Effects of vagotomy on cardiovascular and heart rate variability alterations following chronic normobaric hypoxia in adult rabbits

BACKGROUND: chronic hypoxia increases basal ventilation and pulmonary vascular resistance, with variable changes in arterial blood pressure and heart rate, but it's impact on heart rate variability and autonomic regulation have been less well examined. We studied changes in arterial blood pressure, heart rate and heart rate variability (HRV) in rabbits subjected to chronic normobaric hypoxia (CNH; PB ~ 719 mmHg; FIO2 ~ 9.2%) for 14 days and assess the effect of autonomic control by acute bilateral vagal denervation. RESULTS: exposure to CNH stalled animal weight gain and increased the hematocrit, without affecting heart rate or arterial blood pressure. Nevertheless, Poincaré plots of the electrocardiographic R-R intervals showed a reduced distribution parallel to the line of identity, which interpreted as reduced long-term HRV. In the frequency domain, CNH reduced the very-low- (< 0.2 Hz) and high-frequency components (> 0.8 Hz) of the R-R spectrograms and produced a prominent component in the low-frequency component (0.2-0.5 Hz) of the power spectrum. In control and CNH exposed rabbits, bilateral vagotomy had no apparent effect on the short- and long-term HRV in the Poincaré plots. However, bilateral vagotomy differentially affected higher-frequency components (> 0.8 Hz); reducing it in control animals without modifying it in CNH-exposed rabbits. CONCLUSIONS: These results suggest that CNH exposure shifts the autonomic balance of heart rate towards a sympathetic predominance without modifying resting heart rate or arterial blood pressure.

Carotid body Thermoreceptors, sympathetic neural activation, and cardiometabolic disease

The carotid body (CB) is the main peripheral chemoreceptor that senses the arterial PO2, PCO2 and pH. In response to hypoxemia, hypercapnia and acidosis, carotid chemosensory discharge elicits reflex respiratory, autonomic and cardiovascular adjustments. The classical construct considers the CB as the main peripheral oxygen sensor, triggering reflex physiological responses to acute hypoxemia and facilitating the ventilatory acclimation to chronic hypoxemia at high altitude. However, a growing body of experimental evidence supports the novel concept that an abnormally enhanced CB chemosensory input to the brainstem contributes to overactivation of the sympathetic nervous system, and consequent pathology. Indeed, the CB has been implicated in several diseases associated with increases in central sympathetic outflow. These include hypertension, heart failure, sleep apnea, chronic obstructive pulmonary disease and metabolic syndrome. Indeed, ablation of the CB has been proposed for the treatment of severe and resistant hypertension in humans. In this review, we will analyze and discuss new evidence supporting an important role for the CB chemoreceptor in the progression of autonomic and cardiorespiratory alterations induced by heart failure, obstructive sleep apnea, chronic obstructive pulmonary disease and metabolic syndrome.

Antioxidant and anti hyperglycemic role of wine grape powder in rats fed with a high fructose diet

BACKGROUND: Metabolic syndrome is a growing worldwide health problem. We evaluated the effects of wine grape powder (WGP), rich in antioxidants and fiber, in a rat model of metabolic syndrome induced by a high fructose diet. We tested whether WGP supplementation may prevent glucose intolerance and decrease oxidative stress in rats fed with a high fructose diet. METHODS: Male Sprague-Dawley rats weighing 180 g were divided into four groups according to their feeding protocols. Rats were fed with control diet (C), control plus 20 % WGP (C + WGP), 50 % high fructose (HF) or 50 % fructose plus 20 % WGP (HF + WGP) for 16 weeks. Blood glucose, insulin and triglycerides, weight, and arterial blood pressure were measured. Homeostasis model assessment (HOMA) index was calculated using insulin and glucose values. A glucose tolerance test was performed 2 days before the end of the experiment. As an index of oxidative stress, thio-barbituric acid reactive substances (TBARS) level was measured in plasma and kidney, and superoxide dismutase was measured in the kidney. RESULTS: Thiobarbituric acid reactive substances in plasma and renal tissue were significantly higher when compared to the control group. In addition, the area under the curve of the glucose tolerance test was higher in HF fed animals. Furthermore, fasting blood glucose, plasma insulin levels, and the HOMA index, were also increased. WGP supplementation prevented these alterations in rats fed with the HF diet. We did not find any significant difference in body weight or systolic blood pressure in any of the groups. CONCLUSIONS: Our results show that WGP supplementation prevented hyperglycemia, insulin resistance and reduced oxidative stress in rats fed with HF diet. We propose that WGP may be used as a supplement in human food as well.

Fisiopatología de la hipertensión asociada al síndrome de apnea obstructiva del sueño: Evidencia de estudios clínicos y modelos animales de hipoxia crónica intermitente / Pathophysiology of obstructive sleep apnea-associated hypertension

There is a well established relationship between the obstructive sleep apnea syndrome and hypertension. Current evidence suggests that the increase in arterial pressure is secondary to an enhanced sympathetic tone through peripheral chemoreflexes triggered by intermittent hypoxic stimulation of the carotid bodies. Chronic intermittent hypoxia would activate renal and systemic vasoactive systems through potentiated hypoxic chemoreflexes. These early changes in autonomic tone can be detected through cardiovascular variability and baroreflex sensitivity analysis. Both are relatively simple and noninvasive techniques. The multiplicity of pathogenic mechanisms in obstructive sleep apnea-associated hypertension emphasizes the need of increasing diagnostic sensitivity to detect and correct this common condition, which significantly increases cardiovascular risk.

Cardiovascular and ventilatory acclimatization induced by chronic intermittent hypoxia: A role for the carotid body in the pathophysiology of sleep apnea

Patients with obstructive sleep apnea (OSA) show augmented ventilatory, sympathetic and cardiovascular responses to hypoxia. The facilitatory effect of chronic intermittent hypoxia (CIH) on the hypoxic ventilatory response has been attributed to a potentiation of the carotid body (CB) chemosensory response to hypoxia. However, it is a matter of debate whether the effects induced by CIH on ventilatory responses to hypoxia are due to an enhanced CB activity. Recently, we studied the effects of short cyclic hypoxic episodes on cat cardiorespiratory reflexes, heart rate variability, and CB chemosensory activity. Cats were exposed to cyclic hypoxic episodes repeated during 8 hours for 4 days. Our results showed that CIH selectively enhanced ventilatory and carotid chemosensory responses to acute hypoxia. Exposure to CIH did not increase basal arterial pressure, heart rate, or their changes induced by acute hypoxia. However, the spectral analysis of heart rate variability of CIH cats showed a marked increase of the low/high frequency ratio and an increased variability in the low frequency band of heart rate variability, similar to what is observed in OSA patients. Thus, it is likely that the enhanced CB reactivity to hypoxia may contribute to the augmented ventilatory response to hypoxia.

Nitric oxide and carotid body chemoreception

Nitric oxide (NO) has been proposed as an inhibitory modulator of carotid body chemosensory responses to hypoxia. It is believed that NO modulates carotid chemoreception by several mechanisms, which include the control of carotid body vascular tone and oxygen delivery and reduction of the excitability of chemoreceptor cells and petrosal sensory neurons. In addition to the well-known inhibitory effect, we found that NO has a dual (dose-dependent) effect on carotid chemoreception depending on the oxygen pressure level. During hypoxia, NO is primarily an inhibitory modulator of carotid chemoreception, while in normoxia NO increased the chemosensory activity. This excitatory effect produced by NO is likely mediated by an impairment of mitochondrial electron transport and oxidative phosphorylation, which increases the chemosensory activity. The recent findings that mitochondria contain an isoform of NO synthase, which produces significant amounts of NO for regulating their own respiration, suggest that NO may be important for the regulation of mitochondrial energy metabolism and oxygen sensing in the CB.

Contribution of carotid body chemoreceptors and carotid sinus baroreceptors to the ventilatory and circulatory reflexes produced by common carotid occlusion

En 16 gatos adultos anestesiados con pentobarbitoma y con respiración espontânea, se estuddió los efectos tobaritona y con respiración espontánea, se estudió los efectos evocados por oclusiones de las carótidas comunes de 1 minuto de duración. Las oclusiones unilaterales provocaron caidas de la presión intrasinusal ipsilateral y alzas de la presión arterial sistémica (a 111.5% de la basal). Las oclusiones bilaterales produjeron caidas más pronunciadas de la presión intrasinusal y alzas mayores de la presión arterial sistémica (a 137.5% de la basal), esta vez acompañadas de taquicardia e hiperventilación alveolar y pulmonar. El volumen minuto ciclo a ciclo aumentó (máxima promedio 144.7% de la basal), siendo mayor la contribución del alza del volumen corriente que la del incremento en frecuencia respiratoria. La hiperventilación máxima se relacionó en forma inversa y no lineal a la presión intrasinusal mínima alcanzada al inicio de la oclusión; después la hiperventilación se atenúa a medida que la presión intrasinusal se recupera parcialmente. La barodenervación selectiva de los senos carotídeos redujo las respuestas presoras a las oclusiones bilaterales, sin afectar las respuestas ventilatorias. En gatos con senos carotídeos con inervación intacta o barodenervación, las oclusiones bilaterales realizadas durante ventilación con O2 100% no modificaron las caídas de la presión intrasinusal ni las alzas presoras, pero disminuyeron y retardarón o incluso abolieron las respuestas ventilatorias. La naturaleza refeja de los cambios circulatorios y respiratorios provocados por oclusión carotidea se demostró por su desaparición luego de la sección de ambos nervios carotídeos (sinusales de Hering). Los resultados obtenidos indican que mientras la excitación quimiosensorial es la principal responsable de la respuesta ventilatoria a la oclusión carotídea, la desactivación barosensorial contribuê mayormente a la respuesta circulatoria a dicha maniobra

Carotid body chemoreceptor excitation produced by carotid occlusión

En 20 gatos adultos anestesiados con pentobarbitona, se registró la actividad eléctrica aferente del nervio carotídeo (sinusal). La oclusión de la arteria carótida común ipsilateral disminuyó la presión intrasinusal a 15-100 torr (dependiendo de la presión previa) y silenció la descarga barosensorial. En gatos que respiraban aire y con presión arterial media bajo 125 torr, la oclusión ipsilateral produjo aumento de la frecuencia de descarga quimiosensorial, de aparición rápida (latencia = 4 s), que alcanzó el máximo a los 30 s y después se mantuvo a un nivel submáximo de descarga (80-90% de la frecuencia máxima) al menos por 10 minutos. La oclusión carotídea ipsilateral practicada a estos mismos gatos mientras respiraban 100% O2 produjo excitación quimiosensorial de comienzo más tardío (latencia = 20 s) y menor magnitud (30-40% de la frecuencia máxima en normoxia). La oclusión carotídea ipsilateral practicada cuando la presión arterial media estaba sobre 130 torr sólo aumentó transitoriamente la frecuencia quimiosensorial o suprimió su fluctuación ventilatoria. La oclusión carotídea bilateral redujo pronunciadamente la presión intrasinusal y aumentó considerablemente la frecuencia quimiosensorial. La aplicación de estímulos químicos (inhalación de 100% N2 por 5-10 s, inyección i.v. de NaCN) durante las oclusiones carotídeas aumentó más aún la frecuencia de descarga quimiosensorial, indicando que el flujo sanguíneo a través del cuerpo carotídeo no estaba detenido. Se concluye que la oclusión carotídea puede provocar excitación quimiosensorial, cuya magnitud depende de la duración de la maniobra y condiciones circulatorias y ventilatorias prevalentes. Se sugiere que la excitación quimiosensorial podría interactuar con la desactivación barosensorial en la generación de los cambios reflejos evocados por oclusión carotídea