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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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