Biomedical subjects

Thomas E Dick

Publications and source records attributed to Thomas E Dick.

12 recordsLinked to original sources

PubMed2006

Acute intermittent hypoxia increases both phrenic and sympathetic nerve activities in the rat.

The respiratory system expresses multiple forms of plasticity, defined as alterations in the breathing pattern that persist or develop after a stimulus. Stimulation of breathing with intermittent hypoxia (IH) elicits long-term facilitation (LTF), a type of plasticity in which respiratory motor activity progressively increases in anaesthetized animals, even after the stimuli have ceased and blood gases have normalized. It is unknown whether the sympathetic nervous system similarly expresses IH-induced plasticity, but we predicted that IH would evoke LTF in sympathetic nerve activity (SNA) because respiratory and sympathetic control systems are coupled. To test this idea, we recorded splanchnic (sSNA) and phrenic nerve activities (PNA) in equithesin-anaesthetized rats. Animals were exposed to 10 45 s episodes of 8% O(2)-92% N(2), separated by 5 min intervals of 100% O(2), and recordings were continued for 60 min following the last hypoxic exposure. Cycle-triggered averages of integrated PNA and sSNA from periods preceding, and 5 and 60 min following the hypoxic stimuli were compared. Intermittent hypoxia significantly increased both sSNA and PNA. Treatment with methysergide (3 mg kg(-1), i.v.) 20 min before the intermittent hypoxic exposures prevented the increases in integrated PNA and sSNA 60 min after IH, indicating a role of serotonergic pathways in this form of plasticity. No increases in PNA and sSNA occurred at comparable times (60 and 120 min) in rats not exposed to hypoxia. The increased sSNA was not simply tonic, but was correlated with respiratory bursts, and occurred predominantly during the first half of expiration. These findings support the hypothesis that sympathorespiratory coupling may underlie the sustained increase in SNA associated with the IH that occurs during sleep apnoea.

Acute Disease↗

PubMed2006

Systemic, cellular and molecular analysis of chemoreflex-mediated sympathoexcitation by chronic intermittent hypoxia.

Patients with recurrent apnoeas exhibit autonomic abnormalities manifested as persistent increase in sympathetic nerve activity (SNA). Several studies suggest that chronic intermittent hypoxia (CIH) resulting from recurrent apnoeas is a major stimulus for evoking autonomic morbidity. Although it has been proposed that CIH, by way of activating the chemoreceptor reflex, leads to sympathetic excitation, the underlying mechanisms are incompletely understood. Studies on experimental models have provided new insights into the mechanisms associated with CIH-evoked sympathoexcitation. The purpose of this article is to highlight recent information on systemic, cellular and molecular analysis of the effects of CIH on chemoreceptor-mediated sympathoexcitation. Chronic intermittent hypoxia exerts two major effects on the chemoreceptor reflex: (a) augmentation of the carotid body and sympathetic effector responses to acute hypoxia; and (b) induction of long-lasting activation of both the sensor and the effector that persists several hours after termination of CIH. Available evidence indicates that CIH may facilitate processing of chemoreceptor afferent information at the central nervous system. Recent studies suggest that reactive oxygen species-mediated signalling is a major cellular mechanism, and transcriptional activation by hypoxia-inducible factor-1 is one of the critical molecular mechanisms underlying chemoreceptor-mediated sympathoexcitation by CIH.

Animals↗

PubMed2006

Effects of pulse lung inflation on chest wall expiratory motor activity.

The effects of pulse lung inflation (LI) on expiratory muscle activity and phase duration (Te) were determined in anesthetized, spontaneously breathing dogs (n = 20). A volume syringe was used to inflate the lungs at various times during the expiratory phase. The magnitude of lung volume was assessed by the corresponding change in airway pressure (Paw; range 2-20 cmH(2)O). Electromyographic (EMG) activities were recorded from both thoracic and abdominal muscles. Parasternal muscle EMG was used to record inspiratory activity. Expiratory activity was assessed from the triangularis sterni (TS), internal intercostal (IIC), and transversus abdominis (TA) muscles. Lung inflations <7 cmH(2)O consistently inhibited TS activity but had variable effects on TA and IIC activity and expiratory duration. Lung inflations resulting in Paw values >7 cmH(2)O, however, inhibited expiratory EMG activity of each of the expiratory muscles and lengthened Te in all animals. The responses of expiratory EMG and Te were directly related to the magnitude of the lung inflation. The inhibition of expiratory motor activity was independent of the timing of pulse lung inflation during the expiratory phase. The inhibitory effects of lung inflation were eliminated by bilateral vagotomy and could be reproduced by electrical stimulation of the vagus nerve. We conclude that pulse lung inflation resulting in Paw between 7 and 20 cmH(2)O produces a vagally mediated inhibition of expiratory muscle activity that is directly related to the magnitude of the inflation. Lower inflation pressures produce variable effects that are muscle specific.

Anesthetics↗

PubMed2006

Domperidone and ventilatory behavior: Sprague-Dawley versus Brown Norway rats.

Domperidone, a dopamine D(2) receptor antagonist, is a tool for uncovering the tonic and dynamic effects of the peripheral dopaminergic system in unanesthestized animals. The hypothesis was that domperidone effects would vary between strains of the same species. Ventilatory behavior -- frequency and minute ventilation -- was measured by the plethysmographic method in unrestrained adult male Sprague-Dawley (SD: n=8) and Brown Norway (BN: n=8) rats before, during and after rapid transition to 100% O(2) after 5 min of 13% O(2)/3% CO(2). Tests were done 60 min after intraperitoneal injection of either vehicle (0.1% lactic acid in saline) or a dose of domperidone (0.1, 0.5, 1.0, or 5.0mg/kg) dissolved in vehicle, each on a separate day. Resting frequency and minute ventilation (mean+/-standard deviation) decreased after domperidone in the BN strain (e.g. 94.63/min+/-4.99 versus 87.37/min+/-9.59, p=0.42; 77.3 ml/min+/-9.25 versus 62.13 ml/min+/-11.5, p=0.019, respectively), but did not change in the SD. With increasing doses of domperidone the ventilatory response to hypoxia and reoxygenation became similar owing to a decrease in frequency and minute ventilation in the SD. At a dose altering SD hypoxic responses, the hypercapnic ventilatory response was not significantly affected. In conclusion, breathing frequency and minute ventilation over a challenge with hypoxia and reoxygenation differ with domperidone depending upon genetic background. We speculate that hypoxic ventilatory responses may be differently configured even among strains of the same species.

Animals↗

PubMed2005

Arterial pulse modulated activity is expressed in respiratory neural output.

Although it is well-established that sympathetic activity is modulated with respiration, it is unknown whether neural control of respiration is reciprocally influenced by cardiovascular function. Even though previous studies have suggested the existence of pulse modulation in respiratory neurons, they could not exclude the possibility that such cells were involved in cardiovascular rather than respiratory motor control, owing to neuroanatomic and functional overlaps between brain stem neurons involved in respiratory and cardiovascular control. The aim of this study was to test the hypothesis that respiratory motoneurons and putative premotoneurons are modulated by arterial pulse. An existing data set composed of 72 well-characterized, respiratory-modulated brain stem motoneurons and putative premotoneurons was analyzed using delta(2), a recently described statistic that quantifies the magnitude of arterial pulse-modulated spike activity [Dick TE and Morris KF. J Physiol 556: 959-970, 2004]. Neuronal activity was recorded in the rostral and caudal ventral respiratory groups of 19 decerebrate, neuromuscular-blocked, ventilated cats. Axonal projections were identified by rectified and unrectified spike-triggered averages of recurrent laryngeal nerve activity or by antidromic activation from spinal stimulation electrodes. The firing rates of approximately 30% of these neurons were modulated in phase with both the respiratory and cardiac cycles. Furthermore, arterial pulse modulation occurred preferentially in the expiratory phase in that only expiratory neurons had high delta(2) values and only expiratory activity had significant delta(2) values after partitioning tonic activity into the inspiratory and expiratory phases. The results demonstrate that both respiratory motoneurons and putative premotoneuronal activity can be pulse modulated. We conclude that a cardiac cycle-related modulation is expressed in respiratory motor activity, complementing the long-recognized respiratory modulation of sympathetic nerve activity.

Action Potentials↗

PubMed2004

Pontine GABAergic pathways: role and plasticity in the hypoxic ventilatory response.

The hypoxic ventilatory response (HVR) was compared before and after uni- and bi-lateral injections of bicuculline, a GABA(A) receptor antagonist, into the ventrolateral (vl) pons and before and after conditioning animals to chronic sustained hypoxia (CSH). The HVR was assessed by recording phrenic nerve activity (PNA) during and after brief exposures to hypoxia (8% O(2) and 92% N(2) for 45s). Inspiratory (T(I)) and expiratory (T(E)) durations were averaged before hypoxia, at the peak breathing frequency during hypoxia, before the end of hypoxia, immediately after hypoxia, and 60s after hypoxia. Blocking GABA(A) receptors in the vl pons prolonged T(E) during, but not after hypoxia. After CSH induced by 14 days in a hypobaric chamber (0.5atm), the HVR was attenuated compared to that in the naive animals. This plasticity of HVR was associated with selective induction of alpha6 and delta GABA(A) receptor subunit mRNAs specifically in the pons compared to the medulla. These physiological and molecular results illustrate the importance of pontine GABAergic pathways in shaping the response to hypoxia.

Action Potentials↗

PubMed2004

Entrainment pattern between sympathetic and phrenic nerve activities in the Sprague-Dawley rat: hypoxia-evoked sympathetic activity during expiration.

Sympathetic and respiratory motor activities are entrained centrally. We hypothesize that this coupling may partially underlie changes in sympathetic activity evoked by hypoxia due to activity-dependent changes in the respiratory pattern. Specifically, we tested the hypothesis that sympathetic nerve activity (SNA) expresses a short-term potentiation in activity after hypoxia similar to that expressed in phrenic nerve activity (PNA). Adult male, Sprague-Dawley (Zivic Miller) rats (n = 19) were anesthetized (Equithesin), vagotomized, paralyzed, ventilated, and pneumothoracotomized. We recorded PNA and splanchnic SNA (sSNA) and generated cycle-triggered averages (CTAs) of rectified and integrated sSNA before, during, and after exposures to hypoxia (8% O(2) and 92% N(2) for 45 s). Inspiration (I) and expiration (E) were divided in half, and the average and area of integrated sSNA were calculated and compared at the following time points: before hypoxia, at the peak breathing frequency during hypoxia, immediately before the end of hypoxia, immediately after hypoxia, and 60 s after hypoxia. In our animal model, sSNA bursts consistently followed the I-E phase transition. With hypoxia, sSNA increased in both halves of E, but preferentially in the second rather than the first half of E, and decreased in I. After hypoxia, sSNA decreased abruptly, but the coefficient of variation in respiratory modulation of sSNA was significantly less than that at baseline. The hypoxic-evoked changes in sympathetic activity and respiratory pattern resulted in sSNA in the first half of E being correlated negatively to that in the second half of E (r = -0.65, P < 0.05) and positively to Te (r = 0.40, P < 0.05). Short-term potentiation in sSNA appeared not as an increase in the magnitude of activity but as an increased consistency of its respiratory modulation. By 60 s after hypoxia, the variability in the entrainment pattern had returned to baseline. The preferential recruitment of late expiratory sSNA during hypoxia results from either activation by expiratory-modulated neurons or by non-modulated neurons whose excitatory drive is not gated during late E.

Animals↗

PubMed2004

Quantitative analysis of cardiovascular modulation in respiratory neural activity.

We propose the 'delta(2)-statistic' for assessing the magnitude and statistical significance of arterial pulse-modulated activity of single neurones and present the results of applying this tool to medullary respiratory-modulated units. This analytical tool is a modification of the eta(2)-statistic and, consequently, based on the analysis of variance. The eta(2)-statistic reflects the consistency of respiratory-modulated activity on a cycle-by-cycle basis. However, directly applying this test to activity during the cardiac cycle proved ineffective because subjects-by-treatments matrices did not contain enough 'information'. We increased information by dividing the cardiac cycle into fewer bins, excluding cycles without activity and summing activity over multiple cycles. The analysed neuronal activity was an existing data set examining the neural control of respiration and cough. Neurones were recorded in the nuclei of the solitary tracts, and in the rostral and caudal ventral respiratory groups of decerebrate, neuromuscularly blocked, ventilated cats (n= 19). Two hundred of 246 spike trains were respiratory modulated; of these 53% were inspiratory (I), 36.5% expiratory (E), 6% IE phase spanning and 4.5% EI phase spanning and responsive to airway stimulation. Nearly half (n= 96/200) of the respiratory-modulated units were significantly pulse modulated and 13 were highly modulated with delta(2) values exceeding 0.3. In 10 of these highly modulated units, eta(2) values were greater than 0.3 and all 13 had, at least, a portion of their activity during expiration. We conclude that cardiorespiratory interaction is reciprocal; in addition to respiratory-modulated activity in a subset of neuronal activity patterns controlling the cardiovascular system, pulse-modulated activity exists in a subset of neuronal activity patterns controlling the respiratory system. Thus, cardio-ventilatory coupling apparent in respiratory motor output is evident and, perhaps, derived from the neural substrate driving that output.

Action Potentials↗

PubMed2004

Strain differences in murine ventilatory behavior persist after urethane anesthesia.

Differences in breathing pattern between awake C57BL/6J (B6) and A/J mice are such that A/J mice breathe slower, deeper, and with greater variability than B6. We theorized that urethane anesthesia, by affecting cortical and subcortical function, would test the hypothesis that strain differences require a fully functional neuroaxis. We anesthetized B6 and A/J mice with urethane, placed them in a whole-body plethysmograph, and measured the durations of inspiration and expiration, respiratory frequency (Fr), and peak amplitude during exposure to room air (21% O2), hyperoxia (5 min, 100% O2), hypoxia (5 min, 8% O2), and posthypoxic reoxygenation (5 min, 100% O2). Breathing variability was assessed by calculating the coefficient of variation (CV) and by applying spatial statistics to Poincaré plots constructed from the timing and amplitude data. Even though Fr in anesthetized B6 and A/J mice was greater than that for unanesthetized animals, anesthetized A/J mice still breathed slower, deeper, and with greater variability than B6 mice at rest and during hyperoxia. During the fourth minute of hypoxia, Fr and its CV were not significantly different between strains. Even though Fr was similar between strains immediately after hypoxia, its CV was significantly greater for B6 than A/J mice. Posthypoxic Fr was significantly less than baseline Fr in B6 but not A/J mice, and the CV for posthypoxic Fr was greater for B6 but less for AJ mice compared with baseline CV. This difference in patterning was confirmed by spatial statistical analysis. We conclude that strain-specific differences in respiratory pattern and its variability are robust genetic traits. The neural substrate for these differences, at least partially, exists within subcortical structures generating the breathing pattern.

Anesthetics, Intravenous↗

PubMed2003

7-nitroindazole and posthypoxic ventilatory behavior in the A/J and C57BL/6J mouse strains.

Periodic breathing (PB) is a fundamental breathing pattern in many common cardiopulmonary illnesses. The finding of PB in C57BL/6J (B6) mice was previously ascribed to strain differences in posthypoxic ventilatory and frequency decline in the B6 mice (Han F, Subramanian S, Price ER, Nadeau J, and Strohl KP. J Appl Physiol 92: 1133-1140, 2002). We tested whether the induction of posthypoxic frequency decline in A/J mice, through administration of a neuronal nitric oxide synthase blocker [7-nitroindazole (7-NI); 60 mg/kg], would cause A/J mice to exhibit PB and/or alter PB expression in the B6 strain. Recordings of ventilatory behavior by the plethysmography method were made when unanesthetized B6 (n = 10) or A/J (n = 6) animals were reoxygenated with 100% O2 or room air after exposure to 8% O2. Before undergoing gas challenges, mice were given an intraperitoneal injection of either peanut oil alone (vehicle) or 7-NI suspended in peanut oil. Compared with vehicle, both strains of mice exhibited posthypoxic frequency decline and the absence of short-term potentiation with 7-NI administration. B6 mice continued to exhibit posthypoxic PB; however, the PB was characterized by longer cycle and apnea length. In contrast, A/J mice did not show increased tendency toward posthypoxic PB with 7-NI. We conclude that 7-NI further differentiates the A/J and B6 strains in terms of PB and that strain-related differences in posthypoxic frequency decline are not primary determinants of this strain difference in the occurrence of PB. Metabolism was not associated with either the expression of posthypoxic ventilatory decline or PB. Furthermore, neuronal nitric oxide may be an organizing feature in the presence, length, and/or cycle length of apnea in the susceptible strain.

Animals↗

PubMed2002

L-NAME differentially alters ventilatory behavior in Sprague-Dawley and Brown Norway rats.

Nitric oxide (NO) is a regulating factor in respiration. The question was whether NO synthase (NOS) blockade would affect posthypoxic ventilatory behavior similarly in two rat strains with known differences in steady-state hypoxic and hypercapnic responses and in posthypoxic ventilatory behavior. Ventilatory behavior [respiratory frequency (f) and minute ventilation (VE)] was measured by body plethysmography on unanesthetized, unrestrained adult male Sprague-Dawley (SD; n = 8) and Brown Norway rats (BN; n = 8) at baseline and 1 min after rapid transition to 100% O(2) after 5 min of isocapnic hypoxia (10% O(2)-3% CO(2)-balance N(2)). Testing was performed 30 min after intraperitoneal injection of either saline (vehicle) or 100 mg/kg of N(G)-nitro-L-arginine methyl ester (L-NAME). Resting f and VE increased after L-NAME in both strains, more markedly in SD compared with BN (77 vs. 47% for f, and 42 vs. 16% for VE, respectively; P < 0.05). With vehicle, posthypoxic f and VE decline (Dejours phenomenon) was present only in BN and was absent in SD. With L-NAME, the Dejours phenomena were still present in BN but also were apparent in SD (f: 95.3 vs. 134.4 beats/min at baseline; VE: 66.3 vs. 88.8 ml/min at baseline; P < 0.05). Thus NOS blockade results in a strain-specific alteration in resting ventilation and uncovers the Dejours phenomenon in the SD strain.

Animals↗

PubMedDate not supplied

Cardiovascular alterations by chronic intermittent hypoxia: importance of carotid body chemoreflexes.

1. Humans experiencing intermittent hypoxia (IH) owing to recurrent apnoea syndromes exhibit serious cardiovascular morbidity, including high blood pressure, increased sympathetic nerve activity, cardiac arrhythmia and myocardial infarction. Although apnoeas are accompanied by a simultaneous decrease in arterial O(2) (hypoxia) and an increase in CO(2) (hypercapnia), studies on experimental animals suggest that hypoxia, rather than hypercapnia, is the primary stimulus for developing hypertension and enhanced sympathetic nerve activity. Enhanced hypoxic-sensing ability of the carotid bodies and the ensuing reflex activation of the sympathetic nervous system have been suggested to play a critical role in cardiorespiratory alterations resulting from recurrent apnoeas. 2. The purpose of the present review is to highlight recent studies demonstrating the effects of IH on carotid body sensory activity and its consequences on sympathetic activation in a rodent model of chronic IH. Adult rats exposed to chronic IH (15 s of 5% O(2) followed by 5 min of 21% O(2), nine episodes per h, 8 h/day for 10 days) exhibited selective enhancement of carotid body sensory response to hypoxia. In addition, chronic IH induced a novel form of sensory plasticity in the carotid body, manifested as sensory long-term facilitation (LTF). Functional changes in the carotid body occurred in the absence of morphological changes in the chemoreceptor tissue. 3. Acute hypoxia increased expiratory modulated splanchnic nerve activity (SNA) and acute IH-induced LTF in SNA. Hypoxia-induced SNA activation was prevented by bilateral sectioning of the sinus nerves. Rats exposed to chronic IH exhibited enhanced hypoxia-induced sympathetic activation and augmented LTF of the SNA. Bilateral sectioning of the sinus nerves abolished these responses, suggesting chronic IH-induced alterations in carotid body sensitivity contribute to LTF in SNA and the subsequent cardiovascular alterations.

Animals↗