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Vanilloid type 1 receptor and the acid-sensing ion channel mediate acid phosphate activation of muscle afferent nerves in rats

¹Department of Medicine, Division of Cardiology, Pennsylvania State University College of Medicine, Hershey; and ²Lebanon Veterans Affairs Medical Center, Lebanon, Pennsylvania

Submitted 6 June 2005 ; accepted in final form 29 September 2005

Reflex cardiovascular responses to contracting skeletal muscle are mediated by mechanical and metabolic stimulation of thin-fiber muscle afferents. Diprotonated phosphate (H₂PO₄^–) excites those thin-fiber nerves and evokes the muscle pressor reflex. The receptors mediating this response are unknown. Thus we examined the role played by purinergic receptors, vanilloid type 1 receptors (VR1), and acid-sensing ion channels (ASIC) in mediating H₂PO₄^–-evoked pressor responses. Phosphate and blocking agents were injected into the arterial blood supply of the hindlimb muscles of 53 decerebrated rats. H₂PO₄^– (86 mM, pH 6.0) increased mean arterial pressure by 25 ± 2 mmHg, whereas monoprotonated phosphate (HPO₄^2–, pH 7.5) had no effect. Pyridoxalphosphate-6-azophenyl-2',4'-disulfonic acid (a purinergic receptor antagonist, 2 mM) did not block the response. However, capsazepine (a VR1 antagonist, 1 mg/kg) attenuated the reflex by 60% and amiloride (an ASIC blocker, 6 µg/kg) by 52%. Of note, the H₂PO₄^–-induced pressor response was attenuated by 87% when both capsazepine and amiloride were injected before the H₂PO₄^–. In conclusion, VR1 and ASIC mediate the pressor response due to H₂PO₄^–. The H₂PO₄^–-evoked response was greater when VR1 and ASIC blockers were given simultaneously than when the respective blockers were given separately. Our laboratory's previous study has shown that H⁺ stimulates ASIC (but not VR1) on thin-fiber afferent nerves in evoking the reflex response. Thus VR1 and ASIC are likely to play a coordinated and interactive role in processing the muscle afferent response to H₂PO₄^–. Furthermore, the physiological mechanisms mediating the response to H⁺ and H₂PO₄^– are likely to be different.

hydrogen ion; thin-fiber afferent nerve; muscle reflex

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