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

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<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<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<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<0.05), indicating sensitisation. Testing adenosine transmission, a byproduct of ATP, revealed it does not contribute to CB hyperexcitability in SHRs (P>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.