<b>Glomus cells expansion drive carotid body hyperplasia and contribute to exacerbated ATP transmission in spontaneously hypertensive rats</b>

Aims: ATP acting on P2X3 receptors underpins carotid body (CB) chemoreflex hyperexcitability in the spontaneously hypertensive rat (SHR). However, whether this reflects differences in the amount of ATP released and/or its break down remains elusive. We tested the hypothesis that more ATP is released in CB of SHRs due to its enlarged size and down regulations of ectonucleotide degrading enzymes. Methods: We used multipronged approach to (1) quantify the amount of ATP released from CBs and dissociated glomus cells of Wistar and SHRs, (2) measure the level of gene expression for specific targets, (3) carry out a comparative morphometric study in CBs of both strains, and (4) to functionally test the contribution of both ATP and adenosine transmissions on CB hyperexcitability in SHRs. Results: The CBs of SHR released higher levels of ATP than Wistar rats (P&lt;0.05). Interestingly, ATP depletion was similar between dissociated glomus cells from both strains. This result was associated with both a downregulation of enzyme transcripts Enpp1,3 and Entpd2 (P&lt;0.05). Tyrosine hydroxylase positive area was disproportionally increased in the hyperplasic CB of SHRs (p&lt;0.05). The latter is followed by greater transcript abundance of Epas1, the gene encoding HIF-2α (p&lt;0.05). Focal topical application of ATP or α, β-methylene ATP to the CB produced tachypnoea and sympathetic activation; the latter was greater in SHR relative to Wistars rats (P&lt;0.05). In vitro, adenosine infusions (500 µM) evoked sensitised carotid sinus nerve (CSN) firing in SHRs (P&lt;0.05); however, under normoxia, antagonism of adenosine receptor A2A attenuated CSN tonic firing similarly between strains (P&gt;0.05). Conclusions: The increased ATP release from the CB of SHR may reflect its larger size, which could be potentiated by down regulated enzymes that metabolise ATP. Although the CB of SHR show a sensitised response to exogenous adenosine, the latter does not contribute to CB hyperexcitability.