During exercise by healthy mammals, alveolar ventilation and alveolar-capillary diffusion increase in proportion to the increase in metabolic rate to prevent PaCO2 from increasing and PaO2 from decreasing. There is no known mechanism capable of directly sensing the rate of gas exchange in the muscles or the lungs; thus, for over a century there has been intense interest in elucidating how respiratory neurons adjust their output to variables which can not be directly monitored. Several hypotheses have been tested and supportive data were obtained, but for each hypothesis, there are contradictory data or reasons to question the validity of each hypothesis. Herein, we report a critique of the major hypotheses which has led to the following conclusions. First, a single stimulus or combination of stimuli that convincingly and entirely explains the hyperpnea has not been identified. Second, the coupling of the hyperpnea to metabolic rate is not causal but is due to of these variables each resulting from a common factor which link the circulatory and ventilatory responses to exercise. Third, stimuli postulated to act at pulmonary or cardiac receptors or carotid and intracranial chemoreceptors are not primary mediators of the hyperpnea. Fourth, stimuli originating in exercising limbs and conveyed to the brain by spinal afferents contribute to the exercise hyperpnea. Fifth, the hyperventilation during heavy exercise is not primarily due to lactacidosis stimulation of carotid chemoreceptors. Finally, since volitional exercise requires activation of the CNS, neural feed-forward (central command) mediation of the exercise hyperpnea seems intuitive and is supported by data from several studies. However, there is no compelling evidence to accept this concept as an indisputable fact.

Klingerman CM, Trushin N, Prokopczyk B, Haouzi P. H2S concentrations in the arterial blood during H2S administration in relation to its toxicity and effects on breathing. Am J Physiol Regul Integr Comp Physiol 305: R630 -R638, 2013. First published July 31, 2013; doi:10.1152/ajpregu.00218.2013.-Our aim was to establish in spontaneously breathing urethane-anesthetized rats, the relationship between the concentrations of H2S transported in the blood and the corresponding clinical manifestations, i.e., breathing stimulation and inhibition, during and following infusion of NaHS at increasing rates. The gaseous concentration of H2S (CgH2S, one-third of the total soluble form) was computed from the continuous determination of H2S partial pressure in the alveolar gas, while H2S, both dissolved and combined to hemoglobin, was measured at specific time points by sulfide complexation with monobromobimane (CMBBH2S). We found that using a potent reducing agent in vitro, H 2S added to the whole blood had little interaction with the plasma proteins, as sulfide appeared to be primarily combined and then oxidized by hemoglobin. In vivo, H 2S was undetectable in the blood in its soluble form in baseline conditions, while CMBBH 2S averaged 0.7 Ϯ 0.5 M. During NaHS infusion, H 2S was primarily present in nonsoluble form in the arterial blood: CMBBH 2S was about 50 times higher than CgH 2S at the lowest levels of exposure and 5 or 6 times at the levels wherein fatal apnea occurred. CgH 2S averaged only 1.1 Ϯ 0.7 M when breathing increased, corresponding to a CMBBH 2S of 11.1 Ϯ 5.4 M. Apnea occurred at CgH 2S above 5.1 M and CMBBH2S above 25.4 M. At the cessation of exposure, CMBBH 2S remained elevated, at about 3 times above baseline for at least 15 min. These data provide a frame of reference for studying the putative effects of endogenous H 2S and for testing antidotes against its deadly effects.

The purpose of this study was to examine the influence of the type of exercise (running vs. cycling) on the O2 uptake V(O2) slow component. Ten triathletes performed exhaustive exercise on a treadmill and on a cycloergometer at a work rate corresponding to 90% of maximal VO2 (90% work rate maximal V(O2)). The duration of the tests before exhaustion was superimposable for both type of exercises (10 min 37 s +/- 4 min 11 s vs. 10 min 54 s +/- 4 min 47 s for running and cycling, respectively). The V(O2) slow component (difference between V(O2) at the last minute and minute 3 of exercise) was significantly lower during running compared with cycling (20.9 +/- 2 vs. 268.8 +/- 24 ml/min). Consequently, there was no relationship between the magnitude of the V(O2) slow component and the time to fatigue. Finally, because blood lactate levels at the end of the tests were similar for both running (7.2 +/- 1.9 mmol/l) and cycling (7.3 +/- 2.4 mmol/l), there was a clear dissociation between blood lactate and the V(O2) slow component during running. These data demonstrate that 1) the V(O2) slow component depends on the type of exercise in a group of triathletes and 2) the time to fatigue is independent of the magnitude of the V(O2) slow component and blood lactate concentration. It is speculated that the difference in muscular contraction regimen between running and cycling could account for the difference in the V(O2) slow component.

This study was undertaken to test the hypothesis that group III and IV afferents with endings in skeletal muscle signal the distension of the peripheral vascular network. The responses of these slowly conducting afferents to pharmacologically induced vasodilation and to acute obstruction of the venous drainage of the hindlimbs were studied in barbiturate-anesthetized cats. Afferent impulses arising from endings in the triceps surae muscles were recorded from the L(7) and S(1) dorsal roots. Fifteen of the 48 group IV and 3 of the 19 group III afferents tested were stimulated by intra-aortic injections of papaverine (2-2.5 mg/kg). Sixty-two percent of the afferents that responded to papaverine also responded to isoproterenol (50 microg/kg). Seven of the 36 group IV and 2 of the 12 group III afferents tested were excited by acute distension of the hindlimb venous system. Four of the seven group IV afferents responding to venous distension also responded to papaverine (57 vs. 13% for the nonresponding). Finally, we observed that most of the group IV afferents that were excited by dynamic contractions of the triceps surae muscles also responded either to venous distension or to vasodilatory agents. These results are consistent with the histological findings that a large number of group IV endings have their receptive fields close to the venules and suggest that they can be stimulated by the deformation of these vascular structures when peripheral conductance increases. Moreover, such a mechanism offers the possibility of encoding both the effects of muscle contraction through intramuscular pressure changes and the distension of the venular system, thereby monitoring the activity of the veno-muscular pump.

Hydrogen sulphide (H2S), a chemical hazard in oil and gas production, has recently become a dreadful method of suicide, posing specific risks and challenges for the first responders. Currently, there is no proven effective treatment against H2S poisoning and its severe neurological, respiratory or cardiac after-effects. We have recently described that H2S is present in various compartments, or pools, in the body during sulphide exposure, which have different levels of toxicity. The general goals of our study were to (1) determine the concentrations and kinetics of the various pools of hydrogen sulphide in the blood, i.e., gaseous (CgH2S) versus total sulphide, i.e., reacting with monobromobimane (CMBBH2S), during and following H2S exposure in a small and large mammal and (2) establish the interaction between the pools of H2S and a methemoglobin (MetHb) solution or a high dose of hydroxocobalamin (HyCo). We found that CgH2S during and following H2S infusion was similar in sedated sheep and rats at any given rate of infusion/kg and provoked symptoms, i.e., hyperpnea and apnea, at the same CgH2S. After H2S administration was stopped, CgH2S disappeared within 1 min. CMBBH2S also dropped to 2-3μM, but remained above baseline levels for at least 30 min. Infusion of a MetHb solution during H2S infusion produced an immediate reduction in the free/soluble pool of H2S only, whereas CMBBH2S increased by severalfold. HyCo (70 mg/kg) also decreased the concentrations of free/soluble H2S to almost zero; CgH2S returned to pre-HyCo levels within a maximum of 20 min, if H2S infusion is maintained. These results are discussed in the context of a relevant scenario, wherein antidotes can only be administered after H2S exposure.

This review examines the evidence that skeletal muscles can sense the status of the peripheral vascular network through group III and IV muscle afferent fibers. The anatomic and neurophysiological basis for such a mechanism is the following: 1) a significant portion of group III and IV afferent fibers have been found in the vicinity and the adventitia of the arterioles and the venules; 2) both of these groups of afferent fibers can respond to mechanical stimuli; 3) a population of group III and IV fibers stimulated during muscle contraction has been found to be inhibited to various degrees by arterial occlusion; and 4) more recently, direct evidence has been obtained showing that a part of the group IV muscle afferent fibers is stimulated by venous occlusion and by injection of vasodilatory agents. The physiological relevance of sensing local distension of the vascular network at venular level in the muscles is clearly different from that of the large veins, since the former can directly monitor the degree of tissue perfusion. The possible involvement of this sensing mechanism in respiratory control is discussed mainly in the light of the ventilatory effects of peripheral vascular occlusions during and after muscular exercise. It is proposed that this regulatory system anticipates the chemical changes that would occur in the arterial blood during increased metabolic load and attempts to minimize them by adjusting the level of ventilation to the level of muscle perfusion, thus matching the magnitudes of the peripheral and pulmonary gas exchange.

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Context Hydrogen sulfide (H2S) intoxication produces an acute depression in cardiac contractility-induced circulatory failure, which has been shown to be one of the major contributors to the lethality of H2S intoxication or to the neurological sequelae in surviving animals. Methylene blue (MB), a phenothiazinium dye, can antagonize the effects of the inhibition of mitochondrial electron transport chain, a major effect of H2S toxicity. Objectives We investigated whether MB could affect the immediate outcome of H2S-induced coma in unanesthetized animals. Second, we sought to characterize the acute cardiovascular effects of MB and two of its demethylated metabolites—azure B and thionine—in anesthetized rats during lethal infusion of H2S. Materials and methods First, MB (4 mg/kg, intravenous [IV]) was administered in non-sedated rats during the phase of agonal breathing, following NaHS (20 mg/kg, IP)-induced coma. Second, in 4 groups of urethane-anesthetized rats, NaHS was infused at a rate lethal within 10 min (0.8 mg/min, IV). Whenever cardiac output (CO) reached 40% of its baseline volume, MB, azure B, thionine, or saline were injected, while sulfide infusion was maintained until cardiac arrest occurred. Results Seventy-five percent of the comatose rats that received saline (n = 8) died within 7 min, while all the 7 rats that were given MB survived (p = 0.007). In the anesthetized rats, arterial, left ventricular pressures and CO decreased during NaHS infusion, leading to a pulseless electrical activity within 530 s. MB produced a significant increase in CO and dP/dtmax for about 2 min. A similar effect was produced when MB was also injected in the pre-mortem phase of sulfide exposure, significantly increasing survival time. Azure B produced an even larger increase in blood pressure than MB, while thionine had no effect. Conclusion MB can counteract NaHS-induced acute cardiogenic shock; this effect is also produced by azure B, but not by thionine, suggesting that the presence of methyl groups is a prerequisite for producing this protective effect.