Guinea Pig as a Model to Study the Carotid Body Mediated Chronic Intermittent Hypoxia Effects

Abstract

Clinical and experimental evidence indicates a positive correlation between chronic intermittent hypoxia (CIH), increased carotid body (CB) chemosensitivity, enhanced sympatho-respiratory coupling and arterial hypertension and cardiovascular disease. Several groups have reported that both the afferent and efferent arms of the CB chemo-reflex are enhanced in CIH animal models through the oscillatory CB activation by recurrent hypoxia/reoxygenation episodes. Accordingly, CB ablation or denervation results in the reduction of these effects. To date, no studies have determined the effects of CIH treatment in chemo-reflex sensitization in guinea pig, a rodent with a hypofunctional CB and lacking ventilatory responses to hypoxia. We hypothesized that the lack of CB hypoxia response in guinea pig would suppress chemo-reflex sensitization and thereby would attenuate or eliminate respiratory, sympathetic and cardiovascular effects of CIH treatment. The main purpose of this study was to assess if guinea pig CB undergoes overactivation by CIH and to correlate CIH effects on CB chemoreceptors with cardiovascular and respiratory responses to hypoxia. We measured CB secretory activity, ventilatory parameters, systemic arterial pressure and sympathetic activity, basal and in response to acute hypoxia in two groups of animals: control and 30 days CIH exposed male guinea pigs. Our results indicated that CIH guinea pig CB lacks activity elicited by acute hypoxia measured as catecholamine (CA) secretory response or intracellular calcium transients. Plethysmography data showed that only severe hypoxia (7% O2) and hypercapnia (5% CO2) induced a significant increased ventilatory response in CIH animals, together with higher oxygen consumption. Therefore, CIH exposure blunted hyperventilation to hypoxia and hypercapnia normalized to oxygen consumption. Increase in plasma CA and superior cervical ganglion CA content was found, implying a CIH induced sympathetic hyperactivity. CIH promoted cardiovascular adjustments by increasing heart rate and mean arterial blood pressure without cardiac ventricle hypertrophy. In conclusion, CIH does not sensitize CB chemoreceptor response to hypoxia but promotes cardiovascular adjustments probably not mediated by the CB. Guinea pigs could represent an interesting model to elucidate the mechanisms that underlie the long-term effects of CIH exposure to provide evidence for the role of the CB mediating pathological effects in sleep apnea diseases.

Chronic intermittent hypoxia‐induced hypertension: An expired hypothesis laid to rest?

“…Increased tonicity in carotid body chemoafferent discharge is considered to be a major driver of maladaptive cardiorespiratory outcomes in experimental models of CIH. However, it was recently established that carotid body sensitization is not obligatory for the development of CIH‐induced hypertension (Docio et al., ). It is established that exposure to CIH evokes plasticity within CNS circuits controlling cardiorespiratory function.…”

Efectos inducidos por la hipoxia crónica intermitente en rata y cobaya como modelos animales de la apnea obstructiva del sueño

“…Nuestros datos apoyan parcialmente esta hipótesis, mostrando que los cobayas, comparados con las ratas, tienen un cambio muy pequeño de presión arterial sistémica después de la HCI 288 295,296 . Esta podría ser la razón por la cual los pacientes con AOS, con ciclos de hipoxia grave durante el sueño, no presentan policitemia 297,298 .…”

“…Previamente, se había observado que los cobayas anestesiados tienen una PO2 en sangre arterial considerablemente baja de 60mmHg 129 . Este hallazgo, comparable a otros valores de PaO2 de 66 a 57mmHg descritos en cobayas despiertos y anestesiados [299][300][301] , no se ve afectado después de la exposición a HCI, con presiones de 64mmHg frente a 65mmHg en controles 288 . A diferencia de las ratas hemos medido la saturación de la HbO2 en el cobaya por presentar una P50 parecida a la de los humanos.…”

“…un aumento en los niveles de CA plasmáticos; y iv. un aumento de la síntesis de CA en la arteria renal (~40%) 288 . Los cobayas son animales hipotensos en comparación con otros roedores 129,301 , lo cual se ha relacionado con un tono noradrenérgico disminuido y un aumento de la capilaridad en los tejidos periféricos que disminuye las resistencias periféricas.…”

“…El aumento de los niveles plasmáticos de CA, los niveles aumentados de glucosa en ayunas y las modificaciones de la presión arterial observadas en los cobayas tras la HCI podrían tener su origen en la sensibilización de la MA a la hipoxia. Encontramos un aumento endógeno de CA (principalmente NE) en GCS, pero no hay cambios en el contenido de CA en la MA 288 .…”