Peripheral Dopamine 2-Receptor Antagonist Reverses Hypertension in a Chronic Intermittent Hypoxia Rat Model

Abstract

The sleep apnea-hypopnea syndrome (SAHS) involves periods of intermittent hypoxia, experimentally reproduced by exposing animal models to oscillatory PO2 patterns. In both situations, chronic intermittent hypoxia (CIH) exposure produces carotid body (CB) hyperactivation generating an increased input to the brainstem which originates sympathetic hyperactivity, followed by hypertension that is abolished by CB denervation. CB has dopamine (DA) receptors in chemoreceptor cells acting as DA-2 autoreceptors. The aim was to check if blocking DA-2 receptors could decrease the CB hypersensitivity produced by CIH, minimizing CIH-related effects. Domperidone (DOM), a selective peripheral DA-2 receptor antagonist that does not cross the blood-brain barrier, was used to examine its effect on CIH (30 days) exposed rats. Arterial pressure, CB secretory activity and whole-body plethysmography were measured. DOM, acute or chronically administered during the last 15 days of CIH, reversed the hypertension produced by CIH, an analogous effect to that obtained with CB denervation. DOM marginally decreased blood pressure in control animals and did not affect hypoxic ventilatory response in control or CIH animals. No adverse effects were observed. DOM, used as gastrokinetic and antiemetic drug, could be a therapeutic opportunity for hypertension in SAHS patients’ resistant to standard treatments.

β-Adrenoceptor blockade prevents carotid body hyperactivity and elevated vascular sympathetic nerve density induced by chronic intermittent hypoxia

“…In our experiments, CIH elevated normoxic ventilation but not the response to hypoxia. A heightened chemoafferent output in hypoxia and increased hypoxic ventilatory response after CIH has been reported in some studies [ 8 , 41 , 43 ] but not all [ 40 , 48 , 61 ]. Nevertheless, this was a somewhat unexpected finding.…”

Analysis of Bone Histomorphometry in Rat and Guinea Pig Animal Models Subject to Hypoxia

“…The weight did not differ between group 1 and 2 ( p -value = 0.282). Chronic intermittent hypoxia was characterized by 5% O 2 for 40 s, then 20% O 2 for 80 s (30 episodes/h), 8 h/day (from 8:00 to 16:00), for 15 days), as previously described in [ 40 , 41 ]. The rats subjected to chronic constant hypoxia were exposed to 12% O 2 .…”

“…In addition, male guinea pigs (three months old) were used and divided into controls ( n = 5) and the animals were exposed to chronic intermittent hypoxia ( n = 6) for 15 days. The number of experimental units were determined according to previous reports from our group [ 40 , 41 ], and with the aim of complying the principles of the three Rs of experimental animal welfare. All animals had free access to standard food and water and were maintained under the controlled conditions of temperature, humidity, and a stationary light–dark cycle.…”

G-Protein-Coupled Receptor (GPCR) Signaling in the Carotid Body: Roles in Hypoxia and Cardiovascular and Respiratory Disease

“…The alteration in D 2 -receptor expression has been hypothesized to cause a change in DA signaling in the CB which contributes to the changes in ventilatory adaptation observed with long-term hypoxia associated with chronic obstructive pulmonary disease (COPD) or HF [ 78 ]. A role for DA in establishing CB hyperactivity in response to CIH has recently been investigated [ 79 ]. In this study, CIH augmented CB DA content, CB catecholamine release and arterial blood pressure, but not the HVR.…”