The anti-hypertensive effect of a P2X3 receptor antagonist in the spontaneously hypertensive rat is due to inhibition of sympathetic nerve activity

      Arterial hypertension is associated with both increased peripheral chemoreceptor reflex sensitivity and sympathetic nerve activity. We have shown that bilateral carotid body (CB) resection in spontaneously hypertensive (SH) rats reduces arterial pressure (AP). Since ATP is a major participant in CB transduction signalling (Prasad M, et al. (2001). J Physiol. 537: 667–677) we hypothesized that P2X3 antagonism would reduce sympathetic nerve activity, chemoreflex hypersensitivity and AP in SH rats. SH rats were implanted with radio-telemetry devices to record AP and renal sympathetic nerve activity (RSNA) in conscious animals. Animals were infused with vehicle and 8 mg/kg/h AF-219 i.v. for 1 h at 5 ml/kg/h rate. Changes in both basal AP and SNA were assessed. The chemoreflex was stimulated with sodium cyanide (120 μg/kg i.v.). AF-219 reduced sodium cyanide evoked AP responses (P < 0.05). The low frequency component (LF) of the heart rate spectral analysis, corresponding to its sympathetic modulation (Malliani A., et al. (1991) Circ., 84: 482–492) was decreased from 0.1 ± 0.01 ms2 to 0.02 ± 0.03 ms2. This was accompanied by a reduction in RSNA of 34% (P < 0.01). The basal AP was reduced by AF-219 (P < 0.001): SBP; −17 ± 1 mmHg, DBP; −25 ± 2 mmHg. Following washout of drug, LF of heart rate, RSNA and AP recovered to basal values. P2X3 receptor antagonism with AF-219 depresses chemoreflex hypersensitivity and lowers sympathetic nerve activity and AP in SH rats. AF-219 may provide a novel way to attenuate carotid body tonicity in SH rats and as such becomes a potential new drug for controlling hypertension. Supported by: Afferent Pharmaceuticals and British Heart Foundation.
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