P2X3 Receptor Antagonism Reduces Peripheral Chemoreceptor Reflex Hypersensitivity and Blood Pressure in the Spontaneously Hypertensive Rat

Abstract

Arterial hypertension is associated with increased peripheral chemoreceptor reflex sensitivity. We have shown that bilateral carotid body (CBR) resection in spontaneously hypertensive (SH) rats reduces arterial pressure (AP). Since ATP is a major participant in CB transduction signalling, and P2X3 receptors are associated with visceral afferent sensitisation, we hypothesized that P2X3 antagonism would reduce chemoreflex hypersensitivity and lower AP in SH rats.SH and Wistar rats were implanted with telemeters to record AP. Doses of a P2X3 receptor antagonist (AF‐219) were administered as an i.v. bolus: 0.5 (n=4), 1 (n=4), 2 (n=5), 4 (n=5) and 8 mg/kg (n=4), and changes in both basal AP and chemoreflex sensitivity assessed. The chemoreflex was stimulated with sodium cyanide (NaCN; 120 μg/kg i.v.).At all doses, AF‐219 diminished NaCN evoked AP responses (P=0.084) in SH rats. In SH rats, basal AP was reduced by AF‐219 (P<0.05): ‐8±3 mmHg, 0.5mg/kg; ‐16±1 mmHg, 1mg/kg: ‐18±3 mmHg, 2mg/kg; ‐13±1 mmHg, 4mg/kg; ‐13±2 mmHg, 8mg/kg. In normotensive Wistars, AF‐219 did not reduce AP vs. baseline (‐4±2 mmHg, 1 mg/kg; P>0.05). Injections of vehicle had no effect in either rat strain (n=4). In SH rats, CBR blunted the 1 mg/kg AF‐219 induced fall in AP vs. non‐CBR rats. However, the fall versus baseline in AP in SH‐CBR rats remained significant (‐8±1 mmHg,P<0.01).P2X3 receptor antagonism depresses chemoreflex hypersensitivity and lowers AP in SH rats to a level observed after selective CBR. P2X3 receptor antagonism may provide a novel way to attenuate CB tonicity in SH rats and as such become a novel target for controlling hypertension.Supported by: British Heart Foundation and the NIH