Is the guinea pig a full negative model to study the carotid mediated chronic intermittent hipoxia effects?

Abstract

Chronic Intermittent Hypoxia (CIH) is considered to be one of the main causes of systemic arterial hypertension observed in the obstructive sleep apnea syndrome. It is thought that repetitive episodes of hypoxia/re-oxygenation produce oxidative stress, inflammation and sympathetic hyperactivity, generating endothelial dysfunction and systemic hypertension. It has been proposed that the repeated carotid body (CB) stimulation produced by CIH would induce CB sensitization, increasing chemoreceptor input to the brainstem that originates an exaggerated sympathetic reflex with a rise of circulating catecholamine (CA) and hypertension. Unlike other rodents, preliminary data show a lack of CB sensitivity to acute hypoxia in guinea pigs, in which case, CIH would not induce CB sensitization and the effects derived from the CB hyperactivity would not be observed. Therefore, guinea pigs could be a negative control model to study the effects of CIH mediated by CB. In this study, experiments were performed on adult male Hartley guinea pigs (475±10 g; n=32) control or exposed to CIH (21% O2-80 s/5% O2-40s 8h/day; 30 days). Ventilatory parameters (tidal volume and respiratory rate) were measured in freely moving animals by whole body plethysmography; other measurements were performed on animals anaesthetized with a mixture of ketamine (100 mg/Kg) and diazepam (2 mg/Kg; ip.). Control and CIH guinea pig respiratory minute volume exhibited similar changes when acute hypoxic test was applied (399±5 vs 411±5 in air and 417±15 vs 456±17 ml/min/Kg in 10% O2; n=16). Values are means ± S.E.M. compared by ANOVA. There were no in vitro CB responses to acute hypoxia (CA secretion or Ca2+i changes) in either group of animals. No differences were found in mean arterial blood pressure (37±2 vs 43±3 mmHg; n=8), or in plasma and tissue CA levels (CB, adrenal medulla, renal artery) measured after exposure to CIH. The fact that the guinea pig CB is hypo-functional and is not sensitized by CIH would reinforce our working hypothesis: systemic effects associated to CIH in other species and absent in guinea pigs are due to the CB hyperactivity induced by CIH. However several unexpected results would indicate hypoxic activation of the sympathetic system during acute hypoxic test as increased arterial pulse pressure (20±1 mmHg in air and 28±2 mmHg in 10% O2; p<0.01; n=8), rise of heart rate (25%; p<0.01), renal artery CA synthesis (32%; p<0.05) and CB hypotrophy (50%; p<0.05) after CIH treatment. These results suggest that guinea pigs possess O2-sensitivity responsible for the sympathetic cardio-circulatory reflex, probably through CB stimulation, the main oxygen sensing structure mediating this reflex. The mechanisms are being studied.