meeting stimuli is considered. The functional significance of all these influ- of the Federação de Sociedades de ences in systemic hypoxia is then discussed with emphasis on the fact Biologia Experimental, Caxambu, that these reflex changes can be overcome by the local effects of MG, Brasil, August 27-30, 1997. hypoxia: central neural hypoxia depresses ventilation, hypoxia acting on the heart causes bradycardia and local hypoxia of skeletal muscle and brain induces vasodilatation. Further, it is proposed that these Received January 20, 1998 local influences can become interdependent, so generating a positive Accepted March 17, 1998 feedback loop that may explain sudden infant death syndrome (SIDS). It is also argued that a major contributor to these local influences is adenosine. The role of adenosine in determining the distribution of O2 in skeletal muscle microcirculation in hypoxia is discussed, together with its possible cellular mechanisms of action. Finally, evidence is presented that in chronic systemic hypoxia, the reflex vasoconstrictor influences of the sympathetic nervous system are reduced and/or the local dilator influences of hypoxia are enhanced. In vitro and in vivo findings suggest this is partly explained by upregulation of nitric oxide (NO) synthesis by the vascular endothelium which facilitates vasodi- latation induced by adenosine and other NO-dependent dilators and attenuates noradrenaline-evoked vasoconstriction. Introduction cardiovascular system. Since then, a great deal has been discovered about the respira- The peripheral chemoreceptors have been tory, cardiac and vascular responses evoked known about at least since the beginning of when the chemoreceptors are selectively this century. In the 1920’s and 1930’s it was stimulated and about the ways in which the recognised that stimulation of the carotid responses interact with one another. How- and aortic chemoreceptors could produce ever, still relatively little is known about the reflex effects both on the respiratory and functional importance of peripheral chemore- Braz J Med Biol Res 31(7) 1998 864 J.M. Marshall ceptors in cardiovascular control under natu- of chemoreceptor stimulation could have a ral, physiological conditions, or in patho- large impact on the magnitude and direction logical situations. Over the last 10-15 years of the cardiovascular changes (3). The na- we have been investigating their role in regu- ture of these respiratory and cardiovascular lating the cardiovascular system in acute and interactions was largely established by the chronic systemic hypoxia and in particular, carefully controlled work of M. de Burgh we have been trying to establish how the Daly and colleagues (see Figure 1). reflex responses interact with the local influ- ences of hypoxia. This is the major subject Vascular responses matter of this review. However, in order to put this work into context, it is first neces- In a series of studies on dogs anaesthe- sary to briefly review what is known of the tised with chloralose or barbiturates, Daly effects of selective stimulation of the periph- and co-workers perfused the vascularly iso- eral chemoreceptors. lated carotid regions with blood from a donor dog in such a manner that the perfusion pres- Primary and secondary responses sure and therefore the stimulus to the carotid baroreceptors was maintained constant, Between the 1930’s and 1950’s, several whilst the carotid bodies were exposed either studies were published on the cardiovascu- to normoxic, normocapnic blood or to hy- lar changes that could be evoked by selective poxic, hypercapnic blood. In early studies, stimulation of the carotid bodies, either by the systemic circulation was performed by a local injection of substances such as sodium pump at a constant volume per minute so that cyanide or saline equilibrated with CO2, or any change in perfusion pressure reflected by perfusion with hypoxia and hypercapnic changes in systemic vascular resistance. In blood. The results obtained were somewhat this way they were able to show that when confusing, some studies showing a rise in ventilation was spontaneous, selective stimu- arterial pressure, others a fall, some showing lation of the carotid chemoreceptors induced bradycardia, and others tachycardia (e.g. 1,2). a fall in systemic vascular resistance indicat- However, already it was beginning to be ing peripheral vasodilatation. However, when recognised that the respiratory consequences ventilation was maintained constant during Figure 1 - Schematic diagram showing the primary and sec- PaCO HR + vasodilatation ondary effects of selective stim- 2 ulation of peripheral chemore- ceptors. + indicates an excita- Lung stretch tory effect. Broken arrow indi- + HR + vasodilata- Respiration receptors cates direct or local rather than tion reflex effects. Open arrow to especially in defence areas indicates a higher skeletal muscle Inspiratory threshold effect. For further de- HR + vasoconstriction drive tails see text. HR, Heart rate. + Peripheral + chemoreceptor Defence HR + vasoconstriction + vasodilatation stimulation areas in splanchnic in skeletal and renal muscle HR + vasoconstriction in skeletal muscle, splanchnic and renal Braz J Med Biol Res 31(7) 1998 Chemoreceptors and systemic hypoxia 865 artificial ventilation, the same stimulus tion of aortic chemoreceptors evoked only a evoked an increase in systemic vascular re- small ventilatory response. sistance reflecting peripheral vasoconstric- tion (4,5). This suggested that the primary Cardiac responses reflex response to carotid chemoreceptor stimulation was vasoconstriction and that the The heart rate response was also investi- vasodilatation was secondary to the chemore- gated in other early experiments on the dog. ceptor-induced hyperventilation. Other ex- Selective stimulation of the carotid chemore- periments showed that the peripheral vasodi- ceptors was shown to be more likely to evoke latation induced by chemoreceptor stimula- tachycardia when the ventilatory response tion was also greatly reduced or reversed to was large (~200% higher compared to con- vasoconstriction if the dog was allowed to trol); when the ventilatory response was hyperventilate, but with the vagus nerves cut, small, a bradycardia was often seen (6). Care- or if the partial pressure of CO2 in the arterial ful examination of these responses revealed blood (PaCO2) was maintained constant (4,6). that just as with the vascular responses, two Thus, it was concluded that the two major aspects of the hyperventilatory response to factors that contributed to the secondary va- chemoreceptor stimulation affected the car- sodilatation were a reflex triggered by vagal diac response: both pulmonary stretch re- afferent fibres and the hypocapnia that arose ceptor stimulation and hypocapnia contrib- from hyperventilation. Further experiments uted to the tachycardia, while the underlying demonstrated that vasodilatation secondary primary response was apparently bradycar- to hyperventilation occurred in skeletal dia (6-8). However, even when ventilation muscle and skin of the limbs, and in renal and was maintained constant, carotid chemore- splanchnic vasculature, the response being ceptor stimulation still sometimes evoked most pronounced in muscle (7,8). As far as tachycardia in a way that seemed related to the vagal afferents were concerned, the im- the stimulatory drive to ventilation and which portant receptors turned out to be the slowly was most evident when the cardiac vagal adapting pulmonary stretch receptors (6,9), fibres were intact (6,8). This effect was remi- while the efferent arm of the reflex was shown niscent of the sinus arrhythmia that persists to be an inhibition of sympathetic noradre- after lung denervation and which was at first nergic tone (7). The mechanisms underlying ascribed to “irradiation” of the cardiac vagus the vasodilator effects of hypocapnia have with impulses from the respiratory centre received far less attention: they seem to be (13). More recently, it has become clear that mediated mainly by the unloading of the collaterals of central inspiratory neurones central chemoreceptors for CO2 and the re- exert an inhibitory effect on cardiac vagal sulting fall in sympathetic noradrenergic ac- neurones (14,15). This helps to explain the tivity (see 10-12). increase in heart rate that normally occurs It is worth noting that in the early studies with every inspiration (sinus arrhythmia) and of Daly and Ungar (5), selective stimulation reflects a central neural mechanism by which of