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

Abstract

Carotid body (CB) hyperactivity promotes hypertension in response to chronic intermittent hypoxia (CIH). The plasma concentration of adrenaline is reported to be elevated in CIH and our previous work suggests that adrenaline directly activates the CB. However, a role for chronic adrenergic stimulation in mediating CB hyperactivity is currently unknown. This study evaluated whether beta-blocker treatment with propranolol (Prop) prevented the development of CB hyperactivity, vascular sympathetic nerve growth and hypertension caused by CIH. Adult male Wistar rats were assigned into 1 of 4 groups: Control (N), N + Prop, CIH and CIH + Prop. The CIH paradigm consisted of 8 cycles h−1, 8 h day−1, for 3 weeks. Propranolol was administered via drinking water to achieve a dose of 40 mg kg−1 day−1. Immunohistochemistry revealed the presence of both β1 and β2-adrenoceptor subtypes on the CB type I cell. CIH caused a 2–3-fold elevation in basal CB single-fibre chemoafferent activity and this was prevented by chronic propranolol treatment. Chemoafferent responses to hypoxia and mitochondrial inhibitors were attenuated by propranolol, an effect that was greater in CIH animals. Propranolol decreased respiratory frequency in normoxia and hypoxia in N and CIH. Propranolol also abolished the CIH mediated increase in vascular sympathetic nerve density. Arterial blood pressure was reduced in propranolol groups during hypoxia. Propranolol exaggerated the fall in blood pressure in most (6/7) CIH animals during hypoxia, suggestive of reduced sympathetic tone. These findings therefore identify new roles for β-adrenergic stimulation in evoking CB hyperactivity, sympathetic vascular hyperinnervation and altered blood pressure control in response to CIH.

Chronic intermittent hypoxia remodels catecholaminergic nerve innervation in mouse atria

“…Of note, CIH also induces substantial vasoconstriction and hypertrophy of the pulmonary veins (Gao & Raj, 2005). Furthermore, vascular sympathetic nerve density was reported to induce hypertension following CIH, which was confirmed by using β-adrenoceptors blockers to inhibit the increase in sympathetic nerve density and CIH-induced hypertension (Alzahrani et al, 2021). Additionally, patients with OSA produce sympathetic hyperactivity mediated by increased muscle sympathetic neural activity to blood vessels with endothelial dysfunction and vascular remodelling (Carlson et al, 1993;Patt et al, 2010).…”

The Role of Pharmacological Treatment in the Chemoreflex Modulation

“…Therefore non-selective or NO-active beta-blockers should be preferred, when PChS modulation is aimed. This observation is particularly interesting in the contest of the recently described protective mechanism of propranolol (non-selective β-blocker) on chronic IH induced hypertension in rats ( Alzahrani et al, 2021 ).…”

“…According to the published evidence, it seems that the crucial physiological role of catecholamines in CB is self-limitation of the amplitude and persistence of the response to acute stimulation (PChS modulation) ( Prabhakar, 1994 ). Nevertheless, it was shown recently, that the pre-treatment with propranolol (non-selective beta-blocker) prevents the development of chronic intermittent hypoxia (IH) induced increase in PChT ( Alzahrani et al, 2021 ). It should be finally mentioned, that adrenergic drugs exerts also direct vasomotor effects modulating the perfusion of CB, which may influence the organ functionality ( Iturriaga et al, 2016 ).…”

Mitochondrial Succinate Metabolism and Reactive Oxygen Species Are Important but Not Essential for Eliciting Carotid Body and Ventilatory Responses to Hypoxia in the Rat

“…Respiratory parameters in unrestrained awake animals were recorded using whole body plethysmography (WBP) specifically designed for rats as described [ 34 ]. Gas flow into the chamber was approximately 2 L min −1 .…”