Enhanced sensitivity of Kv channels to hypoxia in the rabbit carotid body in heart failure: role of angiotensin II.
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 versus 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 microM), 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 assessments demonstrated the down-expression of Kv3.4 but not Kv4.3 channels in CHF glomus cells. These results indicate that: (1) Ang II/AT1R signalling 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 versus Kv4.3) in the CB glomus cell may contribute to the suppression of IK and enhanced sensitivity of IK to hypoxia in CHF.
Li
Yu-Long
YL
Department of Cellular and Integrative Physiology, University of, Nebraska Medical Center, Omaha, NE 68198-5850, USA.
Schultz
Harold D
HD
D000804:Angiotensin II / Q000494:pharmacology*; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D000818:Animals; D002344:Carotid Body / Q000187:drug effects* / Q000378:metabolism; D015687:Cell Hypoxia; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D006333:Heart Failure / Q000378:metabolism*; D007093:Imidazoles / Q000494:pharmacology; D008297:Male; D008564:Membrane Potentials; D018408:Patch-Clamp Techniques; D024642:Potassium Channels, Voltage-Gated / Q000187:drug effects* / Q000378:metabolism; D011817:Rabbits; D013777:Tetrazoles / Q000494:pharmacology
D047228:Angiotensin II Type 1 Receptor Blockers; D007093:Imidazoles; D024642:Potassium Channels, Voltage-Gated; D013777:Tetrazoles; D000804:Angiotensin II; C070967:L 158809