bluuebunny/crossref_metadata_2025_split huggingface dataset:
Sex Differences in Cough Responses of Cats
Authors: Rose Melanie J , Shen Tabitha Y , Musselwhite M. Nicholas , Pitts Teresa G , Bolser Donald C 
Published: November 2023

In humans, women are more debilitated by chronic coughing, report to physicians for cough more frequently, and have a greater cough sensitivity than men. These sex differences between men and women begin to emerge at the end of puberty. We conducted a retrospective analysis in anesthetized cats to determine if sex differences could be identified in an animal model that is capable of intense repetitive coughing. Anesthetized cats (13 males, 10 females) were tracheotomized and allowed to breathe spontaneously. Electromyograms of parasternal, transversus abdominis/internal oblique, and laryngeal adductor muscles were recorded. Esophageal pressure (Pes) was recorded via small balloon placed in the midthoracic esophagus. Cough was induced by mechanical stimulation of the intrathoracic trachea with a small polyethylene tube via the trachea cannula. We evaluated the cough response before and after a protocol consisting of 20 consecutive mechanical stimulation trials separated by approximately one minute. This adaptation protocol typically results in a depression of coughing by approximately 50% with the subsequent cough response remaining stable for extended periods of time. There was no difference in the number of trials in the adaptation protocol between males and females (20±1 males, 20±1 females). Likewise, end tidal CO2, as an index of anesthetic level, did not differ between the groups (males 31±0.5, females 32±0.8). Cough frequency (CF‐number of coughs per second) declined significantly in both male and female cats during the adaptation protocol (males control CF 1.3±0.2, post adaptation CF‐0.8±0.1, P<0.001; females control CF‐1.0±0.06, post adaptation CF‐0.5±0.04, P<0.001). Control CF was not significantly different between males and females (P<0.2), but the post adaptation CF was higher in males (P<0.05). Pes declined significantly during the adaptation protocol in both males and females (males control 50±8 cm H2O, post adaptation 26±4 cm H2O, P<0.001; females control 22±3 cm H2O, post adaptation 14±3 cm H2O, P<0.04). Pes was higher in males both in the control period (P<0.05) and post adaptation (P<0.02). However, there was no significant difference between males and females when these changes were expressed as percentages or when normalized to body weight. The results indicate that sex differences in cough responses exist in this model of cough. Differences in cough intensity between sexes can be explained by body weight. CF is a metric of peripheral sensory and/or central excitability and females exhibit greater depression of coughing in a repetitive trial protocol than males. The mechanisms responsible for this sex difference are unknown.Support or Funding InformationNIH HL 103415 and 1OT20D001983
IL‐1R Activation Undermines Respiratory Plasticity
Authors: Hocker Austin Dean , Huxtable Adrianne G 
Published: November 2023

Despite a pervasive role for inflammation in ventilatory control disorders, we are only just beginning to understand the mechanisms by which inflammation undermines respiratory plasticity. Interleukin‐1 (IL‐1) signaling regulates plasticity in other central nervous system regions; promoting central pain in the spinal dorsal horn and inhibiting plasticity in the hippocampus. Thus, we tested the hypothesis that IL‐1 receptor (IL‐1R) activation during systemic inflammation undermines phrenic long‐term facilitation (pLTF), a model of respiratory plasticity induced by acute intermittent hypoxia. pLTF is reduced 24 hours after lipopolysaccharide (LPS; 100 mg/kg; i.p.) compared to control (12 ±8%, n=5; 57 ± 10%, n=6; respectively), similar to previously published studies. Importantly, pLTF is restored by peripheral IL‐1R antagonism (64 ± 6%; n=6; AF‐12198, i.p. 0.5 mg/kg, 24 hours) after LPS. Acute, spinal IL‐1R antagonism (1 mM AF‐12198 in aCSF; 15 mL; intrathecal) also restored pLTF (52 ± 16%; n=2) compared to LPS treated rats (9 ± 8%; n=3). These data suggest both peripheral and spinal IL‐1Rs play important roles in undermining pLTF after systemic inflammation. Understanding the inflammatory mechanisms inhibiting respiratory plasticity is crucial to developing treatment strategies to promote breathing during ventilatory control disorders.Support or Funding InformationSupported by Francis Families Foundation (AGH) and University of Oregon.
Effects of 5‐HT2 and A2A Antagonists on pERK and pAKT Levels in the NTS and Spinal Cord of Rats Exposed to Chronic Sustained Hypoxia
Authors: Moya Esteban A , Powell Frank L 
Published: November 2023

Different patterns of hypoxic exposure can result in long‐term changes of ventilation and the hypoxic ventilatory response. For example, acute intermittent hypoxia (AIH) causes long term facilitation (LTF) of ventilation and phrenic nerve activity, with an increased acute HVR and persistent increase in ventilation in normoxia after AIH. Others have shown that LTF involves plasticity in serotonin 5HT2 neurotransmission (Gq pathway) and A2A adenosine neurotransmission (Gs pathway) in the spinal cord. Chronic sustained hypoxia (CSH) also increases the acute HVR and ventilation remains greater than control when normoxia is restored, which is called ventilatory acclimatization to hypoxia (VAH). We previously showed VAH involves plasticity in the nucleus tractus solitarius (NTS). Here we tested the hypothesis that Gq and Gs signaling play similar roles in LTF and VAH. Systemic inhibition of the Gq pathway (5‐HT2 antagonist Ketanserin, 1 mg/Kg per day) and the Gs pathway (A2A receptor antagonist MSX‐3, 0.5 mg/Kg per day) administered with subcutaneous osmotic pumps during 7 days of CSH (inspired PO2 = 70 mm Hg) decreased but did not eliminate VAH in male adult rats. This is different than previous reports from other laboratories showing LTF is abolished by blocking the Gq pathway with ketanserin but increased by blocking the Gs pathway with MSX‐3 administered before exposure to moderate AIH. To understand the site of action of Gq and Gs effects on VAH, we collected tissue from (1) the NTS, and (2) the spinal cord (between C3 and C5). We used Western blots of pERK and pAKT to measure Gq and Gs activation, respectively, in 4 groups of rats (n≥6 each) administered drugs or vehicle (DMSO) for 7 days as previously described above for ventilation studies: CON = DMSO in normoxia, CSH = DMSO in hypoxia, KET = ketanserin in CSH, MSX = MSX‐3 in CSH. CSH decreased pERK and pAKT in the spinal cord but had no effect on them in the NTS, indicating Gq and Gs pathways respond differently to CSH in the NTS versus spinal cord. In the NTS, pERK decreased with KET but not MSX during CSH. In the spinal cord, MSX during CSH restored pERK and pAKT to normoxic CON levels. Effects of KET on pERK and pAKT in the spinal cord during CSH are not available yet. The data indicate the Gq and Gs signaling with CSH is different than previously reported for AIH in the spinal cord. Also, Gq signaling in the NTS may contribute to VAH. Further study is necessary to determine how such differences in Gq and Gs signaling in the NTS and spinal cord depend on specific neurons in these locations.Support or Funding InformationNIH RO1 HL‐081823
Hypoxic ventilatory response of developing rats exposed to chronic hypoxia at various ages
Authors: Song Monata , Benevides Ethan S. , Bavis Ryan W. 
Published: November 2023

The effects of chronic hypoxia on the hypoxic ventilatory response (HVR) reportedly differs in newborn versus adult rats: chronic hypoxia blunts the HVR in newborn rats but may enhance it in adult rats. To investigate the age at which this transition occurs, we exposed rats to 12% O2 for approximately 7 days beginning at birth (P0), P7, P14, or P21 and measured ventilation by head‐body plethysmography (P7 and P14) or whole‐body plethysmography (P21‐22 and P28‐29). Normoxic ventilation was greater after chronic hypoxia at all ages. Likewise, when expressed as a percentage of baseline ventilation, the HVR was significantly reduced by chronic hypoxia regardless of the age at which chronic hypoxia began. In the youngest groups (i.e., P7 and P14 when measured), we confirmed that the blunted HVR was at least partially explained by diminished carotid body responses to hypoxia (assessed from in vitro single‐unit chemoafferent activity). When initiated at birth, chronic hypoxia appears to delay the postnatal transition from a biphasic HVR to the sustained HVR characteristic of mature animals; in contrast, this effect was not observed when hypoxia began at P7 (i.e., after the HVR was nearly mature). We conclude that chronic hypoxia blunts the HVR across a wide age range in developing rats, but hypoxia may have age‐dependent effects on maturation of the HVR.Support or Funding InformationSupported by NIH grant P20 GM‐103423 (Maine INBRE).
Does reduced carotid body BDNF contribute to developmental hyperoxia‐induced respiratory plasticity?
Authors: Muscato Gwen M. , Kim Maria S. , McDonough Amy B. , Bavis Ryan W. 
Published: November 2023

Chronic exposure to moderate hyperoxia (60% O2) reduces carotid body expression of brain‐derived neurotrophic factor (BDNF) in neonatal rats. Reduced BDNF expression correlates with abnormal carotid body development and blunted hypoxic ventilatory responses, but a causal relationship has not been established. First, we used ELISA to confirm that both sustained and intermittent exposures to 60% O2 reduced carotid body BDNF levels; intermittent hypercapnic hypoxia had the opposite effect. Next, we attempted to block the effects of developmental hyperoxia by administering LM22A4 (50 mg kg−1, i.p., daily), an agonist for BDNF's TrkB receptor. After 7 days of treatment with 60% O2, carotid body volume and the hypoxic ventilatory response were significantly reduced in P7 rats that received either LM22A4 or vehicle (saline) from birth; the drug treatment did not attenuate this effect. Similar results were obtained using an alternate TrkB agonist, 7,8‐dihydroxyflavone (5 mg kg−1, i.p., daily). Although carotid body BDNF expression appears to be regulated by environmental O2, our data do not support the hypothesis that reduced BDNF is directly responsible for hyperoxia‐induced developmental plasticity in respiratory control.Support or Funding InformationSupported by NIH grant R15 HL‐114001.
Prenatal Nicotinic Exposure (PNE) Upregulates Pulmonary 5‐HT and Prolongs Bronchopulmonary C‐fiber (PCF)‐mediated Apnea via Acting on PCF 5‐HT3 in Rat Pups
Authors: Zhao Lei , Zhuang Jianguo , Gao Xiuping , Xu Fadi 
Published: November 2023

Our previous studies have shown a prolonged PCF‐mediated apnea by PNE in rat pups (J. Zhuang et al., Am J Physiol Lung Cell Mol Physiol. 2015), but the relevant mechanisms are not fully elucidated. It is already known that PCFs heavily express 5‐HT3 and its activation induces apneic response (B. J. Undem et al., J physiol. 2012). Thus, we asked if PNE would upregulate 5‐HT in BALF associated with 5‐HT3 upregulation in vagal pulmonary C‐neurons and if so, if these changes are involved in the PNE‐induced prolongation of the PCF‐mediated apnea. In P11– 14 rat pups, we compared: 1) 5‐HT content in BALF; 2) 5‐HT3 protein expression in the nodose ganglion and mRNA level in vagal pulmonary C‐neurons by using single cell RT‐PCR; and 3) the apneic response to right atrial bolus injection of phenylbiguanide (PBG, a selective 5‐HT3 agonist, 10 μg/kg) in Ctrl and PNE pups. Our results showed that PNE obviously increased 5‐HT in BALF and 5‐HT3 mRNA level in pulmonary C neurons (retrogradely labeled). Importantly, the apneic duration in response to PBG was significantly longer in PNE than Ctrl pups. We further tested the dependency of the 5‐HT3‐mediated apnea on PCFs and found that the apneic responses to PBG in both Ctrl and PNE pups were blocked by inactivating PCFs with perineural capsaicin treatment (500 μg/ml, 10 min). Our results suggest that PNE is capable of upregulating pulmonary 5‐HT that prolongs the PCF‐mediated apnea via acting on PCF 5‐HT3.Support or Funding InformationSupported by HL‐107462 and HL‐119683
Unintended Consequences: Renal Denervation Attenuates Hypertension Development but Impairs Glucose Metabolism in Female Fawn‐Hooded Hypertensive Rats
Authors: Banek Christopher T , Gauthier Madeline , Van Helden Dusty A , Asirvatham‐Jeyaraj Ninitha , Osborn John W 
Published: November 2023

For both men and women, hypertension (HTN) is the highest risk factor for cardiovascular disease and stroke – the two leading causes of morbidity and mortality throughout the world. Though HTN etiology remains debated, altered sympathetic nervous activity, particularly to the kidney (RSNA), is regarded as a primary contributor to the development and maintenance of HTN. Ablation of renal sympathetic nerves (RDNx) reportedly prevents and/or reverses several forms of experimental hypertension. Several off‐target improvements are also reported, such as glucose metabolism. However, an overwhelming majority of these experimental models and mechanisms focus only on responses in male subjects. Moreover, the sex differences in sympathetic control of blood pressure in hypertension remain poorly defined. In this study, we assessed the role of RDNx to prevent hypertension development and metabolic dysfunction in the Fawn‐Hooded Hypertensive (FHH) rat model. We hypothesized that RDNx would attenuate the development of HTN, and improve glucose handling in female and male rats. FHH rats (10 weeks old) underwent sham or bilateral RDNx surgeries (n=5/group). For the following six weeks, 24‐hour mean arterial pressure (MAP) was monitored by radiotelemetry. Glucose handling was assessed biweekly by glucose tolerance test (GTT). Cardiovascular data was averaged weekly, and analyzed by two‐way ANOVA with a Bonferroni post‐hoc test (α=.05). Data presented as mean ± SEM. Six weeks post‐treatment, RDNx attenuated the HTN in the females (p<.05) vs. sham controls (107±5 vs. 118±3). Interestingly, no difference in MAP between RDNx and sham males was observed (129±2 vs. 125±1mmHg). Regarding glucose metabolism, baseline fasting blood glucose (FBG) and glucose tolerance (GT) were similar between males and females prior to RDNx. After six weeks, FBG in female sham FHH (100.9±2.3mg/dL) was higher (p<.05) than male shams (89.2±2.7mg/dL). Likewise, GT was impaired in female rats compared to male shams. In contrast to our hypothesis, RDNx worsened the FBG (110±2.6mg/dL) and GT in female vs. female shams. No effect of time or RDNx on glucose handling was observed males. In summary, RDNx attenuated HTN development in female FHH rats; however, glucose metabolism was impaired by RDNx in females but not in males. These results suggest that sex may need to be considered in the use of RDNx to treat HTN. These findings are clinically important in that RDNx responses may be partially dependent on sex, and may result in negative outcomes such as impaired glucose metabolism in females. Further examination of sex differences in the responses to RDNx is underway.Support or Funding InformationNIH 5R01HL116476; NIH 2T32HL7741
Is there a relationship between resting sympathetic nerve activity and leg vascular conductance in aerobically‐trained older adults?
Authors: O'Brien Myles W. , Ramsay Diane J. , Mekary Said , Dogra Shilpa , O'Neill Carley , Kimmerly Derek S. 
Published: November 2023

Inactivity is associated with elevated resting muscle sympathetic nerve activity (MSNA) that directly relates to corresponding reductions in leg vascular conductance (LVC) as one ages. Aerobic training further increases resting MSNA but also augments nitric oxide (NO) bioavailability assessed via the flow‐mediated dilation (FMD) response. How these competing vascular mechanisms contribute to sympathetic‐transduction in older active adults is unclear. We tested the hypothesis that parallel increases in aerobic fitness, lower limb MSNA and FMD would negate the inverse relationship between MSNA and LVC in older active adults. We measured fibular MSNA (microneurography), popliteal artery blood flow (PBF) and FMD (Doppler ultrasound) in 16 (10♂, 25.8 ± 3.1 kg•m−2) older (64 ± 5 years), aerobically‐trained adults (152 ± 37% age‐predicted VO2peak). LVC was calculated as PBF/mean arterial pressure. Resting MSNA burst frequency and relative popliteal artery (PA)‐FMD were 31 ± 15 burst•min−1 and 9.2 ± 3.1%, respectively. Aerobic fitness correlated positively with both MSNA (r=0.56; p=0.03) and relative PA‐FMD (r=0.87; p=0.01). MSNA correlated with PA‐FMD (r=0.60; p=0.02) but not with resting LVC (r=0.02; p=0.94). Similarly, PA‐FMD did not relate to resting LVC (r=−0.01; p=0.96). The main findings include: 1) resting MSNA and PA‐FMD were significantly associated with aerobic fitness in active older adults, and 2) unlike their sedentary peers, LVC was not inversely related to resting MSNA in aerobically‐trained older adults. This latter finding may be due to reduced transduction of the sympathetic vasoconstrictor signal mediated, in part, by a corresponding increase in basal NO bioavailabilitySupport or Funding InformationSupport provided by: Canadian Foundation for Innovation: Leaders Opportunity Fund, Faculty of Health Professions Research Development, and Nova Scotia Health Research Foundation Development/Innovation grants.
Sex Differences in Blood Pressure Control Following a Single Bout of Isometric Handgrip Exercise
Authors: Samora Milena , Teixeira André L , Antonino Diego L , Carmo Jake C , Ritti‐Dias Raphael , Vianna Lauro C 
Published: November 2023

BackgroundRecent studies have shown that isometric handgrip (IHG) training reduces resting arterial blood pressure (BP) in both normotensive and hypertensive populations, but the mechanisms underlying these adaptations remain unclear. Furthermore, little is known regarding the effects of a single bout of IHG on the neural control of BP in humans. This becomes important given the fact that chronic adaptations may result from temporal summation of acute responses. In addition, the majority of studies regarding cardiovascular effects of IHG are performed in men and the possible sex differences in this context are unknown.AimTo test the hypothesis that neural control of BP following a single bout of IHG exercise are different between men and women.MethodsEight healthy men (24 ± 3 years) and 10 healthy women (23 ± 4 years) randomly performed a single bout (four 2‐min static contractions) of experimental (30% MVC) or sham (3% MVC) bilateral IHG exercise. All women are non‐oral contraceptives users and performed experiments in the early follicular phase of the menstrual cycle. Beat‐to‐beat heart rate (HR) and arterial BP was continuously monitored using finger photoplethysmography (Human NIBP, AD instruments) before and following IHG exercise (5–10 and 25–30 min of recovery). Spontaneous cardiac baroreflex sensitivity (cBRS) was assessed via sequence technique (CardioSeries v2.4, Brazil). Power spectral analysis of HR variability (HRV) was employed (CardioSeries v2.4, Brazil) and the ratio between low and high frequency of HRV (LF/HF) was used as a surrogate of sympathovagal balance.ResultsBaseline HR was greater while arterial BP and cBRS gain were lower in women compared with men (P<0.05). Following IHG exercise, SBP increased in men (Δ7 ± 1 mmHg, 10‐min vs. rest, P<0.05), but was unchanged in women (Δ2 ± 1 mmHg, 10‐min vs. rest, P>0.05). At 10‐min following IHG exercise, HR significantly decreased (Δ‐7 ± 1 bpm, P<0.01) and remained attenuated at 30‐min time point (Δ−3 ± 1 bpm, P<0.05) in women, but was unchanged in men (10‐min: Δ−2 ± 1 bpm, and 30‐min: Δ1 ± 2 bpm, P>0.05). In women, cBRS gain significantly increased from rest at 10‐min following IHG (Δ23.7 ± 7%, P=0.01) and returned to baseline values at 30‐min of recovery (14.9 ± 2.0 ms/mmHg, P>0.05). In contrast, no differences were found in cBRS gain in men following IHG (P>0.05). In addition, RMSSD and HF components of HRV, a proxy of cardiac vagal activity, were increased at 10‐min following IHG in women while no differences were found in men. LF/HF ratio was not affected by IHG trials. All physiological variables were unaffected by the sham protocol in both groups.ConclusionThese results allow us to conclude that the acute effects of IHG exercise on neural control of BP is sex dependent and baseline sex differences in spontaneous cBRS were acutely abolished after a single bout of IHG exercise.Support or Funding InformationCAPES, CNPq and FAPDF.
Effect of Sex on Muscle Sympathetic Nerve Responses to Static and Dynamic Exercise
Authors: Notay Karambir , Doherty Connor J. , Incognito Anthony V. , Burns Matthew J. , Nardone Massimo , Seed Jeremy D. , Millar Philip J. 
Published: November 2023

Previous studies investigating sex differences in sympathetic outflow during exercise have produced conflicting results, demonstrating either similar or attenuated increases in muscle sympathetic nerve activity (MSNA) during static handgrip in women. Further, to our knowledge, no studies have investigated whether MSNA responses to low‐to‐moderate intensity dynamic leg exercise, a stimulus which decreases sympathetic outflow, differs between men and women. Therefore, the purpose of the present study was to examine the effect of sex on MSNA responses to static handgrip and dynamic one‐legged cycling. Heart rate (HR), mean arterial pressure (MAP), and MSNA (left fibular nerve; microneurography) were measured continuously in 9 men (22±3 yrs) and 9 women (21±3 yrs) at rest and during 2 minutes of static handgrip (30% maximal voluntary contraction), unloaded one‐legged cycling, and moderate intensity one‐legged cycling (30% of peak power output) in the recumbent position. All cycling was performed with the right leg using a modified arm ergometer. Static and dynamic exercise were separated by 10 minutes of rest. All variables were assessed as the change (Δ) from baseline to the second minute of exercise. Resting HR and MAP were similar between men and women (Both p>0.05) whereas MSNA burst frequency was higher in men (28±6 vs. 23±4; p=0.03). During static handgrip, the increases in HR (Δ11±8 vs. 9±7 bpm; p=0.55), MAP (Δ21±7 vs. 16±4 mmHg; p=0.10), MSNA burst frequency (Δ4±5 vs. 8±9 bursts/min, p=0.26), and total MSNA (Δ11±12 vs. 4±5 a.u./min; p=0.18) were similar between men and women. During one‐legged cycling, changes in HR (unloaded: Δ10±7 vs. 8±5 bpm, p=0.49; loaded: Δ23±6 vs. 23±5 bpm, p=0.94), MAP (unloaded: Δ8±4 vs. 6±5 mmHg, p=0.45; loaded: Δ12±6 vs. 11±4 mmHg, p=0.86), MSNA burst frequency (unloaded: Δ−5±4 vs. −3±4 bursts/min, p=0.39; loaded: Δ−3±8 vs. −1±6 bursts/min, p=0.70), and total MSNA (unloaded: Δ0±3 vs. −3±3 a.u./min, p=0.07; loaded: Δ1±4 vs. 0±4 a.u./min, p=0.36) were comparable between men and women. In summary, these results suggest that sex does not impact muscle sympathetic or blood pressure responses to moderate intensity static handgrip or dynamic one‐legged cycling.Support or Funding InformationThis research was supported by a Natural Science and Engineering Research Council (NSERC) of Canada Discovery Grant (P.J.M), the Canada Foundation for Innovation (P.J.M.), and a Canadian Institutes of Health Research Fredrick Banting and Charles Best Canada Graduate Scholarship (A.V.I.).