<b>Exacerbated ATP transmission in the carotid body is linked to glomus cell proliferation in spontaneously hypertensive rats</b>

ATP acting on P2X3 receptors underpins carotid body (CB) hyperexcitability in spontaneously hypertensive rats (SHR). We investigated whether this reflects differences in ATP release and/or its breakdown. Using a multipronged approach, we found that CBs of SHRs release more ATP than Wistar rats (P&lt;0.05), though intracellular ATP depletion from glomus cells was similar between strains. A morphometric analysis revealed a disproportional increase in glomus tissue (tyrosine hydroxylase-positive area) in juvenile SHRs relative to Wistar rats (P&lt;0.05). The latter was associated with mRNA upregulation of the endothelial PAS domain-containing protein 1 (Epas1), the gene encoding hypoxia-inducible factor 2 alpha (HIF-2α), which drives CB hyperplasia. Additionally, both the ATP degrading enzymes, ectonucleotide pyrophosphatase/phosphodiesterasess 1 and 3 (Enpp1 and Enpp3) and the ectonucleoside triphosphate diphosphohydrolase 2 (Entpd2) were downregulated in SHRs (P&lt;0.05). In vitro and in situ electrophysiological recordings showed that CB topical application of ATP or α, β-methylene ATP produced tachypnoea and sympathoexcitation, with a greater sympathetic reflex in SHRs (P&lt;0.05), indicating sensitisation. Testing adenosine transmission, a byproduct of ATP, revealed it does not contribute to CB hyperexcitability in SHRs (P&gt;0.05). In conclusion, the increased ATP release from the CBs of SHRs may reflect its larger size due to glomus cell proliferation, potentiated by downregulated ATP-degrading enzymes.