Enhanced sensitivity of Kv channels to hypoxia in the rabbit carotid body in heart failure: role of angiotensin II - PubMed (original) (raw)

Comparative Study

Enhanced sensitivity of Kv channels to hypoxia in the rabbit carotid body in heart failure: role of angiotensin II

Yu-Long Li et al. J Physiol. 2006.

Abstract

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.

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Figures

Figure 1

Figure 1. Effect of Ang II on _I_K in CB glomus cells from sham and CHF rabbits under normoxic conditions (_P_O2 = 104 ± 1.4 Torr)

_I_K was evoked by 400 ms depolarizing pulses from −80 to +80 mV, 10 mV steps). A and _B, I_K from a sham and CHF glomus cell, respectively, before (control) and after treatment with 100 n

m

Ang II in the extracellular medium. C, peak I_–_V relationships (n = 10 cells from 7 rabbits in each group) from sham and CHF glomus cells obtained before and after treatment with 100 n

m

Ang II. Data are means ±

s.e.m.

*P < 0.05 versus sham-control; #P < 0.05 versus CHF-control. D, dose–response curves of extracellular Ang II concentration versus percentage reduction of peak _I_K, in sham and CHF glomus cells. Data are means ±

s.e.m.

n = 10 cells from 7 rabbits for each point. *P < 0.05 versus sham. E, peak _I_K of sham and CHF glomus cells before (control) and after exposure to either 100 n

m

Ang II, 1 μ

m

L-158, 809 (AT1R antagonist), or 100 n

m

Ang II + 1 μ

m

L-158, 809. Data are means ±

s.e.m.

n = 10 cells from 7 rabbits in each group. *P < 0.05 versus control; #P < 0.05 versus Ang II; †P < 0.05 versus sham). Peak _I_K in D and E measured in response to a test pulse from −80 to +70 mV.

Figure 2

Figure 2. Effects of Ang II and L-158, 809 on the sensitivity of _I_K to hypoxia (_P_O2 = 41.7 ± 2.2 Torr) in CB glomus cells from sham rabbits

_I_K was elicited as in Fig. 1. A and B, effects of hypoxia on _I_K before (A) and after (B) administration of 100 p

m

Ang II to the extracellular medium. C, peak I_–_V relationships in 10 cells from 7 sham rabbits for data illustrated in A and B. Data are means ±

s.e.m.

*P < 0.05 versus control; #P < 0.05 versus hypoxia before Ang II. D, percentage change of _I_K by hypoxia (_I_control–_I_hypoxia)/_I_control) in sham glomus cells before (hypoxia alone) and after exposure to either 100 p

m

Ang II, 1 μ

m

L-158, 809 (AT1R antagonist), or 100 p

m

Ang II + 1 μ

m

L-158, 809. Data are means ±

s.e.m.

n = 10 cells from 7 rabbits in each condition. *P < 0.05 versus hypoxia alone; #P < 0.05 versus Ang II (100 p

m

) + hypoxia)

Figure 3

Figure 3. Effects of Ang II and L-158, 809 on the sensitivity of _I_K to hypoxia (_P_O2 = 42.2 ± 1.3 Torr) in CB glomus cells from CHF rabbits

_I_K was elicited as in Fig. 1. A and B, effects of hypoxia on _I_K before (A) and after (B) administration of 100 p

m

Ang II to the extracellular medium. C, peak I_–_V relationships in 10 cells from 7 CHF rabbits for data illustrated in A and B. Data are means ±

s.e.m.

*P < 0.05 versus control; #P < 0.05 versus hypoxia before L-158, 809). D, percentage change of _I_K by hypoxia (_I_control–_I_hypoxia)/_I_control) in CHF glomus cells before (hypoxia alone) and after exposure to either 100 p

m

Ang II, 1 μ

m

L-158, 809 (AT1R antagonist), or 100 p

m

Ang II + 1 μ

m

L-158,809. Data are means ±

s.e.m.

n = 10 cells from 7 rabbits in each condition. *P < 0.05 versus hypoxia alone; #P < 0.05 versus Ang II (100 p

m

) + hypoxia).

Figure 4

Figure 4. Effects of Hyproxia, Ang II, and L-158, 809 on RMP in CB glomus cells from sham and CHF rabbits

A, effect of hypoxia (41.9 ± 2.1 Torr) on resting membrane potential (RMP) at different conditions in CB glomus cells from sham and CHF rabbits. Data are means ±

s.e.m.

n = 8 cells from 5 rabbits in each condition. *P < 0.05 versus sham-normoxia or CHF-normoxia; #P < 0.05 versus sham-normoxia. B, percentage reduction of RMP by hypoxia (_I_control–_I_hypoxia)/_I_control) in sham and CHF glomus cells before (hypoxia alone) and after exposure to either 100 p

m

Ang II, 1 μ

m

L-158, 809 (AT1R antagonist), or 100 p

m

Ang II + 1 μ

m

L-158, 809. Data are means ±

s.e.m.

n = 8 cells from 5 rabbits in each condition. *P < 0.05 versus hypoxia alone; #P < 0.05 versus Ang II (100 p

m

) + hypoxia).

Figure 5

Figure 5. Co-localization of tyrosine hydroxylase (TH) and Kv3.4 in CB glomus cells from sham and CHF rabbits

A, CB from a sham rabbit (a_–_c) and CHF rabbit (d_–_f). Green immunofluorescent image for TH in a and d, red immunofluorescent image for Kv3.4 showed in b and e, and the merged image for overlap of TH and Kv3.4 in c and f. B, normalized fluorescence intensity for Kv3.4 in CB glomus cells from sham and CHF rabbits (see detail in Methods). Data are means ±

s.e.m.

n = 5 rabbits for each group. *P < 0.05 versus sham.

Figure 6

Figure 6. Co-localization of tyrosine hydroxylase (TH) and Kv4.3 in CB glomus cells from sham and CHF rabbits

A, CB from a sham (a_–_c) and CHF (d_–_f) rabbit. Green immunofluorescent image for TH in a and d, red immunofluorescent image for Kv4.3 in b and e, and the merged image for overlap of TH and Kv4.3 in c and f. B, normalized fluorescence intensity for Kv4.3 in CB glomus cells from sham and CHF rabbits (see detail in Methods). Data are means ±

s.e.m.

n = 5 rabbits for each group. *P < 0.05 versus sham.

Figure 7

Figure 7. Protein expression of Kv3.4 and Kv4.3

The representative (A) and summary (B) data for protein expression of Kv3.4 and Kv4.3 in the CBs from sham and CHF rabbits. Data are means ±

s.e.m.

n = 4 samples in each group. *P < 0.05 versus sham.

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