The interaction of breath holding and muscle mechanoreflex on cardiovascular responses in breath-hold divers and non-breath-hold divers.

Cardiovascular responses to diving are characterized by two opposing responses: tachycardia resulting from exercise and bradycardia resulting from the apnea. The convergence of bradycardia and tachycardia may determine the cardiovascular responses to diving. The purpose of this study was to investigate the interaction of breath holding and muscle mechanoreflex on cardiovascular responses in breath-hold divers (BHDs) and non-BHDs. We compared the cardiovascular responses to combined apnea and the mechanoreflex in BHDs and non-BHDs. All participants undertook three trials-apnea, passive leg cycling (PLC), and combined trials-for 30 s after rest. Cardiovascular variables were measured continuously. Nine BHD (male:female, 4:5; [means ± SD] age, 35 ± 6 years; height, 168.6 ± 4.6 cm; body mass, 58.4 ± 5.9 kg) and eight non-BHD (male:female, 4:4; [means ± SD] age, 35 ± 7 years; height, 163.9 ± 9.1 cm; body mass, 55.6 ± 7.2 kg) participants were included. Compared to the resting baseline, heart rate (HR) and cardiac output (CO) significantly decreased during the combined trial in the BHD group, while they significantly increased during the combined trials in the non-BHD group (P < 0.05). Changes in the HR and CO were significantly lower in the BHD group than in the non-BHD group in the combined trial (P < 0.05). These results suggest that bradycardia with apnea in BHDs is prioritized over tachycardia with the mechanoreflex, whereas that in non-BHDs is not. This finding implies that diving training changes the interaction between apnea and the mechanoreflex in cardiovascular control.

Vascular Reactions of the Diving Reflex in Men and Women Carrying Different ADRA1A Genotypes.

The diving reflex is an oxygen-saving mechanism which is accompanied by apnea, reflex bradycardia development, peripheral vasoconstriction, spleen erythrocyte release, and selective redistribution of blood flow to the organs most vulnerable to lack of oxygen, such as the brain, heart, and lungs. However, this is a poorly studied form of hypoxia, with a knowledge gap on physiological and biochemical adaptation mechanisms. The reflective sympathetic constriction of the resistive vessels is realized via ADRA1A. It has been shown that ADRA1A SNP (p.Arg347Cys; rs1048101) is associated with changes in tonus in vessel walls. Moreover, the Cys347 allele has been shown to regulate systolic blood pressure. The aim of this work was to evaluate whether the ADRA1A polymorphism affected the pulmonary vascular reactions in men and women in response to the diving reflex. Men (n = 52) and women (n = 50) untrained in diving aged 18 to 25 were recruited into the study. The vascular reactions and blood flow were examined by integrated rheography and rheography of the pulmonary artery. Peripheral blood circulation was registered by plethysmography. The ADRA1A gene polymorphism (p.Arg347Cys; rs1048101) was determined by PCR-RFLP. In both men and women, reflective pulmonary vasodilation did occur in response to the diving reflex, but in women this vasodilation was more pronounced and was accompanied by a higher filling of the lungs with blood.. Additionally, ADRA1A SNP (p.Arg347Cys; rs1048101) is associated with sex. Interestingly, women with the Arg347 allele demonstrated the highest vasodilation of the lung vessels. Therefore, our data may help to indicate women with the most prominent adaptive reactions to the diving reflex. Our data also indicate that women and men with the Cys allele of the ADRA1A gene polymorphism have the highest risk of developing lung hypertension in response to the diving reflex. The diving reflex is an oxygen-saving mechanism which is accompanied by apnea, reflex bradycardia development, peripheral vasoconstriction, spleen erythrocyte release, and selective redistribution of blood flow to the organs most vulnerable to lack of oxygen, such as the brain, heart, and lungs. However, this is a poorly studied form of hypoxia, with a knowledge gap on physiological and biochemical adaptation mechanisms.

Vascular responses to simulated breath-hold diving involving multiple reflexes.

Breath-hold diving evokes a complex cardiovascular response. The degrees of hypertension induced by the diving reflex are substantial and accentuated by the underwater swimming. This condition provides a circulatory challenge to properly buffer and cushion cardiac pulsations. We determined hemodynamic changes during the diving maneuver and hypothesized that central artery compliance would be augmented during simulated breath-hold diving. A total of 20 healthy young adults were studied. Hemodynamics were measured during exercise on a cycle ergometer, apnea, face immersion in cold water (trigeminal stimulation), and simulated breath-hold diving. Arterial compliance was measured by recording the carotid artery diameter from images derived from an ultrasound machine at the cephalic portion of the common carotid artery 1-2 cm proximal to the carotid bulb, whereas arterial pressure waveforms were obtained using an arterial tonometry placed on the contralateral carotid artery and recorded on a data acquisition software. The change in diameter was divided by the change in blood pressure to calculate arterial compliance. Arterial compliance increased with simulated diving compared with rest (P = 0.007) and was elevated compared with exercise and apnea alone (P < 0.01). A significant increase in heart rate was observed with exercise, apnea, and facial immersion when compared with rest (P < 0.001). However, simulated diving brought the heart rate down to resting levels. Cardiac output increased with all conditions (P < 0.001), with an attenuated response during simulated diving compared with exercise and facial immersion (P < 0.05). Mean blood pressure was elevated during all conditions (P < 0.001), with a further elevation observed during simulated diving compared with exercise (P < 0.001), apnea (P = 0.016), and facial immersion (P < 0.001). Total peripheral resistance was decreased during exercise and facial immersion compared with rest (P < 0.001) but was increased during simulated diving compared with exercise (P < 0.001), apnea (P = 0.008), and facial immersion (P = 0.003). We concluded that central artery compliance is augmented during simulated breath-hold diving to help buffer cardiac pulsations.

Recuperando el "hilo perdido" en la madeja de la enterocolitis necrotizante del recién nacido / Recovering the "lost thread" in the skein of necrotizing enterocolitis of the newborn / Recuperando o "fio perdido" no novelo de enterocolite necrosante do recém-nascido

Propósito de la revisión: el objetivo de la revisión es delinear la fisiopatología de la Entero Colitis Necrotizante (ECN) clásica del recién nacido, proponer un listado de antecedentes perinatales que definan un grupo de riesgo y establecer parámetros simples y objetivos, que ayuden a establecer un diagnóstico clínico precoz. Recientes hallazgos: La mortalidad de la Entero Colitis Necrotizante clásica del recién nacido sigue siendo elevada. Aunque la enfermedad tiene varias presentaciones, es única con una única vía de instalación, la hipoperfusión intestinal como agente agresor inicial. Extracto: La falta de estrategias de prevención y el diagnóstico clínico muy tardío explican la mortalidad elevada de la ECN. Existe una gran confusión sobre el origen de la enferme-dad, dando a entender que existen diferentes tipos de ECN, aunque la enfermedad es única, tiene diferentes manifestaciones según las condiciones del recién nacido con una vía común de instalación, la hipoperfusión intestinal como agente agresor inicial. En este artículo se postula que reconocer a la hipoperfusión intestinal como agente agresor inicial, es "encontrar el hilo perdido", que permitirá desarrollar estrategias de prevención y tratamiento, al identificar los pacientes en riesgo de ECN y lograr el diagnóstico de manera precoz.

Purpose of the review: The objective of the review is to delineate the pathophysiology of the classic Entero Necrotizing Colitis (NEC) of the newborn, propose a list of perinatal ante-cedents that define a risk group and establish simple and objective parameters that help to establish an early clinical diagnosis. Recent findings: The mortality of the classic Necrotizing Entero Colitis of the newborn is still high. Although the disease has several presentations, it is unique with a single installation route, intestinal hypoperfusion as the initial offending agent. Excerpt: The lack of prevention strategies and very late clinical diagnosis explain the high mortality of NEC. There is great confusion about the origin of the disease, giving to under-stand that there are different types of NEC, although the disease is unique, it has different manifestations according to the conditions of the newborn with a common route of installation, intestinal hypoperfusion as an initial assailant agent. This article postulates that recog-nizing intestinal hypoperfusion as the initial offending agent is "finding the lost thread", that developing prevention and treatment strategies, by identifying patients at risk of NEC and achieving a diagnosis in a way early.

Objetivo da revisão: O objetivo da revisão é delinear a fisiopatologia da Entero Colite Necrosante (NEC) clássica do recém-nascido, propor uma lista de antecedentes perinatais que definem um grupo de risco e estabelecer parâmetros simples e objetivos que auxiliem no diagnóstico clínico precoce. Descobertas recentes: A mortalidade da Entero Colite Necrosante clássica do recém-nascido ainda é alta. Embora a doença tenha várias apresentações, é única com uma única via de instalação, a hipoperfusão intestinal como agente agressor inicial. Resumo: A falta de estratégias de prevenção e o diagnóstico clínico muito tardio explicam a alta mortalidade da NEC. Há grande confusão sobre a origem da doença, sugerindo que existem diferentes tipos de NEC, embora a doença seja única, ela tem diferentes manifestações dependendo das condições do recém-nascido com uma via comum de instalação, a hipoperfusão intestinal como agente. assaltante inicial. Este artigo postula que reconhecer a hipoperfusão intestinal como agente agressor inicial é "encontrar o fio condutor", o que permitirá o desenvolvimento de estratégias de prevenção e tratamento, por meio da identificação de pacientes em risco de NEC e do diagnóstico precoce.

Carotid body chemosensitivity is not attenuated during cold water diving.

Tonic carotid body (CB) activity is reduced during exposure to cold and hyperoxia. We tested the hypotheses that cold water diving lowers CB chemosensitivity and augments CO2 retention more than thermoneutral diving. Thirteen subjects [age: 26 ± 4 yr; body mass index (BMI): 26 ± 2 kg/m2) completed two 4-h head-out water immersion protocols in a hyperbaric chamber (1.6 ATA) in cold (15°C) and thermoneutral (25°C) water. CB chemosensitivity was assessed with brief hypercapnic ventilatory response ([Formula: see text]) and hypoxic ventilatory response ([Formula: see text]) tests before dive, 80 and 160 min into the dive (D80 and D160, respectively), and immediately after and 60 min after dive. Data are reported as an absolute mean (SD) change from predive. End-tidal CO2 pressure increased during both the thermoneutral water dive [D160: +2 (3) mmHg; P = 0.02] and the cold water dive [D160: +1 (2) mmHg; P = 0.03]. Ventilation increased during the cold water dive [D80: 4.13 (4.38) and D160: 7.75 (5.23) L·min-1; both P < 0.01] and was greater than the thermoneutral water dive at both time points (both P < 0.01). [Formula: see text] was unchanged during the dive (P = 0.24) and was not different between conditions (P = 0.23). [Formula: see text] decreased during the thermoneutral water dive [D80: -3.45 (3.61) and D160: -2.76 (4.04) L·min·mmHg-1; P < 0.01 and P = 0.03, respectively] but not the cold water dive. However, [Formula: see text] was not different between conditions (P = 0.17). In conclusion, CB chemosensitivity was not attenuated during the cold stress diving condition and does not appear to contribute to changes in ventilation or CO2 retention.

Ictal activation of oxygen-conserving reflexes as a mechanism for sudden death in epilepsy.

OBJECTIVE: To test the hypothesis that death with physiological parallels to human cases of sudden unexpected death in epilepsy (SUDEP) can be induced in seizing rats by ictal activation of oxygen-conserving reflexes (OCRs). METHODS: Urethane-anesthetized female Long-Evans rats were implanted with electrodes for electrocardiography (ECG), electrocorticography (ECoG), and respiratory thermocouple; venous and arterial cannulas; and a laryngoscope guide and cannula or nasal cannula for activation of the laryngeal chemoreflex (LCR) or mammalian diving reflex (MDR), respectively. Kainic acid injection, either systemic or into the ventral hippocampus, induced prolonged acute seizures. RESULTS: Reflex challenges during seizures caused sudden death in 18 of 20 rats-all MDR rats (10) and all but two LCR rats (8) failed to recover from ictal activation of OCRs and died within minutes of the reflexes. By comparison, 4 of 4 control (ie, nonseizing) rats recovered from 64 induced diving reflexes (16 per rat), and 4 of 4 controls recovered from 64 induced chemoreflexes (16 per rat). Multiple measures were consistent with reports of human SUDEP. Terminal central apnea preceded terminal asystole in all cases. Heart and respiratory rate fluctuations that paralleled those seen in human SUDEP occurred during OCR-induced sudden death, and mean arterial pressure (MAP) was predictive of death, showing a 17 or 15 mm Hg drop (MDR and LCR, respectively) in the 20 s window centered on the time of brain death. OCR activation was never fatal in nonseizing rats. SIGNIFICANCE: These results present a method of inducing sudden death in two seizure models that show pathophysiology consistent with that observed in human cases of SUDEP. This proposed mechanism directly informs previous findings by our group and others in the field; provides a repeatable, inducible animal model for the study of sudden death; and offers a potential explanation for observations made in cases of human SUDEP.

Efficacy of Diving Reflex in Near-Term Fetal Tachycardia.

BACKGROUND: Sustained fetal supraventricular tachycardia is a potentially life-threatening disorder and is usually treated by administering antiarrhythmia drugs to the mother, which can require at least 48-72 hours to achieve normal sinus rhythm. In neonates with supraventricular tachycardia, first-line treatment is stimulation of the vagus nerve to elicit the diving reflex, commonly by application of a cold pack to the face, with a high, albeit sometimes temporary, success rate. CASE: We describe a case of fetal supraventricular tachycardia at term treated successfully by eliciting the diving reflex with an ice pack to the maternal abdomen over the lower uterine segment. The neonate was given propranolol augmented with flecainide because of recurrent supraventricular tachycardia. He remained in a stable sinus rhythm without side effects 5 months later. CONCLUSIONS: Cardioversion of fetal supraventricular tachycardia at term by eliciting the diving reflex could be offered to allow normal labor and vaginal delivery.

Autonomic regulation of the heart and arrhythmogenesis in trained breath-hold divers.

AbstractBreath-hold divers are known to develop cardiac autonomic changes and brady-arrthymias during prolonged breath-holding (BH). The effects of BH-induced hypoxemia were investigated upon both cardiac autonomic status and arrhythmogenesis by comparing breath-hold divers (BHDs) to non-divers (NDs). Eighteen participants (9 BHDs, 9 NDs) performed a maximal voluntary BH with face immersion. BHDs were asked to perform an additional BH at water surface to increase the degree of hypoxemia. Beat-to-beat changes in heart rate (HR), short-term fractal scaling exponent (DFAα1), the number of arrhythmic events [premature ventricular contractions (PVCs), premature atrial contractions (PACs)] and peripheral oxygen saturation (SpO2) were recorded during and immediately following BH. The corrected QT-intervals (QTc) were analyzed pre- and post-acute BH. A regression-based model was used to split BH into a normoxic (NX) and a hypoxemic phase (HX). During the HX phase of BH, BHDs showed a progressive decrease in DFAα1 during BH with face immersion (p < 0.01) and BH with whole-body immersion (p < 0.01) whereas NDs did not (p > 0.05). In addition, BHDs had more arrhythmic events during the HX of BH with whole-body immersion when compared to the corresponding NX phase (5.9 ± 6.7 vs 0.4 ± 1.3; p < 0.05; respectively). The number of PVCs was negatively correlated with SpO2 during BH with whole-body immersion (r = -0.72; p < 0.05). The hypoxemic stage of voluntary BH is concomitant with significant cardiac autonomic changes toward a synergistic sympathetic and parasympathetic stimulation. Co-activation led ultimately to increased bradycardic response and cardiac electrophysiological disturbances.

Long QT syndrome type 1 and 2 patients respond differently to arrhythmic triggers: The TriQarr in vivo study.

BACKGROUND: In patients with long QT syndrome (LQTS), swimming and loud noises have been identified as genotype-specific arrhythmic triggers in LQTS type 1 (LQTS1) and LQTS type 2 (LQTS2), respectively. OBJECTIVE: The purpose of this study was to compare LQTS group responses to arrhythmic triggers. METHODS: LQTS1 and LQTS2 patients were included. Before and after beta-blocker intake, electrocardiograms were recorded as participants (1) were exposed to a loud noise of ∼100 dB; and (2) had their face immersed into cold water. RESULTS: Twenty-three patients (9 LQTS1, 14 LQTS2) participated. In response to noise, LQTS groups showed similarly increased heart rate, but LQTS2 patients had corrected QT interval (Fridericia formula) (QTcF) prolonged significantly more than LQTS1 patients (37 ± 8 ms vs 15 ± 6 ms; P = .02). After intake of beta-blocker, QTcF prolongation in LQTS2 patients was significantly blunted and similar to that of LQTS1 patients (P = .90). In response to simulated diving, LQTS groups experienced a heart rate drop of ∼28 bpm, which shortened QTcF similarly in both groups. After intake of beta-blockers, heart rate dropped to 28 ± 2 bpm in LQTS1 patients and 20 ± 3 bpm in LQTS2, resulting in a slower heart rate in LQTS1 compared with LQTS2 (P = .01). In response, QTcF shortened similarly in LQTS1 and LQTS2 patients (57 ± 9 ms vs 36 ± 7 ms; P = .10). CONCLUSION: When exposed to noise, LQTS2 patients had QTc prolonged significantly more than did LQTS1 patients. Importantly, beta-blockers reduced noise-induced QTc prolongation in LQTS2 patients, thus demonstrating the protective effect of beta-blockers. In response to simulated diving, LQTS groups responded similarly, but a slower heart rate was observed in LQTS1 patients during simulated diving after beta-blocker intake.

Electrical Stimulation of the Infraorbital Nerve Induces Diving Reflex in a Dose-Controlled Manner.

The "diving reflex" (DR) is a very powerful autonomic reflex that facilitates survival in hypoxic/anoxic conditions and could trigger multifaceted physiologic effects for the treatment of various diseases by modulating the cardiovascular, respiratory, and nervous systems. The DR can be induced by cold water or noxious gases applied to the anterior nasal mucosa and paranasal regions, which can stimulate trigeminal thermo- or chemo-receptors to send afferent signals to medullary nuclei which mediate the sympathetic and parasympathetic nervous systems. Although promising, these approaches have yet to be adopted in routine clinical practice due to the inability to precisely control exposure-response relationships, lack of reproducibility, and difficulty implementing in a clinical setting. In this study, we present the ability of electrical Trigeminal (Infraorbital) Nerve Stimulation (eTINS) to induce the DR in a dose-controllable manner. We found that eTINS not only triggered specific physiological changes compatible with the pattern of "classic" DR observed in animals/humans, but also controlled the induced-DR at varying levels. This study demonstrates, for the first time, that the intensity of the DR is controllable by dose and opens possibility to investigate its protective mechanism against various pathologies in well-controlled research settings.

A robust diving response in the laboratory mouse.

The diving response is a coordinated physiological response to submersion under water and has been documented amongst all mammals tested to date. The physiological response consists of three primary reflexes: an immediate bradycardia, apnea, and selective constriction of peripheral blood vessels. We hypothesized that mice would exhibit a diving response upon voluntary submersion into water typically seen in other mammals. In this study, telemeters that measure arterial pressure were implanted into male and female C57Bl/6J mice. These mice were trained to voluntarily dive underwater for a distance of 40 cm over a 4-6 s period. Just before the dive, the interbeat interval (IBI) was 87 ± 6 ms (mean ± SD) and diastolic pressure was 99 ± 14 mmHg. Underwater submersion caused (1) a dramatic bradycardia immediately at the onset of each dive, as IBI increased to 458 ± 104 ms, and (2) a large drop in diastolic pressure, to 56 ± 16 mmHg despite the elevation in peripheral resistance. Mice experienced a short bout (~ 2 s) of hypertension (diastolic pressure rose to 131 ± 17 mmHg) upon emergence. The bradycardia and hypotension appeared to be vagally mediated, since both these responses were blocked with atropine pre-treatment. These data demonstrate that the mouse exhibits a robust diving response upon voluntary submersion into water.

Shining new light on mammalian diving physiology using wearable near-infrared spectroscopy.

Investigation of marine mammal dive-by-dive blood distribution and oxygenation has been limited by a lack of noninvasive technology for use in freely diving animals. Here, we developed a noninvasive near-infrared spectroscopy (NIRS) device to measure relative changes in blood volume and haemoglobin oxygenation continuously in the blubber and brain of voluntarily diving harbour seals. Our results show that seals routinely exhibit preparatory peripheral vasoconstriction accompanied by increased cerebral blood volume approximately 15 s before submersion. These anticipatory adjustments confirm that blood redistribution in seals is under some degree of cognitive control that precedes the mammalian dive response. Seals also routinely increase cerebral oxygenation at a consistent time during each dive, despite a lack of access to ambient air. We suggest that this frequent and reproducible reoxygenation pattern, without access to ambient air, is underpinned by previously unrecognised changes in cerebral drainage. The ability to track blood volume and oxygenation in different tissues using NIRS will facilitate a more accurate understanding of physiological plasticity in diving animals in an increasingly disturbed and exploited environment.

Diving responses elicited by nasopharyngeal irrigation mimic seizure-associated central apneic episodes in a rat model.

The spread of epileptic seizure activity to brainstem respiratory and autonomic regions can elicit episodes of obstructive apnea and of central apnea with significant oxygen desaturation and bradycardia. Previously, we argued that central apneic events were not consequences of respiratory or autonomic activity failure, but rather an active brainstem behavior equivalent to the diving response resulting from seizure spread. To test the similarities of spontaneous seizure-associated central apneic episodes to evoked diving responses, we used nasopharyngeal irrigation with either cold water or mist for 10 or 60 s to elicit the diving response in urethane-anesthetized animals with or without kainic acid-induced seizure activity. Diving responses included larger cardiovascular changes during mist stimuli than during water stimuli. Apneic responses lasted longer than 10 s in response to 10 s stimuli or about 40 s in response to 60 s stimuli, and outlasted bradycardia. Repeated 10 s mist applications led to an uncoupling of the apneic episodes (which always occurred) from the bradycardia (which became less pronounced with repetition). These uncoupled events matched the features of observed spontaneous seizure-associated central apneic episodes. The duration of spontaneous central apneic episodes correlated with their frequency, i.e. longer events occurred when there were more events. Based on our ability to replicate the properties of seizure-associated central apneic events with evoked diving responses during seizure activity, we conclude that seizure-associated central apnea and the diving response share a common neural basis and may reflect an attempt by brainstem networks to protect core physiology during seizure activity.

Cardiac Arrest and Death Attributable to the "Diving Response" Triggered During Incision and Debridement of an Abscess of the Forehead.

The authors discuss about a patient who, while undergoing a routine procedure to drain a subcutaneous abscess within his forehead, suffered cardiac arrest that we conclude was caused by an activation of the diving response. This reflex affects homeostatic function which alters respiration and preferentially distributes oxygen stores to the heart and brain. Under some conditions, however, this reflex can also trigger cardiovascular collapse and death. The diving reflex is can begin with triggering receptors that are sensitive to cold water, submersion, or pressure within the nasal cavity and other areas supplied by the trigeminal nerve. Studies have shown that this afferent response primarily involves branches of the infraorbital nerve and the anterior ethmoidal nerve. However, other more superior nerves such as those exclusive to the forehead region may also be involved. This study demonstrates for the first time the risks and dangers involved in surgical procedures or manipulation of the trigeminal innervated areas of the human face and in particular the forehead.

Cardiovascular response to trigeminal nerve stimulation at rest and during exercise in humans: does sex matter?

We sought to investigate the possibility that there are sex differences in the cardiovascular responses to trigeminal nerve stimulation (TGS) with cold exposure to the face at rest and during dynamic exercise. In 9 healthy men (age: 28 ± 3 yr; height: 178 ± 1 cm; weight: 77 ± 8 kg) and 13 women (age 26 ± 5 yr; height 164 ± 3 cm; weight 63 ± 7 kg) beat-to-beat heart rate (HR) and blood pressure were recorded. Mean arterial pressure (MAP), stroke volume (SV), cardiac index (CI), and total vascular resistance index (TVRI) were calculated. TGS was applied for 3 min at rest and in-between 10-min steady-state cycling exercise at a HR of 110 beats/min, the measurements were obtained during the last minute of each period. At rest, TGS increased MAP (men: Δ18 ± 8 mmHg; women: Δ23 ± 8 mmHg; means ± SD), TVRI (men: Δ1.1 ± 0.6 mmHg·l-1·min·m-2; women: Δ1.2 ± 1.2 mmHg·l-1·min·m-2) and SV (men: Δ19 ± 15 ml; women: Δ16 ± 11 ml) in both groups. CI increased with TGS in women but not in men. However, men presented a bradycardic response to TGS (Δ-11 ± 8 beats/min) that was not significant in women compared with baseline. Cycling exercise increased HR, MAP, SV, and CI and decreased TVRI in men and women. TGS during exercise further increased MAP in men and women and did not change CI in either group. SV and TVRI increased with TGS during exercise only in women. TGS during exercise evoked bradycardia in men (Δ-7 ± 9 beats/min), whereas HR was unchanged in women. Our findings indicate sex differences in TGS-related cardiovascular responses at rest and during exercise.

The diving reflex and asphyxia: working across species in physiological ecology.

Beginning in the mid-1930s the comparative physiologists Laurence Irving and Per Fredrik (Pete) Scholander pioneered the study of diving mammals, particularly harbor seals. Although resting on earlier work dating back to the late nineteenth century, their research was distinctive in several ways. In contrast to medically oriented physiology, the approaches of Irving and Scholander were strongly influenced by natural history, zoology, ecology, and evolutionary biology. Diving mammals, they argued, shared the cardiopulmonary physiology of terrestrial mammals, but evolution had modified these basic adaptive processes in extreme ways. In particular, seals' remarkable ability to hold breath, lower metabolism, produce energy anaerobically, and resist asphyxiation, provided a sharp contrast with terrestrial mammals, including humans. This diving physiology was an extreme elaboration of a general regulatory mechanism that allowed seals and other diving mammals to remain active underwater for extended periods. The decrease in heart rate referred to as bradycardia or the "diving reflex" was highly developed in diving mammals, but also found in less developed form in many other organisms faced by asphyxia. It therefore served as a kind of "master switch" for lowering metabolism in diving, hibernation, parturition, drowning, and other physiological responses involving lack of oxygen. Studying bradycardia unified a wide diversity of physiological phenomena, while also providing a context for contrasting the physiological responses of various species, including humans. Conducted in the laboratory and the field, this research served as a bridge between a comparative physiological ecology focused on non-human species and a human-centered general physiology.

How important is the CO2 chemoreflex for the control of breathing? Environmental and evolutionary considerations.

Haldane and Priestley (1905) discovered that the ventilatory control system is highly sensitive to CO2. This "CO2 chemoreflex" has been interpreted to dominate control of resting arterial PCO2/pH (PaCO2/pHa) by monitoring PaCO2/pHa and altering ventilation through negative feedback. However, PaCO2/pHa varies little in mammals as ventilation tightly couples to metabolic demands, which may minimize chemoreflex control of PaCO2. The purpose of this synthesis is to (1) interpret data from experimental models with meager CO2 chemoreflexes to infer their role in ventilatory control of steady-state PaCO2, and (2) identify physiological causes of respiratory acidosis occurring normally across vertebrate classes. Interestingly, multiple rodent and amphibian models with minimal/absent CO2 chemoreflexes exhibit normal ventilation, gas exchange, and PaCO2/pHa. The chemoreflex, therefore, plays at most a minor role in ventilatory control at rest; however, the chemoreflex may be critical for recovering PaCO2 following acute respiratory acidosis induced by breath-holding and activity in many ectothermic vertebrates. An apparently small role for CO2 feedback in the genesis of normal breathing contradicts the prevailing view that central CO2/pH chemoreceptors increased in importance throughout vertebrate evolution. Since the CO2 chemoreflex contributes minimally to resting ventilation, these CO2 chemoreceptors may have instead decreased importance throughout tetrapod evolution, particularly with the onset and refinement of neural innovations that improved the matching of ventilation to tissue metabolic demands. This distinct and elusive "metabolic ventilatory drive" likely underlies steady-state PaCO2 in air-breathers. Uncovering the mechanisms and evolution of the metabolic ventilatory drive presents a challenge to clinically-oriented and comparative respiratory physiologists alike.

Seizure-associated central apnea in a rat model: Evidence for resetting the respiratory rhythm and activation of the diving reflex.

Respiratory derangements, including irregular, tachypnic breathing and central or obstructive apnea can be consequences of seizure activity in epilepsy patients and animal models. Periods of seizure-associated central apnea, defined as periods >1s with rapid onset and offset of no airflow during plethysmography, suggest that seizures spread to brainstem respiratory regions to disrupt breathing. We sought to characterize seizure-associated central apneic episodes as an indicator of seizure impact on the respiratory rhythm in rats anesthetized with urethane and given parenteral kainic acid to induce recurring seizures. We measured central apneic period onsets and offsets to determine if onset-offset relations were a consequence of 1) a reset of the respiratory rhythm, 2) a transient pausing of the respiratory rhythm, resuming from the pause point at the end of the apneic period, 3) a transient suppression of respiratory behavior with apnea offset predicted by a continuation of the breathing pattern preceding apnea, or 4) a random re-entry into the respiratory cycle. Animals were monitored with continuous ECG, EEG, and plethysmography. One hundred ninety central apnea episodes (1.04 to 36.18s, mean: 3.2±3.7s) were recorded during seizure activity from 7 rats with multiple apneic episodes. The majority of apneic period onsets occurred during expiration (125/161 apneic episodes, 78%). In either expiration or inspiration, apneic onsets tended to occur late in the cycle, i.e. between the time of the peak and end of expiration (82/125, 66%) or inspiration (34/36, 94%). Apneic period offsets were more uniformly distributed between early and late expiration (27%, 34%) and inspiration (16%, 23%). Differences between the respiratory phase at the onset of apnea and the corresponding offset phase varied widely, even within individual animals. Each central apneic episode was associated with a high frequency event in EEG or ECG records at onset. High frequency events that were not associated with flatline plethysmographs revealed a constant plethysmograph pattern within each animal, suggesting a clear reset of the respiratory rhythm. The respiratory rhythm became highly variable after about 1s, however, accounting for the unpredictability of the offset phase. The dissociation of respiratory rhythm reset from the cessation of airflow also suggested that central apneic periods involved activation of brainstem regions serving the diving reflex to eliminate the expression of respiratory movements. This conclusion was supported by the decreased heart rate as a function of apnea duration. We conclude that seizure-associated central apnea episodes are associated with 1) a reset of the respiratory rhythm, and 2) activation of brainstem regions serving the diving reflex to suppress respiratory behavior. The significance of these conclusions is that these details of seizure impact on brainstem circuitry represent metrics for assessing seizure spread and potentially subclassifying seizure patterns.

Genetic determination of the vascular reactions in humans in response to the diving reflex.

The purpose of this study was to investigate the genetic mechanisms of the defense vascular reactions in response to the diving reflex in humans with polymorphisms in the genes ADBR2, ACE, AGTR1, BDKRB2, and REN We hypothesized that protective vascular reactions, in response to the diving reflex, are genetically determined and are distinguished in humans with gene polymorphisms of the renin-angiotensin and kinin-bradykinin system. A total of 80 subjects (19 ± 1.4 yr) participated in the study. The intensity of the vascular response was estimated using photoplethysmogram. The I/D polymorphism (rs4340) of ACE was analyzed by PCR. REN (G/A, rs2368564), AGTR1 (A/C, rs5186), BDKRB2 (T/C, rs1799722), and ADBR2 (A/G, rs1042713) polymorphisms were examined using the two-step multiplex PCR followed by carrying allele hybridization on the biochip. Subjects with the BDKRB2 (C/C), ACE (D/D), and ADBR2 (G/G, G/A) genotypes exhibited the strongest peripheral vasoconstriction in response to diving. In subjects with a combination of the BDKRB2 (C/C) plus ACE (D/D) genotypes, we observed the lowest pulse wave amplitude and pulse transit time values and the highest arterial blood pressure during face immersion compared with the heterozygous individuals, suggesting that these subjects are more susceptible to diving hypoxia. This study observed that humans with gene polymorphisms of the renin-angiotensin and kinin-bradykinin systems demonstrate various expressions of protective vascular reactions in response to the diving reflex. The obtained results might be used in estimation of resistance to hypoxia of any origin in human beings or in a medical practice.NEW & NOTEWORTHY Our study demonstrates that the vascular reactions in response to the diving reflex are genetically determined and depend on gene polymorphisms of the kinin-bradykinin and the renin-angiotensin systems.