Exercise training improves peripheral chemoreflex function in heart failure rabbits

Abstract

An enhancement of peripheral chemoreflex sensitivity contributes to sympathetic hyperactivity in chronic heart failure (CHF) rabbits. The enhanced chemoreflex function in CHF involves augmented carotid body (CB) chemoreceptor activity via upregulation of the angiotensin II (ANG II) type 1 (AT(1))-receptor pathway and downregulation of the neuronal nitric oxide synthase (nNOS)-nitric oxide (NO) pathway in the CB. Here we investigated whether exercise training (EXT) normalizes the enhanced peripheral chemoreflex function in CHF rabbits and possible mechanisms mediating this effect. EXT partially, but not fully, normalized the exaggerated baseline renal sympathetic nerve activity (RSNA) and the response of RSNA to hypoxia in CHF rabbits. EXT also decreased the baseline CB nerve single-fiber discharge (4.9 +/- 0.4 vs. 7.7 +/- 0.4 imp/s at Po(2) = 103 +/- 2.3 Torr) and the response to hypoxia (20.6 +/- 1.1 vs. 36.3 +/- 1.3 imp/s at Po(2) = 41 +/- 2.2 Torr) from CB chemoreceptors in CHF rabbits, which could be reversed by treatment of the CB with ANG II or a nNOS inhibitor. Our results also showed that NO concentration and protein expression of nNOS were increased in the CBs from EXT + CHF rabbits, compared with that in CHF rabbits. On the other hand, elevated ANG II concentration and AT(1)-receptor overexpression of the CBs in CHF state were blunted by EXT. These results indicate that EXT normalizes the CB chemoreflex in CHF by preventing an increase in afferent CB chemoreceptor activity. EXT reverses the alterations in the nNOS-NO and ANG II-AT(1)-receptor pathways in the CB responsible for chemoreceptor sensitization in CHF.

Fig. 1.

Chart recordings of renal sympathetic nerve activity (RSNA) under normoxic and hypoxic states from sedentary (SED)-sham, exercise-trained (EXT)-sham, SED-chronic heart failure (CHF), and EXT-CHF rabbits. Pa_O2, arterial oxygen partial pressure.

Fig. 2.

A: RSNA-Pa_O2 relationship in SED-sham, EXT-sham, SED-CHF, and EXT-CHF rabbits. B: slope coefficient (b) for RSNA-Pa_O2 relationship in SED-sham, EXT-sham, SED-CHF, and EXT-CHF rabbits. Values are means ± SE; n = 8 in each group. *P < 0.05 vs. SED-sham, #P < 0.05 vs. SED-CHF.

Fig. 3.

Representative recording of afferent discharge in carotid body (CB) chemoreceptor fibers from SED-sham, EXT-sham, SED-CHF, and EXT-CHF rabbits. DF, discharge frequency; AP, action potential.

Fig. 4.

A: effect of EXT on CB chemoreceptor sensitivity in sham and CHF rabbits. B: slope coefficient (b) for the DF-Po₂ relationship in SED-sham, EXT-sham, SED-CHF, and EXT-CHF rabbits. Values are means ± SE; n = 8 in each group. *P < 0.05 vs. SED-sham, #P < 0.05 vs. SED-CHF.

Fig. 5.

Effects of S-methyl-l-thiocitrulline (SMTC; 1 μM) and angiotensin II (ANG II; 100 pM) on CB chemoreceptor response to severe hypoxia (Pa_O2 = 40.5 ± 2.1 Torr) in EXT-CHF rabbits. Values are means ± SE; n = 4 in each group. *P < 0.05 vs. SED-CHF, #P < 0.05 vs. EXT-CHF.

Fig. 6.

Expression of neuronal nitric oxide synthase (nNOS) protein in the CB from SED-sham, EX-sham, SED-CHF, and EXT-CHF rabbits. The representative (A) and summary (B) results for protein expression of nNOS are given. Values are means ± SE; n = 6 in each group. *P < 0.05 vs. SED-sham, #P < 0.05 vs. SED-CHF.

Fig. 7.

Nitric oxide (NO) level in the CBs from SED-sham, EXT-sham, SED-CHF, and EXT-CHF rabbits. A: dose-response standard curve of S-nitroso-N-acetyl-l-penicillamine (SNAP) (a NO donor, see details in text). B: representative measurement of NO level in the CB homogenate from SED-sham (Ba), SED-CHF (Bb), and EXT-CHF (Bc) rabbits. C: NO concentration in the CBs from SED-sham, EXT-sham, SED-CHF, and EXT-CHF rabbits. Values are means ± SE; n = 5 in each group. *P < 0.05 vs. SED-sham, #P < 0.05 vs. SED-CHF.

Fig. 8.

Expression of ANG II type 1 (AT₁) receptor (AT₁R) protein and ANG II concentration in the CB from SED-sham, EXT-sham, SED-CHF, and EXT-CHF rabbits. The representative (A) and summary (B) results for protein expression of AT₁R are given. *P < 0.05 vs. SED-sham, #P < 0.05 vs. SED-CHF. C: ANG II concentration in the CBs from SED-sham, EXT-sham, SED-CHF, and EXT-CHF rabbits. Values are means ± SE; n = 6 (A and B) and n = 5 (C) in each group. *P < 0.05 vs. SED-sham, #P < 0.05 vs. SED-CHF.