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Received March 30, 2006
Revised May 8, 2006
Accepted after revision June 11, 2006
1 University of Nebraska Medical Center
2 University of Nebraska Medical Centre
* To whom correspondence should be addressed. E-mail: hschultz{at}unmc.edu.
Angiotensin II (Ang II) plays an important role in the enhanced chemoreflex function that occurs in congestive heart failure (CHF), but the mechanism of this effect within the carotid body (CB) is not known. We investigated the sensitivity of Ca2+ independent, voltage-gated K+ (Kv) channels to hypoxia in CB glomus cells from CHF rabbits, and whether endogenous angiotensin II (Ang II) modulates this action. Using the conventional whole-cell patch clamp technique, we found that Kv currents (IK) under normoxic conditions were blunted in the CB glomus cells from CHF rabbits compared with sham rabbits. In addition, the inhibition of IK and the decrease of resting membrane potential (RMP) induced by hypoxia were greater in CHF vs. sham glomus cells. Ang II at 100 pM, had no direct effect on IK at constant normoxic PO2, but increased the sensitivity of IK and RMP to hypoxia in sham glomus cells. In CHF glomus cells, an AT1 receptor (AT1R) antagonist, L-158,809 (1 µM), alone did not affect IK at normoxia, but it decreased the sensitivity of IK and RMP to hypoxia. At higher concentrations, Ang II dose-dependently (0.1-100 nM) reduced IK under constant normoxic conditions in sham and CHF glomus cells, with threshold concentrations of about 900 and 600 pM, respectively. Immunocytochemical and western blot assessment demonstrated the down-expression of Kv3.4 but not Kv4.3 channels in CHF glomus cells. These results indicate that: (1) Ang II/AT1R signaling increases the sensitivity of Kv channels to hypoxia in CB glomus cells from CHF rabbits; (2) high concentrations of Ang II (>1 nM) directly inhibit IK in CB glomus cells from sham and CHF rabbits; (3) changes in Kv channel protein expression (Kv3.4 vs. Kv4.3) in the CB glomus cell may contribute to the suppression of IK and enhanced sensitivity of IK to hypoxia in CHF.
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