Stimulation Of Arterial Chemoreceptors Research Articles

Neural reflex regulation of systemic inflammation: potential new targets for sepsis therapy.

Sepsis progresses to multiple organ dysfunction due to the uncontrolled release of inflammatory mediators, and a growing body of evidence shows that neural signals play a significant role in modulating the immune response. Thus, similar toall other physiological systems, the immune system is both connected to and regulated by the central nervous system. The efferent arc consists of the activation of the hypothalamic–pituitary–adrenal axis, sympathetic activation, the cholinergic anti-inflammatory reflex, and the local release of physiological neuromodulators. Immunosensory activity is centered on the production of pro-inflammatory cytokines, signals that are conveyed to the brain through different pathways. The activation of peripheral sensory nerves, i.e., vagal paraganglia by the vagus nerve, and carotid body (CB) chemoreceptors by the carotid/sinus nerve are broadly discussed here. Despite cytokine receptor expression in vagal afferent fibers, pro-inflammatory cytokines have no significant effect on vagus nerve activity. Thus, the CB may be the source of immunosensory inputs and incoming neural signals and, in fact, sense inflammatory mediators, playing a protective role during sepsis. Considering that CB stimulation increases sympathetic activity and adrenal glucocorticoids release, the electrical stimulation of arterial chemoreceptors may be suitable therapeutic approach for regulating systemic inflammation.

Inhibitory effects of hyperoxia and methemoglobinemia on H2S induced ventilatory stimulation in the rat

The aim of this study was to clarify, using in vitro and in vivo approaches in the rat, the site of mediation of the inhibition of H2S induced arterial chemoreceptor stimulation, by hyperoxia and methemoglobinemia. We first determined the ventilatory dose–response curves during intravenous injections of H2S. A very high dose of NaHS, i.e. 0.4μmol (concentration: 800μM), was needed to stimulate breathing within 1s following i.v. injection. Above this level (and up to 2.4μmol, with a concentration of 4800μM), a dose-dependent effect of H2S injection was observed. NaHS injection into the thoracic aorta produced the same effect, suggesting that within one circulatory time, H2S pulmonary exchange does not dramatically reduce H2S concentrations in the arterial blood. The ventilatory response to H2S was abolished in the presence of MetHb (12.8%) and was significantly depressed in hyperoxia and, surprisingly, in 10% hypoxia. MetHb per se did not affect the ventilatory response to hypoxia or hyperoxia, but dramatically enhanced the oxidation of H2S in vitro, with very fast kinetics. These findings suggest that, the decrease/oxidation of exogenous H2S in the blood is the primary effect of MetHb in vivo. In contrast, the in vitro oxidative properties of blood for H2S were not affected by the level of PaO2 between 23 and >760mmHg. This suggests that the inhibition of the ventilatory response to H2S by hyperoxia during aortic or venous injection originates within the CB and not in the blood. The implications of these results on the role of endogenous H2S in the arterial chemoreflex are discussed.

Hypoxia-induced arterial chemoreceptor stimulation and Hydrogen sulfide: Too much or too little?

This brief review presents and discusses some of the important issues surrounding the theory which asserts that endogenous hydrogen sulfide (H(2)S) is the mediator of, or at least an important contributor to, hypoxia-induced arterial chemorereceptor stimulation. The view presented here is that before H(2)S can seriously be considered as a candidate for transducing the O(2)-signal in the carotid bodies (CB), fundamental contradictions need to be resolved. One of these major contradictions is certainly the discrepancy between the levels of H(2)S endogenously present in the CB during hypoxia compared to the levels required to stimulate the arterial chemoreceptors in vitro. Very small amounts of H(2)S are thought to be produced endogenously during a given level of hypoxia, yet the partial pressure of tissue H(2)S which is needed to produce an effect commensurate with that of hypoxia is thousands to millions of times higher. This review discusses this and other contradictions in light of what is known about H(2)S concentration and production in various tissues, the lessons we have learnt from the response to exogenous sulfide and the ability of the blood and the mitochondria to oxidize very large amounts of sulfide. These considerations suggest that the increased production of H(2)S in hypoxia and exogenous sulfide cannot produce the same effect on the carotid bodies and breathing. While the effects of the endogenous H(2)S on breathing remains to be established, the effects exogenous sulfide can be accounted for by its long established toxicity on cytochrome C oxidase.

Arterial Chemoreceptors and Sympathetic Nerve Activity

Chronic elevation in sympathetic nerve activity (SNA) is associated with the development and maintenance of certain types of hypertension1 and contributes to the progression of chronic heart failure (CHF).2 The mechanisms involved in sympathetic dysfunction in these disorders appear to be complex and multifactorial. A unified hypothesis is likely to encompass alterations in multiple autonomic reflex pathways, central integratory sites, and chemical mediators that control sympathetic outflow. For example, tonic restraint of sympathetic outflow by arterial and cardiopulmonary baroreflexes is depressed in CHF2 and depressed or reset in hypertension.3 Moreover, maladaptive changes also occur in the central nervous system at integrative sites for autonomic control in both disease processes.4,5 It is also clear that sympathoexcitatory cardiac,6 somatic,7 and central/peripheral chemoreceptor reflexes8 are enhanced in CHF and hypertension. Arterial chemoreceptors serve an important regulatory role in the control of alveolar ventilation, but they also exert a powerful influence on cardiovascular function.9 Activation of arterial chemoreceptors by hypoxemia increases sympathetic outflow to systemic vascular beds to compensate for the direct vasodilating effects of hypoxia on these vessels and to redistribute blood flow to essential organs. In this review, we highlight relevant information that implicates the arterial chemoreflex as a contributory mechanism for the sympathetic hyperactivity in CHF and hypertension and illustrate proposed mechanisms for this altered function. Arterial chemoreceptors located in the aortic and carotid bodies (CBs) respond to hypoxemia and hypercapnia. Because central chemoreceptors also respond to hypercapnia, hypoxia is typically used as a specific stimulus to arterial chemoreceptors. In some mammals, such as rats and rabbits, reflex responses to hypoxemia arise solely from the CB, whereas in other species, the aortic chemoreceptor contribution can be significant. However, it is not possible to experimentally separate the relative contribution of the aortic and …

Non‐nicotinic transmission in autonomic ganglia revisited – an important physiological function?

Autonomic ganglia, in particular sympathetic ones, have fascinated investigators since ancient times. It was believed that these structures are ‘little brains’ that integrate, carry and distribute the ‘animal spirits’ from the brain to the periphery leading to coordinated actions of the peripheral target organs (the ‘sympathies’) in association with the activity of the brain (McLachlan, 1995). However, their primary function is to distribute messages to the periphery from relatively small pools of preganglionic neurones to large pools of postganglionic neurones. Integration occurs in some sympathetic pathways of prevertebral ganglia (Janig, 1995). The primary transmitter in all ganglia is acetylcholine (ACh) acting on nicotinic receptors. ACh released by preganglionic fibres also acts on muscarinic receptors and preganglionic fibres may release neuropeptides, both generating slow excitatory synaptic potentials (EPSPs) in some types of postganglionic neurone by decrease of potassium conductance (M currents). What is the function of these slow EPSPs in postganglionic neurones? The paper by Morris et al. (2005) in this issue of The Journal of Physiology describes experiments on an in vitro preparation of the anterior pelvic (paracervical) ganglia with attached uterine artery and nerves that contain the preganglionic sympathetic or parasympathetic axons innervating the postganglionic vasodilator (VD) neurones to the uterine artery. Repetitive electrical stimulation of the preganglionic axons dilates the artery. This preganglionically induced VD is generated by release of NO and VIP, outlasts the train of stimuli by more then 10 min, and is only slightly reduced in amplitude and delayed after complete block of nicotinic transmission in the paracervical ganglia. It is generated by continuous discharge of the postganglionic VD neurones produced by a slow EPSP. The transmitter involved is unknown (but unlikely to be substance P, ATP, 5-HT, glutamate or ACh (muscarinic action)). The continuous discharge of the postganglionic neurones cannot be due to a long-term potentiation of cholinergic nicotinic transmission since VD neurones in the paracervical ganglia receive synaptic inputs from two preganglionic fibres, one being strong (i.e. always suprathreshold). The results of Morris et al. (2005) compare with those obtained more than 20 years ago in vivo in the cat. Repetitive electrical stimulation of preganglionic axons in the lumbar sympathetic trunk (LST; 50 stimuli at 25 Hz) elicits, in a decentralized preparation, early high frequency discharges and late cholinergic mucarinic and/or non-cholinergic long-lasting afterdischarges in many postganglionic neurones supplying the cat hindlimb (Fig. 1B). These afterdischarges can only be elicited when small-diameter (largely unmyelinated) preganglionic axons are stimulated (Janig et al. 1984); they require trains of 50 stimuli of at least 3–4 Hz or 3–10 stimuli at 25 Hz, and only occur in vasoconstrictor (VC) neurones (most muscle (MVC) and some 30% cutaneous VC neurones) but not in sudomotor or pilomotor neurones (Hoffmeister et al. 1978). In a preparation with intact LST the rate of ongoing activity in VC neurones is enhanced for 4–40 min or longer following repetitive stimulation of the small-diameter preganglionic axons (Fig. 1C). This enhancement can also be elicited heterosynaptically and is associated with a long-lasting decrease of blood flow (Blumberg & Janig, 1983; Janig & Koltzenburg, 1991). Stimulation of arterial chemoreceptors by hypoxia (8% O2 in N2) excites MVC neurones. This reflex excitation is also present in many MVC neurones after blockade of nicotinic transmission or of both nicotinic and muscarinic transmission (Fig. 1D) (Janig et al. 1983). Figure 1 Muscarinic and non-cholinergic responses elicited in postganglionic vasoconstrictor neurones (skin (CVC), muscle (MVC)) projecting to the cat hindlimb by activation of preganglionic neurones In conclusion, non-nicotinic (muscarinic and/or peptidergic) synaptic transmission in postganglionic VC neurones may be important under certain functional conditions (Fig. 1E). Infrequent bursts of impulses in preganglionic neurones with slowly conducting axons that converge on postganglionic VC neurones are necessary to generate a long-term increase in ongoing activity in postganglionic VC neurones. This may also apply to the VD and secretomotor pathways supplying the internal reproductive organs in females, leading via a non-cholinergic mechanism in paracervical ganglia to long-lasting effector responses (vasodilatation, secretion) as shown by Morris et al. (2005). These results tie up with observations in the cat that preganglionic non-VC neurones projecting in lumbar splanchnic nerves can be activated reflexly for 1–12 min after mechanical stimulation of sacral afferents for 20 s (e.g. from the anal canal; Bahr et al. 1986). The mechanism underlying this unique reflex activation that outlasts the afferent stimulus by many minutes is most likely to lie within the spinal pathways. Thus, it may be hypothesized that a centrally potentiated reflex in preganglionic neurones, that probably have VD and secretomotor function, is further amplified by non-cholinergic synaptic transmission in paracervical ganglia. This sequential cascade of amplification of a central signal might turn out to be of considerable importance in the regulation of the reproductive organs.

Augmented sympathetic neural response to simulated obstructive apnoea in human heart failure.

Sleep apnoea in heart failure increases mortality risk, possibly as a result of greater activation of the sympathetic nervous system. In healthy subjects, simulated central apnoeas (holding breath) and obstructive apnoeas (Mueller manoeuvres) increase muscle sympathetic activity equally, primarily through chemoreceptor stimulation. In heart failure, however, Mueller manoeuvres cause greater reductions in blood pressure than breath holds. We hypothesized that in heart failure, the summation of arterial baroreceptor unloading and chemoreceptor stimulation would increase sympathetic activity more during obstructive than central apnoeas. Healthy human subjects and heart failure patients (seven of each) performed 15-s breath holds and 15-s Mueller manoeuvres. Breath holds evoked a progressive increase in muscle sympathetic nerve activity in both groups, but had no effect on blood pressure. In healthy subjects, breath holds and Mueller manoeuvres caused equal peaks in sympathetic activity. In contrast, in heart failure patients, Mueller manoeuvres caused a progressive decrease in blood pressure (P < 0.05) and greater increases in sympathetic activity than breath holds (P < 0.01). In heart failure, simulated obstructive apnoea elicits greater increases in sympathetic activity than simulated central apnoea, due to its additional hypotensive effect. These present findings offer novel insight into the potential role of sleep apnoea in augmenting sympathetic activity and accelerating disease progression in heart failure.

Augmented sympathetic neural response to simulated obstructive apnoea in human heart failure

Sleep apnoea in heart failure increases mortality risk, possibly as a result of greater activation of the sympathetic nervous system. In healthy subjects, simulated central apnoeas (holding breath) and obstructive apnoeas (Mueller manoeuvres) increase muscle sympathetic activity equally, primarily through chemoreceptor stimulation. In heart failure, however, Mueller manoeuvres cause greater reductions in blood pressure than breath holds. We hypothesized that in heart failure, the summation of arterial baroreceptor unloading and chemoreceptor stimulation would increase sympathetic activity more during obstructive than central apnoeas. Healthy human subjects and heart failure patients (seven of each) performed 15-s breath holds and 15-s Mueller manoeuvres. Breath holds evoked a progressive increase in muscle sympathetic nerve activity in both groups, but had no effect on blood pressure. In healthy subjects, breath holds and Mueller manoeuvres caused equal peaks in sympathetic activity. In contrast, in heart failure patients, Mueller manoeuvres caused a progressive decrease in blood pressure (P&lt;0.05) and greater increases in sympathetic activity than breath holds (P&lt;0.01). In heart failure, simulated obstructive apnoea elicits greater increases in sympathetic activity than simulated central apnoea, due to its additional hypotensive effect. These present findings offer novel insight into the potential role of sleep apnoea in augmenting sympathetic activity and accelerating disease progression in heart failure.

Ventilatory sensitivity to changes in inspired and arterial carbon dioxide partial pressures in the chicken

To determine if intrapulmonary chemoreceptors could be the sole peripheral chemoreceptors responsible for ventilatory responses to inhaled CO2, we studied the relationships of minute ventilation, tidal volume, and respiratory frequency to inspired and arterial partial pressure of CO2 (P(I)CO2 and PaCO2) in decerebrate upright chickens when the birds inspired gases containing four low partial pressures of CO2 (0.02, 5.0, 8.2, and 11.4 torr). Because of variability in the measured variables from time to time in the same birds, as well as between birds, and because of the limited precision in measuring PaCO2, a 4 × 4 Latin square design and four statistical methods of data analyses (modified reduced major axis estimator, maximum likelihood estimator, average slope method, and summary slope method) were used. Tidal volume, minute ventilation, and PaCO2 increased, but respiratory frequency remained unchanged, as gases containing increased partial pressures of CO2 were inhaled. The results indicate that intrapulmonary chemoreceptors are not the sole receptors stimulated by inhaling gas containing even low partial pressures of CO2 and that stimulation of arterial and central chemoreceptors also occurs. Stimulation of these latter chemoreceptors may account for the increase in ventilation. Further, the results demonstrate the importance of maintaining a low level of environmental CO2 in poultry houses to minimize its influence on ventilation.

Hypoxia augments apnea-induced peripheral vasoconstriction in humans.

Obstructive apnea and voluntary breath holding are associated with transient increases in muscle sympathetic nerve activity (MSNA) and arterial pressure. The contribution of changes in blood flow relative to the contribution of changes in vascular resistance to the apnea-induced transient rise in arterial pressure is unclear. We measured heart rate, mean arterial blood pressure (MAP), MSNA (peroneal microneurography), and femoral artery blood velocity (V(FA), Doppler) in humans during voluntary end-expiratory apnea while they were exposed to room air, hypoxia (10.5% inspiratory fraction of O2), and hyperoxia (100% inspiratory fraction of O2). Changes from baseline of leg blood flow (Q) and vascular resistance (R) were estimated from the following relationships: Q proportional to V(FA), corrected for the heart rate, and R proportional to MAP/Q. During apnea, MSNA rose; this rise in MSNA was followed by a rise in MAP, which peaked a few seconds after resumption of breathing. Responses of MSNA and MAP to apnea were greatest during hypoxia and smallest during hyperoxia (P < 0.05 for both compared with room air breathing). Similarly, apnea was associated with a decrease in Q and an increase in R. The decrease in Q was greatest during hypoxia and smallest during hyperoxia (-25 +/- 3 vs. -6 +/- 4%, P < 0.05), and the increase in R was the greatest during hypoxia and the least during hyperoxia (60 +/- 8 vs. 21 +/- 6%, P < 0.05). Thus voluntary apnea is associated with vasoconstriction, which is in part mediated by the sympathetic nervous system. Because apnea-induced vasoconstriction is most intense during hypoxia and attenuated during hyperoxia, it appears to depend at least in part on stimulation of arterial chemoreceptors.

Comparative physiological study of arbutamine with exercise in humans

Pharmacological stress testing may be used in the diagnosis of coronary artery disease when there are contra-indications to the use of conventional exercise protocols. The responses to such testing using arbutamine and to conventional treadmill exercise were compared in eight patients. Respiratory gas analysis and cardiovascular observations were performed during both tests. For an equivalent increment in heart rate, both protocols increased systolic blood pressure and serum lactate. Minute ventilation and oxygen consumption also rose during both protocols, but much more so with exercise. The end-tidal partial pressure of CO(2) [35.1 (S.D. 3. 1) to 30.8 (6.6) mmHg] and the dead space/tidal volume ratio (V(D)/V(T)) [0.37 (0.09) to 0.33 (0.08)] fell significantly during arbutamine infusion, but the respiratory exchange ratio did not change during either protocol. Oxygen pulse, a marker of stroke volume, did not change significantly after arbutamine, but rose markedly after exercise [arbutamine, 3.9 (1.1) to 3.37 (0.7) ml. min(-1).beat(-1); exercise, 4.7 (1.4) to 16.1 (4.6) ml.min(-1). beat(-1) (P<0.0001 compared with baseline); difference between peak responses: P<0.0001]. We conclude that arbutamine simulates some of the physiological responses to exercise, although a number of these responses are less marked than during conventional exercise, in particular cardiac output (oxygen pulse). An increase in ventilation is produced, possibly due to direct stimulation of arterial chemoreceptors. These data suggest that the main action of arbutamine is to increase central drive rather than to establish peripheral demand.

Reflex changes in heart rate during chemoreceptor stimulation in monkeys

The changes in heart rate induced by the stimulation of arterial chemoreceptors by apneic asphyxia and left atrial - intracarotid injections of sodium cyanide were investigated in anesthetized artificially ventilated and paralysed monkeys. Apneic asphyxia and sodium cyanide injection caused tachycardia, bradycardia, or both in monkeys paralysed with decamethonium bromide and tachycardia only, in monkeys paralysed with gallamine. In both groups, the tachycardia was abolished by prior administration of propranolol and the bradycardia, by atropine. Prior ventilation with 100% O2 abolished the heart rate responses produced by apnea. Recording of phrenic efferent activity showed that the neural discharge increased in response to apneic asphyxia and sodium cyanide injections. It remained so during the manifestation of tachycardia, bradycardia, or no change in heart rate, suggesting that even though "higher centres" may have an important influence in the heart rate responses elicited, central respiratory drive may not be the only mechanism. The present results show that in the nonhuman primate, arterial chemoreceptor stimulation elicits both cardioacceleratory and cardioinhibitory reflexes, and the net effect of their stimulation on heart rate depends upon the balance between these opposing mechanisms.

Inhibition of Baroreflex Vagal Bradycardia by Selective Stimulation of Arterial Chemoreceptors in Rats

We reported recently that hypoxia inhibits baroreflex vagal bradycardia (BVB) in rats and that this inhibition persists following chemoreceptor denervation. However, since it is possible that hypoxia also affects the central processing of chemoreceptive input, the existence of chemoreceptor-mediated inhibition of BVB cannot be ruled out. Therefore, we have studied whether selective chemoreceptor activation affects BVB in normoxic conditions. In pentobarbital-urethane-anaesthetized, succinylcholine-immobilized, artificially ventilated rats, BVB was provoked by electrical stimulation of the aortic depressor nerve. Arterial chemoreceptors were selectively activated by intracarotid injection of a minute amount of sodium cyanide. Cyanide injection consistently increased blood pressure while changing heart rate variably. BVB was inhibited in a dose-dependent manner. This inhibition, as well as changes in blood pressure and heart rate, was abolished following transection of the carotid sinus nerve (CSN) ipsilateral to the injection. Spinal cord transection at the C2 level did not affect the inhibition. On the other hand, intracarotid cyanide had no effect on bradycardia elicited by electrical stimulation of a peripheral cut end of the cervical vagus nerve. We conclude that chemoreceptor activation definitely inhibits BVB and that this inhibition is mediated by the CSN, and predominantly occurs in the central nervous system. The possibility is suggested that severe hypoxia suppresses not only BVB but also the chemoreceptor-mediated inhibition of BVB, both via the direct, central action.

Chronic hypoxia enhances the phrenic nerve response to arterial chemoreceptor stimulation in anesthetized rats.

Chronic exposure to hypoxia results in a time-dependent increase in ventilation called ventilatory acclimatization to hypoxia. Increased O(2) sensitivity of arterial chemoreceptors contributes to ventilatory acclimatization to hypoxia, but other mechanisms have also been hypothesized. We designed this experiment to determine whether central nervous system processing of peripheral chemoreceptor input is affected by chronic hypoxic exposure. The carotid sinus nerve was stimulated supramaximally at different frequencies (0.5-20 Hz, 0.2-ms duration) during recording of phrenic nerve activity in two groups of anesthetized, ventilated, vagotomized rats. In the chronically hypoxic group (7 days at 80 Torr inspired PO(2)), phrenic burst frequency (f(R), bursts/min) was significantly higher than in the normoxic control group with carotid sinus nerve stimulation frequencies >5 Hz. In the chronically hypoxic group, peak amplitude of integrated phrenic nerve activity ( integral Phr, percent baseline) or change in integral Phr was significantly greater at stimulation frequencies between 5 and 17 Hz, and minute phrenic activity ( integral Phr x f(R)) was significantly greater at stimulation frequencies >5 Hz. These experiments show that chronic hypoxia facilitates the translation of arterial chemoreceptor afferent input to ventilatory efferent output through a mechanism in the central nervous system.

Reflex changes in heart rate during chemoreceptor stimulation in monkeys

The changes in heart rate induced by the stimulation of arterial chemoreceptors by apneic asphyxia and left atrial - intracarotid injections of sodium cyanide were investigated in anesthetized artificially ventilated and paralysed monkeys. Apneic asphyxia and sodium cyanide injection caused tachycardia, bradycardia, or both in monkeys paralysed with decamethonium bromide and tachycardia only, in monkeys paralysed with gallamine. In both groups, the tachycardia was abolished by prior administration of propranolol and the bradycardia, by atropine. Prior ventilation with 100% O2 abolished the heart rate responses produced by apnea. Recording of phrenic efferent activity showed that the neural discharge increased in response to apneic asphyxia and sodium cyanide injections. It remained so during the manifestation of tachycardia, bradycardia, or no change in heart rate, suggesting that even though "higher centres" may have an important influence in the heart rate responses elicited, central respiratory drive may not be the only mechanism. The present results show that in the nonhuman primate, arterial chemoreceptor stimulation elicits both cardioacceleratory and cardioinhibitory reflexes, and the net effect of their stimulation on heart rate depends upon the balance between these opposing mechanisms.

Reflex effects on components of synchronized renal sympathetic nerve activity.

The effects of peripheral thermal receptor stimulation (tail in hot water, n = 8, anesthetized) and cardiac baroreceptor stimulation (volume loading, n = 8, conscious) on components of synchronized renal sympathetic nerve activity (RSNA) were examined in rats. The peak height and peak frequency of synchronized RSNA were determined. The renal sympathoexcitatory response to peripheral thermal receptor stimulation was associated with an increase in the peak height. The renal sympathoinhibitory response to cardiac baroreceptor stimulation was associated with a decrease in the peak height. Although heart rate was significantly increased with peripheral thermal receptor stimulation and significantly decreased with cardiac baroreceptor stimulation, peak frequency was unchanged. As peak height reflects the number of active fibers, reflex increases and decreases in synchronized RSNA are mediated by parallel increases and decreases in the number of active renal nerve fibers rather than changes in the centrally based rhythm or peak frequency. The increase in the number of active renal nerve fibers produced by peripheral thermal receptor stimulation reflects the engagement of a unique group of silent renal sympathetic nerve fibers with a characteristic response pattern to stimulation of arterial baroreceptors, peripheral and central chemoreceptors, and peripheral thermal receptors.

Pharmacological stimulation of arterial chemoreceptors in conscious rats produces differential responses in renal cortical and medullary blood flow.

1. There have been no previously published data regarding intrarenal blood flow distribution in acute whole-body hypoxic hypoxia and/or arterial chemoreceptor stimulation in normoxic mammals. 2. Cortical and medullary blood flows were measured simultaneously before and in response to pharmacological stimulation of peripheral arterial chemoreceptors by i.v. injection of almitrine bismesylate (0.25 mg/kg). 3. Arterial chemoreceptor excitation reduced cortical blood flow but only in innervated kidneys. An effect on medullary blood flow was observed in neither innervated nor denervated kidneys. 4. These data indicate that renal cortical and medullary blood flows react differently to arterial chemoreceptor stimulation.

Responses of neurons in the insular cortex to gustatory, visceral, and nociceptive stimuli in rats.

Extracellular unit responses to baroreceptor and chemoreceptor stimulation, gustatory stimulation of the posterior tongue, electrical stimulation of the superior laryngeal (SL) nerve, and tail pinch were recorded from the insular cortex of anesthetized and paralyzed rats. Forty-three neurons identified responded to stimulation by at least one of the stimuli used in the present study. Of the 43 neurons, 33 responded to tail pinch, and the remaining 10 had no response; 18 showed an excitatory response, and 15 showed an inhibitory response. Of the 43 neurons, 35 responded to electrical stimulation of the SL nerve; 27 showed an excitatory response, and 8 showed an inhibitory response. Of the 20 neurons that responded to baroreceptor stimulation by an intravenous injection of methoxamine hydrochloride (Mex), 11 were excitatory and 9 were inhibitory. Twenty-seven neurons were responsive to an intravenous injection of sodium nitroprusside (SNP); 10 were excitatory and 17 were inhibitory. Ten neurons were excited and 16 neurons were inhibited by arterial chemoreceptor stimulation by an intravenous injection of sodium cyanide (NaCN). Twenty-six neurons were responsive to at least one of the gustatory stimuli (1.0 M NaCl, 30 mM HCl, 30 mM quinine HCl, and 1.0 M sucrose): four to six excitatory neurons and three to nine inhibitory neurons for each stimulus. A large number of the neurons (42/43) received convergent inputs from more than one stimulus among the nine stimuli used in the present study. Most neurons (38/43) were responsive to two or more stimulus groups when the natural stimuli used in the present study are grouped into three, gustatory, visceral, and nociceptive stimuli. The neurons recorded were located in the insular cortex between 2.8 mm anterior and 1.1 mm posterior to the anterior edge of the joining of the anterior commissure (AC); the mean location was 1.0 mm (n = 43) anterior to the AC. This indicates that most of the neurons identified in the present study were located in the region posterior to the taste area and anterior to the visceral area in the insular cortex. These results indicate that the insular cortex neurons distributing between the taste area and the visceral area receive convergent inputs from baroreceptor, chemoreceptor, gustatory, and nociceptive organs and may have roles in taste aversion or in regulation of visceral responses.

Neurons in the posterior insular cortex are responsive to gustatory stimulation of the pharyngolarynx, baroreceptor and chemoreceptor stimulation, and tail pinch in rats

Extracellular unit responses to gustatory stimulation of the pharyngolaryngeal region, baroreceptor and chemoreceptor stimulation, and tail pinch were recorded from the insular cortex of anesthetized and paralyzed rats. Of the 32 neurons identified, 28 responded to at least one of the nine stimuli used in the present study. Of the 32 neurons, 11 showed an excitatory response to tail pinch, 13 showed an inhibitory response, and the remaining eight had no response. Of the 32 neurons, eight responded to baroreceptor stimulation by an intravenous (i.v.) injection of methoxamine hydrochloride (Mex), four were excitatory and four were inhibitory. Thirteen neurons were excited and six neurons were inhibited by an arterial chemoreceptor stimulation by an i.v. injection of sodium cyanide (NaCN). Twenty-two neurons were responsive to at least one of the gustatory stimuli (deionized water, 1.0 M NaCl, 30 mM HCl, 30 mM quinine HCl, and 1.0 M sucrose); five to 11 excitatory neurons and three to seven inhibitory neurons for each stimulus. A large number of the neurons (25/32) received converging inputs from more than one stimulus among the nine stimuli used in the present study. Most neurons (23/32) received converging inputs from different modalities (gustatory, visceral, and tail pinch). The neurons responded were located in the insular cortex between 2.0 mm anterior and 0.2 mm posterior to the anterior edge of the joining of the anterior commissure (AC); the mean location was 1.2 mm ( n=28) anterior to the AC. This indicates that most of the neurons identified in the present study seem to be located in the region posterior to the taste area and anterior to the visceral area in the insular cortex. These results indicate that the insular cortex neurons distributing between the taste area and the visceral area receive convergent inputs from gustatory, baroreceptor, chemoreceptor, and nociceptive organs.

Cardiorespiratory and renal responses to arterial chemoreceptor stimulation by hypoxia or almitrine in men.

1. The cardiorespiratory and renal responses to 3 h of normobaric whole-body hypoxic hypoxia (FiO2 = 0.12) as well as to arterial chemoreceptor stimulation by the oral administration of 100 mg almitrine bismesylate during normoxia were measured in 12 normotensive young men undergoing water diuresis. A third series of responses obtained under comparable conditions in the same subjects served as time controls. 2. No significant changes could be detected over time in the parameters measured in control experiments. The subjects reacted to both whole-body hypoxic hypoxia and to pharmacological chemoreceptor stimulation with significant increases in heart rate, tidal volume, minute ventilation and filtration-fraction. Overall renal vascular resistance rose significantly in hypoxia; increases in renal vascular resistance in almitrine experiments were not significant. 3. Renal fractional lithium excretion decreased significantly in response to whole-body hypoxic hypoxia and increased slightly in response to almitrine. Fractional urine and sodium excretion showed negligible changes. 4. The data indicate that, in humans, both almitrine and whole-body hypoxic hypoxia affect not only alveolar ventilation but also renal haemodynamics. 5. The renal electrolyte excretion pattern suggests that under certain circumstances (e.g. dilated renal vascular bed) acute, but well-tolerated, whole-body hypoxic hypoxia can simultaneously stimulate renal proximal tubular sodium reabsorption and inhibit distal tubular sodium reabsorption. The renal tubular responses also indicate that almitrine may influence renal tubular lithium reabsorption by, thus far, unknown mechanisms.

Differentiated sympathetic neural control of the kidney.

Anatomic and neurophysiological methods were used to identify functionally specific subgroups of renal sympathetic nerve fibers. The distribution of diameters of the predominating unmyelinated fibers showed a major mode at 1.1 microns and a minor mode at 1.6 microns. The conduction velocity was 2.10 +/- 0.10 m/s, consistent with unmyelinated C fibers. Analysis of strength-duration relationships during renal nerve stimulation showed that both rheobase and chronaxie values for renal blood flow were greater than those for urinary flow rate and were independent of stimulation frequency. This difference suggests a higher stimulation threshold (smaller diameter) for those renal nerve fibers involved in the renal blood flow response (renal vasoconstriction) compared with those for the urinary flow rate response (antidiuresis) to renal nerve stimulation. Single renal units that responded to preganglionic splanchnic nerve stimulation were studied. Those with spontaneous activity (88%) responded to stimulation of arterial baroreceptors, arterial and central chemoreceptors, and peripheral thermoreceptors, whereas those that lacked spontaneous activity (12%) responded only to stimulation of peripheral thermoreceptors (known to produce renal vasoconstriction). A minority population of single renal units has been identified that, although renal vasoconstrictor, does not exhibit other characteristic features of vasoconstrictor neurons (i.e., responsiveness to stimulation of arterial baroreceptors and arterial and central chemoreceptors). These findings suggest the existence of functionally specific subgroups of renal nerve fibers.