ISH NIA OS-04 P2X3 RECEPTOR ACTIVITY IN THE CAROTID BODY (CB) OF SPONTANEOUSLY HYPERTENSIVE (SH) RATS CONTRIBUTES TO INCREASED CHEMOREFLEX HYPERSENSITIVITY AND HYPERTENSION.

OBJECTIVE: Arterial hypertension is associated with increases in both peripheral chemoreceptor reflex sensitivity and sympathetic nerve activity (SNA). We have shown that CB resection in SH rats reduces arterial pressure (AP; McBryde et al. 2013). Since P2X3 receptors exist in the rat CB and P2X3 receptor activity is associated with afferent hyperreflexia (Ford et al. 2015), we hypothesized that P2X3 receptor would be upregulated in the CB of SH vs normotensive (Wistar) control rats and that a selective P2X3 receptor antagonist (AF-219) would reduce chemoreflex hypersensitivity, AP and SNA in SH rats.

DESIGN AND METHOD: SH and Wistar rats were implanted with radio-telemetry devices to record AP and renal SNA (RSNA) in conscious animals. Animals were infused with AF-219 (8 mg/kg/h) or vehicle i.v. for 1 h. The CB was stimulated with sodium cyanide (120 μg/kg i.v.). Western blotting and immunohistochemistry revealed the level of expression and localisation of P2X3 receptor protein in the CB, respectively.

RESULTS: In the CB, P2X3 receptor protein was upregulated four fold in SH vs Wistar rat (P < 0.05). Glomus cells of SH rat (identified as expressing tyrosine hydroxylase) and afferent nerve fibres were immunopositive for P2X3 receptors. In contrast, in Wistar rats, glomus cells expressing P2X3 receptors were fewer and P2X3 was not detected in nerve fibres. Infusion of AF-219 reduced: CB hyperreflexia (P < 0.05); AP (systolic -28 ± 3mmHg; P < 0.001) and RSNA (34%; P < 0.01). No changes in chemoreflex sensitivity, AP or RSNA were detected after vehicle or AF-219 infusion in Wistar rats.

CONCLUSIONS: We surmise that upregulation of P2X3 receptors in the CB of SH rats contributes to chemoreflex hypersensitivity. Further, antagonism of P2X3 receptors lowers both AP and RSNA substantially in SH rats. Thus, P2X3 receptor antagonists may provide a novel way to attenuate CB over-activity and offer a novel approach for controlling hypertension.Supported by: Afferent Pharmaceuticals.