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BACKGROUND: Prenatal nicotine exposure (PNE) has been documented to cause numerous deleterious effects on fetal development. However, the epigenetic changes promoted by nicotine exposure on germ cells are still not well understood. OBJECTIVES: In this study, we focused on elucidating the impact of prenatal nicotine exposure on regulatory epigenetic mechanisms important for germ cell development. METHODS: Sprague-Dawley rats were exposed to nicotine during pregnancy and male progeny was analyzed at 11 weeks of age. Testis morphology was analyzed using frozen testis sections and expression of germ cell markers was examined by RT-qPCR; histone modifications were assessed by Western Blot (WB). DNA methylation analysis was performed by methylation-specific PCR of bisulfite converted DNA. Genome-wide DNA methylation was analyzed using Methylated DNA immunoprecipitation (MeDIP)-seq. We also carried out transcriptomics analysis of pituitary glands by RNA-seq. RESULTS: We show that gestational exposure to nicotine reduces germ cell numbers, perturbs meiosis, affects the expression of germ line reprogramming responsive genes, and impacts the DNA methylation of nervous system genes in the testis. PNE also causes perturbation of gene expression in the pituitary gland of the brain. CONCLUSIONS: Our data demonstrate that PNE leads to perturbation of male spermatogenesis, and the observed effects are associated with changes of peripheral nervous system signaling pathways. Alterations in the expression of genes associated with diverse biological activities such as cell migration, cell adhesion and GABA signaling in the pituitary gland underscore the complexity of the effects of nicotine exposure during pregnancy.
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Metilación de ADN , Epigénesis Genética , Nicotina , Efectos Tardíos de la Exposición Prenatal , Ratas Sprague-Dawley , Testículo , Animales , Masculino , Femenino , Embarazo , Ratas , Testículo/efectos de los fármacos , Testículo/metabolismo , Epigénesis Genética/efectos de los fármacos , Metilación de ADN/efectos de los fármacos , Efectos Tardíos de la Exposición Prenatal/inducido químicamente , Efectos Tardíos de la Exposición Prenatal/metabolismo , Transducción de Señal/efectos de los fármacos , Espermatogénesis/efectos de los fármacos , Espermatogénesis/genética , Sistema Nervioso Periférico/efectos de los fármacos , Sistema Nervioso Periférico/metabolismoRESUMEN
Tobacco smoking is the leading cause of preventable death. Numerous reports link smoking in pregnancy with serious adverse outcomes, such as miscarriage, stillbirth, prematurity, low birth weight, perinatal morbidity, and infant mortality. Corollaries of consuming nicotine in pregnancy, separate from smoking, are less explored, and the mechanisms of nicotine action on maternal-fetal communication are poorly understood. This study examined alterations in the maternal gut microbiome in response to nicotine exposure during pregnancy. We report that changes in the maternal gut microbiota milieu are an important intermediary that may mediate the prenatal nicotine exposure effects, affect gene expression, and alter fetal exposure to circulating short-chain fatty acids (SCFAs) and leptin during in utero development.
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INTRODUCTION: Both smoking and infection adversely impact pregnancy. Previously, our group identified in a rodent model that 6 mg/kg/d nicotine increased the risk of fetal infection at gestation day (GD) 18. Here, we investigate lower nicotine doses. METHODS: Pregnant Sprague-Dawley rats received nicotine infusion at 0, 1, or 3 mg/kg/d (no, low-, and mid-dose nicotine, respectively) from GD 6, with intravenous inoculation with Mycoplasma pulmonis (MP) at 107 CFU (N = 20) or sterile broth (sham) (N = 11) on GD 14. Uterus and fetuses were retrieved on GD 18 for MP culture and histopathologic evaluation of maternal and fetal inflammatory responses (MIR and FIR). RESULTS: At 1 mg/kg/d nicotine, MP colonization rates were decreased, from 100% (9 of 9) to 40% (2 of 5) of MP-inoculated dams (p = .03), and 59% (66 of 111) to 39% (24 of 62) of fetuses (p = .01), versus no nicotine. Low-dose nicotine resulted in increased MIR and FIR in the sham-inoculated group; in the MP-inoculated group, this resulted in reduced relative risk (RR) for placental colonization (RR, 95% CI with high MIR = 0.14, 0.02 to 0.65; FIR = 0.38, 0.12 to 0.93). In contrast, 3 mg/kg/d nicotine treatment did not alter colonization rates; furthermore, FIR was completely suppressed, even in the face of placental or amniotic fluid colonization. CONCLUSION: The 1 mg/kg/d nicotine dose decreased risk of intrauterine infection, with increased MIR and FIR. The 3 mg/kg/d nicotine dose inhibited FIR, and increased risk for intrauterine infection. Nicotine alterations of the intrauterine environment were markedly dose-dependent. IMPLICATIONS: Nicotine exposure alters intrauterine infection and inflammation in a dose-dependent manner, potentially impacting fetal development and programming. Previous work in a rodent model showed that high-dose nicotine (6 mg/kg/d) exposure exacerbated intrauterine infection during pregnancy. The current study found that low-dose nicotine (1 mg/kg/d) exposure reduced colonization of placenta and amniotic fluid; this decrease was associated with increased intrauterine inflammation. Exposure to mid-dose nicotine (3 mg/kg/d) suppressed fetal inflammation. Elucidation of underlying mechanisms of these phenomena will inform public health and clinical care decisions, particularly in the context of risk assessment of nicotine replacement therapy during pregnancy for smoking cessation.
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Nicotina , Cese del Hábito de Fumar , Líquido Amniótico , Animales , Femenino , Nicotina/toxicidad , Placenta , Embarazo , Ratas , Ratas Sprague-Dawley , Dispositivos para Dejar de Fumar TabacoRESUMEN
NEW FINDINGS: What is the topic of this review? This manuscript provides a review of the current understanding of the role of the sympathetic nervous system in regulation of bone marrow-derived immune cells and the effect that the infiltrating bone marrow cells may have on perpetuation of the sympathetic over-activation in hypertension. What advances does it highlight? We highlight the recent advances in understanding of the neuroimmune interactions both peripherally and centrally as they relate to blood pressure control. ABSTRACT: The sympathetic nervous system (SNS) plays a crucial role in maintaining physiological homeostasis, in part by regulating, integrating and orchestrating processes between many physiological systems, including the immune system. Sympathetic nerves innervate all primary and secondary immune organs, and all cells of the immune system express ß-adrenoreceptors. In turn, immune cells can produce cytokines, chemokines and neurotransmitters capable of modulating neuronal activity and, ultimately, SNS activity. Thus, the essential role of the SNS in the regulation of innate and adaptive immune functions is mediated, in part, via ß-adrenoreceptor-induced activation of bone marrow cells by noradrenaline. Interestingly, both central and systemic inflammation are well-established hallmarks of hypertension and its co-morbidities, including an inflammatory process involving the transmigration and infiltration of immune cells into tissues. We propose that physiological states that prolong ß-adrenoreceptor activation in bone marrow can disrupt neuroimmune homeostasis and impair communication between the immune system and SNS, leading to immune dysregulation, which, in turn, is sustained via a central mechanism involving neuroinflammation.
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Médula Ósea , Hipertensión , Presión Sanguínea , Humanos , Inflamación , Sistema Nervioso Simpático/fisiologíaRESUMEN
Heart failure with reduced ejection fraction (HFREF) increases neutral sphingomyelinase (NSMase) activity and mitochondrial reactive oxygen species (ROS) emission and causes diaphragm weakness. We tested whether a systemic pharmacological NSMase inhibitor or short-hairpin RNA (shRNA) targeting NSMase isoform 3 (NSMase3) would prevent diaphragm abnormalities induced by HFREF caused by myocardial infarction. In the pharmacological intervention, we used intraperitoneal injection of GW4869 or vehicle. In the genetic intervention, we injected adeno-associated virus serotype 9 (AAV9) containing shRNA targeting NSMase3 or a scrambled sequence directly into the diaphragm. We also studied acid sphingomyelinase-knockout mice. GW4869 prevented the increase in diaphragm ceramide content, weakness, and tachypnea caused by HFREF. For example, maximal specific forces (in N/cm2) were vehicle [sham 31 ± 2 and HFREF 26 ± 2 ( P < 0.05)] and GW4869 (sham 31 ± 2 and HFREF 31 ± 1). Respiratory rates were (in breaths/min) vehicle [sham 61 ± 3 and HFREF 84 ± 11 ( P < 0.05)] and GW4869 (sham 66 ± 2 and HFREF 72 ± 2). AAV9-NSMase3 shRNA prevented heightening of diaphragm mitochondrial ROS and weakness [in N/cm2, AAV9-scrambled shRNA: sham 31 ± 2 and HFREF 27 ± 2 ( P < 0.05); AAV9-NSMase3 shRNA: sham 30 ± 1 and HFREF 30 ± 1] but displayed tachypnea. Both wild-type and ASMase-knockout mice with HFREF displayed diaphragm weakness. Our study suggests that activation of NSMase3 causes diaphragm weakness in HFREF, presumably through accumulation of ceramide and elevation in mitochondrial ROS. Our data also reveal a novel inhibitory effect of GW4869 on tachypnea in HFREF likely mediated by changes in neural control of breathing.
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Diafragma/fisiopatología , Insuficiencia Cardíaca/fisiopatología , Debilidad Muscular/prevención & control , ARN Interferente Pequeño/genética , Esfingomielina Fosfodiesterasa/antagonistas & inhibidores , Esfingomielina Fosfodiesterasa/genética , Compuestos de Anilina/farmacología , Animales , Compuestos de Bencilideno/farmacología , Diafragma/enzimología , Modelos Animales de Enfermedad , Insuficiencia Cardíaca/genética , Insuficiencia Cardíaca/terapia , Humanos , Masculino , Ratones , Ratones Noqueados , Debilidad Muscular/genética , Debilidad Muscular/fisiopatología , Ratas , Ratas Wistar , Esfingomielina Fosfodiesterasa/deficiencia , Volumen Sistólico/genética , Volumen Sistólico/fisiologíaRESUMEN
We investigated the interaction between prenatal nicotine exposure and intrauterine infection using established rat models. Beginning at gestation day (GD) 6, dams were continuously infused with either saline or 6 mg/kg/day nicotine (Nic). At GD 14, dams received either sterile broth or 105 colony-forming units Mycoplasma pulmonis (MP), resulting in four treatment groups: control (4 dams, 33 fetal units); MP only (5 dams, 55 fetal units); Nic only (5 dams, 61 fetal units), and Nic + MP (7 dams, 82 fetal units). At GD 18, nicotine exposure significantly increased (P ≤ 0.02) the percentage of amniotic fluids and fetuses infected by MP but did not impact colonization rates of maternal sites. Nicotine exposure significantly reduced the numbers of MP in the placenta required for high microbial loads (≥104 color-changing units) in the amniotic fluid (P < 0.01). Fetal inflammatory response lesions were most extensive in the Nic only and Nic + MP groups (P < 0.0001). Control and MP only placentas were interleukin (IL)10-dominant, consistent with an M2/Th2 environment. Placentas exposed to nicotine shifted to a neutral environment, with equivalent levels of interferon gamma (IFNG) and IL10. Both IL6 and tumor necrosis factor (TNF) levels in amniotic fluid were highly elevated when both nicotine and infection were present. Our study suggests that prenatal exposure to nicotine increases the risk for intrauterine infection, lowers the infectious dose required to breach the placental barrier and infect the amniotic fluid and fetus, and alters the pathology and inflammatory profile associated with maternal and fetal sites.
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Enfermedades Fetales/microbiología , Infecciones por Mycoplasma/microbiología , Mycoplasma pulmonis , Nicotina/toxicidad , Agonistas Nicotínicos/toxicidad , Complicaciones Infecciosas del Embarazo/microbiología , Líquido Amniótico/metabolismo , Líquido Amniótico/microbiología , Animales , Carga Bacteriana , Recuento de Colonia Microbiana , Citocinas/metabolismo , Femenino , Enfermedades Fetales/patología , Inflamación/patología , Infecciones por Mycoplasma/patología , Placenta/microbiología , Placenta/patología , Embarazo , Complicaciones Infecciosas del Embarazo/patología , Ratas , Ratas Sprague-DawleyRESUMEN
This study tested the hypothesis that orexin plays a role in the elevated pressor response to acute stress in the spontaneously hypertensive rat (SHR). The pressor response to air jet stress (AJS) (n=11/group) was 2.5 times greater in vehicle treated SHR versus Wistar (WIS) rats. Systemic delivery of 30mg/kg of the dual orexin receptor antagonist almorexant did not significantly change resting mean arterial pressure (MAP) but did attenuate the pressor response elicited by AJS to a greater extent in the SHR compared to the Wistar rats (~65% versus ~33% reduction respectively; n=6/group). Alternatively 100mg/kg almorexant reduced resting MAP in the SHR (~25mm Hg drop) and attenuated both the heart rate (HR; ~50% reduction) and MAP (~62% reduction) response to AJS in both strains (n=6/group). Systemic application of SB-334867 (3mg/kg), an orexin receptor type 1 antagonist (n=5/group), selectively reduced resting MAP and attenuated the HR response to AJS in the SHR but had no effect on the pressor response in either strain. The potential role of endogenous orexin release in cardiovascular control in the SHR was linked to a significant increase in brain-derived neurotrophic factor mRNA expression in the hypothalamus and elevated orexin receptor expression (type 2 only) in the dorsal pons when compared to WIS (n=4/group). These results demonstrate that the exaggerated pressor response in the SHR to stress is linked to increased orexin receptor activation and possibly altered orexin receptor expression in the dorsal pons and BDNF expression in the hypothalamus.
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Acetamidas/farmacología , Benzoxazoles/farmacología , Presión Sanguínea/efectos de los fármacos , Frecuencia Cardíaca/efectos de los fármacos , Isoquinolinas/farmacología , Antagonistas de los Receptores de Orexina/farmacología , Estrés Psicológico/tratamiento farmacológico , Urea/análogos & derivados , Aire , Animales , Presión Sanguínea/fisiología , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Fármacos Cardiovasculares/farmacología , Relación Dosis-Respuesta a Droga , Frecuencia Cardíaca/fisiología , Masculino , Naftiridinas , Receptores de Orexina/metabolismo , Estimulación Física , ARN Mensajero/metabolismo , Distribución Aleatoria , Ratas Endogámicas SHR , Ratas Wistar , Especificidad de la Especie , Estrés Psicológico/metabolismo , Urea/farmacologíaRESUMEN
OBJECTIVE: The aim of this study was to investigate the effect of chronic heart failure (HF; 16 weeks post left coronary artery ligation) on the brain's orexin (ORX) and related neuropeptide systems. METHODS: Indicators of cardiac function, including the percent fractional shortening (%FS) left ventricular posterior wall shortening velocity (LVPWSV) were assessed via echocardiography at 16 weeks post myocardial infarction or sham treatment in male Lewis rats (n=5/group). Changes in gene expression in HF versus control (CON) groups were quantified by real-time PCR in the hypothalamus, amygdala and dorsal pons. RESULTS: HF significantly reduced both the %FS and LVPWSV when compared to CON animals (P<0.02). In the hypothalamus ORX gene expression was significantly reduced in HF and correlated with changes in cardiac function when compared to CON (P<0.02). No significant changes in hypothalamic ORX receptor (type 1 or type 2) gene expression were identified. Alternatively hypothalamic melanin concentrating hormone (MCH) gene expression was significantly upregulated in HF animals and negatively correlated with LVPWSV (P<0.006). In both the amygdala and dorsal pons ORX type 2 receptor expression was significantly down-regulated in HF compared to CON. ORX receptor type 1, CRH and CRH type 1 and type 2 receptor expressions were unchanged by HF in all brain regions analyzed. CONCLUSION: These observations support previous work demonstrating that cardiovascular disease modulates the ORX system and identify that in the case of chronic HF the ORX system is altered in parallel with changes in MCH expression but independent of any significant changes in the central CRH system. This raises the new possibility that ORX and MCH systems may play an important role in the pathophysiology of HF.
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Encéfalo/metabolismo , Hormona Liberadora de Corticotropina/metabolismo , Insuficiencia Cardíaca/metabolismo , Hormonas Hipotalámicas/metabolismo , Melaninas/metabolismo , Receptores de Orexina/metabolismo , Orexinas/metabolismo , Hormonas Hipofisarias/metabolismo , Animales , Encéfalo/fisiopatología , Enfermedad Crónica , Expresión Génica , Insuficiencia Cardíaca/fisiopatología , Masculino , ARN Mensajero/metabolismo , Ratas , Ratas Endogámicas LewRESUMEN
Brain-derived neurotrophic factor (BDNF) expression increases in the paraventricular nucleus of the hypothalamus (PVN) in response to hypertensive stimuli including stress and hyperosmolarity. However, it is unclear whether BDNF in the PVN contributes to increases in blood pressure (BP). We tested the hypothesis that increased BDNF levels within the PVN would elevate baseline BP and heart rate (HR) and cardiovascular stress responses by altering central angiotensin signaling. BP was recorded using radiotelemetry in male Sprague-Dawley rats after bilateral PVN injections of adeno-associated viral vectors expressing green fluorescent protein (GFP) or myc epitope-tagged BDNF fusion protein. Cardiovascular responses to acute stress were evaluated 3 to 4 wk after injections. Additional GFP and BDNF-treated animals were equipped with osmotic pumps for intracerebroventricular infusion of saline or the angiotensin type-1 receptor (AT1R) inhibitor losartan (15 µg·0.5 µl(-1)·h(-1)). BDNF treatment significantly increased baseline BP (121 ± 3 mmHg vs. 99 ± 2 mmHg in GFP), HR (394 ± 9 beats/min vs. 314 ± 4 beats/min in GFP), and sympathetic tone indicated by HR- and BP-variability analysis and adrenomedullary tyrosine hydroxylase protein expression. In contrast, body weight and BP elevations to acute stressors decreased. BDNF upregulated AT1R mRNA by â¼80% and downregulated Mas receptor mRNA by â¼50% in the PVN, and losartan infusion partially inhibited weight loss and increases in BP and HR in BDNF-treated animals without any effect in GFP rats. Our results demonstrate that BDNF overexpression in the PVN results in sympathoexcitation, BP and HR elevations, and weight loss that are mediated, at least in part, by modulating angiotensin signaling in the PVN.
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Angiotensinas/metabolismo , Presión Sanguínea , Factor Neurotrófico Derivado del Encéfalo/biosíntesis , Sistema Cardiovascular/inervación , Hipertensión/metabolismo , Núcleo Hipotalámico Paraventricular/metabolismo , Sistema Renina-Angiotensina , Transducción de Señal , Sistema Nervioso Simpático/fisiopatología , Médula Suprarrenal/metabolismo , Bloqueadores del Receptor Tipo 1 de Angiotensina II/administración & dosificación , Animales , Presión Sanguínea/efectos de los fármacos , Peso Corporal , Factor Neurotrófico Derivado del Encéfalo/genética , Dependovirus/genética , Técnicas de Transferencia de Gen , Vectores Genéticos , Frecuencia Cardíaca , Hipertensión/genética , Hipertensión/fisiopatología , Infusiones Intraventriculares , Masculino , Núcleo Hipotalámico Paraventricular/efectos de los fármacos , Proto-Oncogenes Mas , Proteínas Proto-Oncogénicas/metabolismo , Ratas Sprague-Dawley , Receptor de Angiotensina Tipo 1/efectos de los fármacos , Receptor de Angiotensina Tipo 1/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Sistema Renina-Angiotensina/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Estrés Psicológico/metabolismo , Estrés Psicológico/fisiopatología , Sistema Nervioso Simpático/efectos de los fármacos , Sistema Nervioso Simpático/metabolismo , Factores de Tiempo , Tirosina 3-Monooxigenasa/metabolismo , Regulación hacia ArribaRESUMEN
The effects of DOCA/salt treatment on amygdala-area CRF gene expression and the autonomic response to air jet stress (AJS) were evaluated in conscious male Sprague Dawley (SD) rats. Fifteen days of DOCA/salt treatment significantly increased resting arterial pressure (AP), decreased resting heart rate (HR) and significantly reduced regional CRF mRNA compared to controls (23±7% vs. 100±26%) independent of changes in regional CRF receptor expression. Twenty min of AJS elicited a rise in AP (~15mmHg) that was similar in both DOCA/salt animals (n=11) and controls (n=6). Alternatively, increases in HR were significantly different in the DOCA/salt animals compared to controls; including one group of DOCA/salt animals (n=5) which responded with an attenuated HR response at the onset of AJS (low-responders) and a second group (n=6) which demonstrated an elevated HR response to AJS (high-responders), specifically during the last 10min of AJS. The divergent HR responses to AJS in the DOCA/salt animals were linked to differences in resting heart rate variability. During recovery HR returned to baseline within 10min in both control and the low responder DOCA group but indicators of spontaneous baroreflex gain only increased significantly in controls. HR in the high-responder DOCA animals did not return to baseline during the same period. These results show that DOCA/salt treatment triggers downregulation of CRF gene expression in the region of the amygdala and significantly alters the HR response to acute stress but does not alter the pressor response to stress compared to normotensive controls.
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Amígdala del Cerebelo/fisiopatología , Barorreflejo/fisiología , Hormona Liberadora de Corticotropina/metabolismo , Frecuencia Cardíaca/fisiología , Hipertensión/fisiopatología , Estrés Psicológico/fisiopatología , Animales , Sistema Nervioso Autónomo/fisiopatología , Presión Sanguínea/fisiología , Estado de Conciencia , Acetato de Desoxicorticosterona , Modelos Animales de Enfermedad , Masculino , ARN Mensajero/metabolismo , Distribución Aleatoria , Ratas Sprague-Dawley , Cloruro de Sodio Dietético , Taquicardia/fisiopatologíaRESUMEN
Some of the benefits of exercise appear to be mediated through modulation of neuronal excitability in central autonomic control circuits. Previously, we identified that six weeks of voluntary wheel running had a protective effect during hemorrhage (HEM), limiting both the hypotensive phase of HEM and enhancing recovery. The present study was undertaken to evaluate the role of opioid release in the lateral parabrachial nucleus (LPBN) on the response to severe HEM in chronically exercised (EX, voluntary) versus sedentary (SED) controls. Male Sprague Dawley rats were allowed either free access to running wheels (EX) or normal cage conditions (SED). After 6 weeks of "training" animals were instrumented with a bilateral cannula directed toward the dorsolateral pons and arterial catheters. After a recovery period, animals underwent central microinjection of either vehicle (VEH; n=3/group) or the opioid receptor antagonist naloxone (NAL; n=6/group) followed by withdrawal of 30% of their total estimated blood volume. Following VEH injection, the drop in MAP during and following HEM was significantly attenuated in the EX vs SED animals. Alternatively, NAL microinjection in the dorsolateral pons (20 µM, 200-500 nl) reversed the beneficial effect of EX on the HEM response. NAL microinjection in SED rats did not significantly alter the response to HEM. These data suggest chronic voluntary EX has a beneficial effect on the autonomic response to severe HEM which is mediated, in part, via EX-induced plasticity of the opioid system within the dorsolateral pons.
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Hemorragia/fisiopatología , Hemorragia/terapia , Hipotensión/fisiopatología , Hipotensión/terapia , Condicionamiento Físico Animal/fisiología , Puente/efectos de los fármacos , Receptores Opioides/fisiología , Animales , Presión Sanguínea/efectos de los fármacos , Presión Sanguínea/fisiología , Frecuencia Cardíaca/efectos de los fármacos , Frecuencia Cardíaca/fisiología , Hemorragia/complicaciones , Hipotensión/complicaciones , Masculino , Microinyecciones , Naloxona/administración & dosificación , Naloxona/farmacología , Antagonistas de Narcóticos/administración & dosificación , Antagonistas de Narcóticos/farmacología , Puente/fisiopatología , Ratas , Ratas Sprague-DawleyRESUMEN
The present study tested the hypothesis that prenatal nicotine exposure (PNE) induces sex specific alternations in indices of cardiorespiratory coupling during early development. Rat pups exposed to either nicotine (6 mg/kg/day) or saline (control) in utero were chronically instrumented with ECG electrodes for measurement of heart rate (HR) and respiratory frequency (RF) was monitored by whole body plethysmography on postnatal days (P)13, P16 and P26. PNE had no identifiable effect on resting respiratory frequency (RF) in either sex. There was however a strong trend (p=0.057) for resting HR to be elevated by PNE in male offspring only. Alternatively, the HR response to hypoxia (10% O(2)), was significantly blunted at P13 but significantly elevated at P26 s in the absence of any significant change in RF in PNE males only. Indicators of respiratory sinus arrhythmia (RSA) were also significantly reduced in P26 PNE males. No significant effects of PNE on HR, RF or RSA were identified in female offspring at any age. Our results demonstrate that PNE induces very specific changes in cardiorespiratory integration at select postnatal ages and these changes are more prominent in males. Additionally, alternations in cardiorespiratory integration appear to persist into later development in males only, potentially increasing the risk for cardiovascular diseases such as hypertension later in life.
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Arritmia Sinusal/fisiopatología , Frecuencia Cardíaca/fisiología , Hipoxia/fisiopatología , Nicotina/farmacología , Efectos Tardíos de la Exposición Prenatal/fisiopatología , Frecuencia Respiratoria/fisiología , Caracteres Sexuales , Factores de Edad , Animales , Femenino , Masculino , Agonistas Nicotínicos/farmacología , Embarazo , Ratas , Ratas Sprague-Dawley , Maduración Sexual/fisiologíaRESUMEN
The present study tested the hypothesis that voluntary wheel-exercised rats would better tolerate severe hemorrhage (HEM) compared to age matched sedentary (SED) controls. Conscious rats housed with (EX, n = 8) or without (SED, n = 8) a running wheel for 6 weeks underwent a 30% total blood volume HEM over 15 min and were euthanized 90 min later and brain tissue was processed for Fos-like immunoreactivity (FLI). Both EX and SED groups displayed typical responses to HEM (initial tachycardia followed by decreased HR and MAP) but at the end of HEM, mean arterial pressure (93 ± 6 vs 58 ± 3 mm Hg) and heart rate (316 ± 17 vs. 247 ± 22 bpm,) were higher in the EX vs. SED animals and 60 min following the end of HEM, HR remained significantly elevated in the EX vs SED animals. The altered HR response to HEM in the EX animals was linked to a significant difference in sympatho-vagal drive identified by heart rate variability analysis and an augmented baroreflex response to hypotension tested in a separate group of animals (n = 4-5/group). In many of the brain regions analyzed, EX rats displayed lower levels of FLI compared to SED rats. Significantly lower levels of FLI in the EX vs SED rats were identified in the middle and caudal external lateral subnucleus of the lateral parabrachial nucleus and the dorsal cap of the hypothalamic paraventricular nucleus. These results suggest that enhanced tolerance to HEM following daily exercise may result from an EX-induced reduction in excitation or exaggerated inhibition in central circuits involved in autonomic control.
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Fenómenos Fisiológicos Cardiovasculares , Hemodinámica/fisiología , Hemorragia/fisiopatología , Condicionamiento Físico Animal/fisiología , Animales , Estado de Conciencia , Inmunohistoquímica , Masculino , Proteínas Proto-Oncogénicas c-fos/biosíntesis , Ratas , Ratas Sprague-DawleyRESUMEN
The influence of both prenatal nicotine exposure (PNE; 6 mg/kg/day) and sex on heart rate (HR) regulation during sleep versus wakefulness was evaluated in 13, 16 and 26 day old rat pups. Pups were chronically instrumented at least 24 h before testing. On postnatal day 13 (P13), PNE males spent significantly more time in NREM sleep and demonstrated a greater drop in HR when transitioning from quiet wake to sleep compared to age and sex matched controls (-14±5 bpm versus -1±3 bpm, respectively). Heart rate variability (HRV) analysis indicated that this state-dependent drop in HR was primarily associated with a greater reduction in sympathovagal balance (LF/HF ratio) in PNE males compared to controls. No parallel changes in indices of parasympathetic drive (HF power) were identified. In contrast, no significant effect of PNE on HR during sleep versus wakefulness was identified in P13 females. However, independent of state, a significant decrease in HF power was identified in P13 PNE females compared to controls. At P16, state-dependent differences in HR or HRV between PNE and sex-matched control pups were resolved. Additionally, at P26 no significant effect of PNE on state-dependent changes in HR or HRV was identified in either sex. Analysis of the hypothalamic peptide orexin identified that PNE induced approximately a 50% reduction in hypothalamic prepro-orexin mRNA and total mRNA was lowest in PNE males. These findings suggest that PNE induces sex dependent changes in sleep related autonomic regulation of HR during early postnatal development and these changes may be related to epigenetic alterations in the orexin system.
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Frecuencia Cardíaca/fisiología , Nicotina/farmacología , Agonistas Nicotínicos/farmacología , Sueño/efectos de los fármacos , Envejecimiento/psicología , Animales , Peso Corporal/fisiología , Femenino , Hipotálamo/metabolismo , Inmunohistoquímica , Péptidos y Proteínas de Señalización Intracelular/fisiología , Masculino , Neuropéptidos/biosíntesis , Neuropéptidos/fisiología , Orexinas , Embarazo , Efectos Tardíos de la Exposición Prenatal/fisiopatología , Ratas , Ratas Sprague-Dawley , Frecuencia Respiratoria/fisiología , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Caracteres Sexuales , Transducción de Señal/fisiología , Sueño/fisiología , Sueño REM/fisiologíaRESUMEN
The present study was undertaken to test the hypothesis that dysregulation of the amygdala contributes to the exaggerated autonomic response to stress in an animal model of essential hypertension. Spontaneously hypertensive (SHR) and normotensive Wistar male rats were chronically instrumented and exposed to 20 min of either air jet stress (AJS) or air noise alone (CON). AJS induced a significant increase in both heart rate and arterial pressure that was greater in the SHR. AJS induced a significant increase in c-Fos-like immunoreactivity (FLI) throughout the caudal-rostral extent of the basolateral, medial, and central (CEA) subnuclei of the amygdala. Differences in FLI between strains were localized to the rostral CEA and the SHR expressed significantly less FLI. AJS also induced a significant increase in the number of corticotrophin releasing hormone (CRH) positive neurons in the CEA. Differences between strains were localized to the caudal CEA and the number of CRH-positive cells was significantly greater in the SHR. The stress-induced increase in CRH labeling in caudal CEA of the SHR was coupled to a greater increase in FLI in the rostral locus coeruleus (LC) of the SHR versus the Wistar. AJS also induced significant increases in FLI in several hypothalamus subnuclei, but no strain-related differences were identified. These results suggest for the first time that dysregulation of CRH-positive cells in the caudal CEA and reduced excitation and/or exaggerated inhibition of rostral CEA neurons may contribute to the exaggerated cardiovascular response to stress in the SHR, possibly through descending modulation of the rostral LC.
Asunto(s)
Amígdala del Cerebelo/metabolismo , Hormona Liberadora de Corticotropina/metabolismo , Hipertensión/metabolismo , Proteínas Proto-Oncogénicas c-fos/metabolismo , Estrés Fisiológico/fisiología , Adaptación Fisiológica , Animales , Hipertensión/psicología , Inmunohistoquímica , Masculino , Ratas , Ratas Endogámicas SHR , Ratas Wistar , Especificidad de la Especie , Distribución TisularRESUMEN
This study was undertaken to evaluate heart rate (HR) regulation during severe hemorrhage (HEM) at different rates of blood loss. Chronically instrumented male rats underwent HEM at one of three rates: slow (0.5 ml/min/kg; S-HEM), intermediate (1.0 ml/min/kg I-HEM), or 2.0 ml/min/kg (fast; F-HEM) until 30% of the estimated total blood volume (ETBV) was withdrawn. Heart rate variability analysis was performed and the absolute power within the low frequency (LF; 0.16-0.6 Hz) and high frequency (HF; 0.6-3 Hz) ranges was evaluated. During the first 15% of ETBV loss, arterial pressure (AP) was maintained while HR increased. The increase in HR was greatest in the S-HEM and I-HEM groups and was associated with a significant reduction in HF power in the S-HEM group only. As blood loss progressed, AP and HR declined in all treatment groups. The decrease in HR was associated with a significant increase in HF power in the F-HEM and I-HEM groups only. Parasympathetic blockade with atropine methyl bromide eliminated all decreases in HR, independent of the rate of hemorrhage. Blockade of parasympathetic activity also significantly increased the AP at ETBV losses > or =20% independent of the rate of hemorrhage. The effect of atropine on AP was most noticeable in the S-HEM and F-HEM groups. These results demonstrate that rate of blood loss has an important impact on autonomic regulation during severe HEM and support previous findings that neural strategies underlying autonomic control may vary depending on the rate of blood loss.
Asunto(s)
Frecuencia Cardíaca/fisiología , Hemorragia/fisiopatología , Análisis de Varianza , Animales , Atropina/farmacología , Presión Sanguínea/fisiología , Estado de Conciencia , Modelos Animales de Enfermedad , Electrocardiografía , Masculino , Parasimpatectomía/métodos , Parasimpatolíticos/farmacología , Ratas , Ratas Sprague-Dawley , Espectrometría RamanRESUMEN
The dorsal periaqueductal gray (dPAG) is an essential neural component for central integration of defense behavior and associated autonomic regulation. Electrical and chemical stimulation of this region results in a significant decrease of inspiratory (Ti) and expiratory (Te) breathing durations. In the present study it was hypothesized that breath timing changes elicited by dPAG activation would modulate respiratory load compensation volume-timing reflexes. The effect of dPAG activation of breathing pattern was investigated using chemical stimulation with microinjection of the excitatory amino acid D,L-homocysteic acid (DLH) or disinhibition with GABA(A) (gamma-aminobutyric acid) receptor antagonist bicuculline (BIC) in urethane-anesthetized, spontaneously breathing rats. Volume-timing reflexes were studied using inspiratory and expiratory occlusion before and after DLH or BIC dPAG activation. Both BIC and DLH activation of the dPAG significantly increased breathing frequency. Inspiratory occlusion significantly increased Ti before dPAG activation and DLH and BIC potentiated the relative increase in Ti during occlusion. BIC elicited a greater increase in inspiratory occlusion Ti than DLH. Inspiratory occlusion alone also significantly increased diaphragm EMG activity and this response was potentiated with dPAG activation. Expiratory occlusion significantly increased Te and DLH and BIC potentiated the relative increase in Te during expiratory occlusion. These results suggest that dPAG activation modulates the respiratory neural network, resulting in an increased respiratory drive and a decrease in volume-timing reflex sensitivity.
Asunto(s)
Sustancia Gris Periacueductal/fisiología , Reflejo/fisiología , Respiración , Animales , Bicuculina/farmacología , Diafragma/efectos de los fármacos , Diafragma/fisiología , Electromiografía/métodos , Antagonistas del GABA/farmacología , Homocisteína/análogos & derivados , Homocisteína/farmacología , Masculino , Sustancia Gris Periacueductal/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Reflejo/efectos de los fármacos , Respiración/efectos de los fármacos , Estimulación Química , Factores de TiempoRESUMEN
The periaqueductal gray (PAG) is a central neural region essential for defense behavior and coordination of accompanying autonomic responses. Activation of rostral versus caudal dorsal (dPAG) regions mediates different cardiovascular response patterns. Stimulation of the dPAG also elicits increased respiratory activity, however, it is unknown if there is a regional difference in dPAG modulation of respiratory pattern. The present study was undertaken to identify whether activation of rostral vs caudal dPAG modulates respiration differently. In anesthetized, spontaneously breathing rats, chemical and electrical stimulation in rostral and caudal dPAG evoked an increased respiratory frequency (f(R)) with significant shortening of both inspiratory (Ti) and expiratory time (Te). Stimulation in the dPAG also evoked significant increases in electromyography activity of the diaphragm (dEMG), arterial pressure, and heart rate. Caudal dPAG stimulation evoked a greater increase in f(R) due to a significantly greater decrease in Ti and Te than the rostral dPAG. Caudal dPAG stimulation also evoked a greater increase in baseline dEMG activity and elicited a significantly greater increase in dEMG amplitude above baseline than rostral dPAG. There was a rostro-caudal difference in the post-stimulus respiratory recovery response, with the caudal dPAG eliciting a longer sustained effect. No regional differences were identified in the arterial blood pressure and heart rate during dPAG stimulation. The results demonstrate that the magnitude of the respiratory response during and immediately after activation of the caudal dPAG is greater than during rostral dPAG stimulation.
Asunto(s)
Diafragma/inervación , Diafragma/fisiología , Espiración/fisiología , Inhalación/fisiología , Sustancia Gris Periacueductal/fisiología , Animales , Estimulación Eléctrica , Electromiografía , Espiración/efectos de los fármacos , Homocisteína/análogos & derivados , Homocisteína/farmacología , Inhalación/efectos de los fármacos , Masculino , Microinyecciones , Sustancia Gris Periacueductal/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Estimulación QuímicaRESUMEN
Activation of the dorsal periaqueductal gray (PAG) evokes defense-like behavior including a marked increase in sympathetic drive and resetting of baroreflex function. The goal of this study was to investigate the role of the lateral parabrachial nucleus (LPBN) in mediating dorsal PAG modulation of the arterial baroreflex. Reflex responses were elicited by electrical stimulation of the aortic depressor nerve (ADN) at 5 Hz or 15 Hz in urethane anesthetized rats (n=18). Electrical stimulation of the dorsal PAG at 10 Hz did not alter baseline mean arterial pressure (MAP) but did significantly attenuate baroreflex control of heart rate (HR) evoked by low frequency ADN stimulation. Alternatively, 40 Hz dorsal PAG stimulation increased baseline MAP (43+/-3 mm Hg) and HR (33+/-3 bpm) and attenuated baroreflex control of HR at both ADN stimulation frequencies. Reflex control of MAP was generally unchanged by dorsal PAG stimulation. Bilateral inhibition of neurons in LPBN area (n=6) with muscimol (0.45 nmol per side) reduced dorsal PAG-evoked increases in MAP and HR by 50+/-4% and 95+/-4%, respectively, and significantly reduced, but did not completely eliminate dorsal PAG attenuation of the cardiac baroreflex. Bilateral blockade of glutamate receptors in the LPBN area (n=6) with kynurenic acid (1.8 nmol) had a similar effect on dorsal PAG-evoked increases in MAP, HR and cardiac baroreflex function. Reflex control of MAP was unchanged with either treatment. These findings suggest that the LPBN area is one of several brainstem regions involved in descending modulation of the cardiac baroreflex function during defensive behavior.
Asunto(s)
Barorreflejo/fisiología , Corazón/fisiología , Vías Nerviosas/fisiología , Neuronas/fisiología , Sustancia Gris Periacueductal/fisiología , Puente/fisiología , Animales , Barorreflejo/efectos de los fármacos , Presión Sanguínea/efectos de los fármacos , Presión Sanguínea/fisiología , Estimulación Eléctrica , Antagonistas de Aminoácidos Excitadores/farmacología , Agonistas del GABA/farmacología , Corazón/inervación , Frecuencia Cardíaca/efectos de los fármacos , Frecuencia Cardíaca/fisiología , Masculino , Muscimol/farmacología , Vías Nerviosas/anatomía & histología , Sustancia Gris Periacueductal/anatomía & histología , Puente/anatomía & histología , Ratas , Ratas Sprague-Dawley , Receptores de Glutamato/efectos de los fármacos , Receptores de Glutamato/metabolismo , Nervio Vago/fisiología , Aferentes Viscerales/efectos de los fármacos , Aferentes Viscerales/fisiologíaRESUMEN
The central mechanisms underlying the transition from compensation to decompensation during severe hemorrhage (HEM) are poorly understood. Furthermore, a lack of consistency in HEM protocols exists in the current literature. This study assessed the cardiovascular response and Fos-like immunoreactivity (FLI) in specific brain regions following severe HEM at three rates (2, 1, or 0.5 ml.kg(-1).min(-1)) in conscious rats. Heart rate (HR) and arterial pressure were recorded during the withdrawal of 30% of total blood volume (TBV). Data from animals hemorrhaged at the fast (F-HEM, n = 6), intermediate (I-HEM, n = 7), or slow (S-HEM, n = 7) rates were compared with saline (SAL, n = 5) and hypotensive (hydrazaline-induced, HYDRAZ, n = 5) controls. All HEM rates produced similar degrees of hypotension at the time of 30% TBV withdrawal. All HEM rates also produced bradycardia, but the change in HR was only significant in the F-HEM and I-HEM groups. Associated with I-HEM and F-HEM, but not HYDRAZ treatment were significant increases in FLI in the caudal ventrolateral periaqueductal gray (PAG), the central lateral nucleus of the rostral parabrachial nucleus, and locus coeruleus compared with SAL treatment. I-HEM also induced significant increases in FLI in the dorsomedial PAG, A7 region, and the cuneiform nucleus compared with SAL. S-HEM did not induce any significant change in FLI. Our results suggest that HEM at a rate of 1 ml.kg(-1).min(-1) may be most useful for investigating the potential role of the rostral brainstem regions in mediating hemorrhagic decompensation in conscious rats.