Targeting ecto-5'-nucleotidase (CD73) and cAMP alleviates carotid body hyperactivity and reduces blood pressure in...

Chronic hypoxia (CH) is a key feature of chronic obstructive pulmonary disease (COPD), and carotid body hyperactivity is a major contributor to the cardiovascular pathology seen in these patients. CD73, an ecto-5'-nucleotidase that converts AMP to adenosine, is functionally important in the healthy carotid body. However it is unknown if CD73 contributes to carotid body hyperactivity associated with CH. The current work investigated whether selective targeting of CD73 could attenuate carotid body hyperactivity and ameliorate cardiovascular function in CH animals. CH rats (F_iO₂ of 12% for 10 days) exhibited basal carotid body chemoafferent hyperactivity, augmented hypoxic sensitivity and increased minute ventilation. Immunohistochemical analysis demonstrated that CH increased the number of tyrosine hydroxylase positive (TH⁺) type I cells containing CD73 (CD73⁺TH⁺) within the carotid body. Pharmacological inhibition of CD73 using α, β-methylene ADP (AOPCP) abolished CH-induced basal chemoafferent hyperactivity and normalised the heightened hypoxic sensitivity ex vivo. These effects were largely mimicked by the transmembrane adenylyl cyclase (tmAC) inhibitor SQ22536. In vivo administration of AOPCP to CH animals caused a dose-dependent decrease in arterial blood pressure, an effect that was attenuated following carotid sinus nerve section (CSNX). Therefore this research identifies CD73 and tmAC as important determinants of carotid body hyperactivity associated with CH. Effective targeting of CD73 alleviates carotid body hyperactivity, leading to a decrease in blood pressure, without abolishing reflex responses to hypoxia. These findings should be a first step towards the development of selective CD73/tmAC targeted therapies in the carotid body to safely improve cardiovascular outcomes in CH patients. KEY POINTS: Chronic hypoxia (CH), a key feature of chronic obstructive pulmonary disease, causes carotid body hyperactivity and cardiovascular pathology. The current work evaluated whether ecto-5'-nucleotidase (CD73) is important in promoting carotid body hyperactivity in CH animals. CH increases the proportion of type I cells containing CD73 (CD73⁺TH⁺) in the carotid body. Pharmacological targeting of CD73 and transmembrane adenylyl cyclases (tmAC) abolishes basal carotid body chemoafferent hyperactivity in CH and normalises the exaggerated responses to acute hypoxia ex vivo. In vivo inhibition of CD73 induces a dose-dependent decrease in arterial blood pressure in normoxia, which is attenuated following carotid sinus nerve section. However AOPCP does not abolish cardiovascular-respiratory responses to severe hypoxia. CD73 and tmAC are important in promoting carotid body hyperactivity in CH. Selective targeting of CD73 and cAMP signalling may safely reduce carotid body hyperactivity and thus improve cardiovascular outcomes in chronically hypoxic patients.