Oxidative stress and the muscle reflex in heart failure

Abstract

Muscle contraction stimulates thin fibre muscle afferents and evokes a reflex increase in blood pressure. In heart failure (HF) this reflex is accentuated. Of note, superoxide and other reactive oxygen species are increased in HF. In this report, we tested the hypothesis that excess superoxide contributes to the exaggerated muscle reflex in HF. HF was induced in rats by coronary artery ligation. Electrically induced 30 s hindlimb muscle contraction in decerebrate rats with myocardial infarction (MI) (left ventricular fractional shortening (FS) = 24 +/- 1%; n = 15) evoked larger (P < 0.05) increases in mean arterial pressure (MAP) and renal sympathetic nerve activity (RSNA) as compared to control rats (FS = 47 +/- 1%; n = 14). In the MI rats, the pressor and RSNA responses to contraction were reduced by intra-arterial injection into the hindlimb circulation of tempol (10 mg), a superoxide dismutase mimetic (DeltaMAP: 22 +/- 2 vs. 11 +/- 1 mmHg; integral DeltaRSNA: 1032 +/- 204 vs. 431 +/- 73 arbitrary units (a.u.); before vs. after tempol; P < 0.05). Tempol also attenuated the RSNA response to 1 min intermittent (1-4 s stimulation to relaxation) bouts of static contraction in the MI rats (116 +/- 17 vs. 72 +/- 11 a.u.; P < 0.05; n = 16). In the control rats, tempol had no effect on these responses. These results suggest that excess superoxide in HF sensitizes mechanically sensitive muscle afferents engaged during contraction. We hypothesize that oxidative stress contributes to the exaggerated muscle reflex in HF.

Figure 1

Representative recordings from one myocardial infarction (MI) rat (fractional shortening = 17%) of tension developed within the left triceps surae muscles, arterial pressure (AP), heart rate (HR) (bpm = beats min⁻¹), renal sympathetic nerve activity (RSNA), and the relative changes in RSNA during 30 s continuous contraction of the left hindlimb muscles before (left) and after (right) intra-arterial injection of tempol (10 mg) into the hindlimb circulation. Note that RSNA increased rapidly towards peak values from the onset of muscle tension development, and that the elevated RSNA gradually decreased towards baseline level.

Five-second-averaged changes from baseline in muscle tension and RSNA during continuous static contraction before and after injection of tempol in healthy controls (n= 14, A) and MI rats (n= 15, B). Values are means ±s.e.m. Baseline data were obtained from the averaged values for 30 s immediately before contraction. Horizontal bars indicate significant (P < 0.05) differences from baseline, detected by Dunnett's post hoc test following one-way repeated ANOVA.

Figure 3

Comparisons of Δtension, tension–time index (TTI), ΔMAP, ΔHR, ΔRSNA and the integrated ΔRSNA during 30 s continuous static contraction before and after injection of tempol in 14 healthy controls and 15 MI rats. Δvalues are the peak increases seen during 30 s contraction. TTI and the integrated ΔRSNA are the 30 s integrated values. Values are means ±s.e.m.*P < 0.05 vs. healthy controls. †P < 0.05 vs. before tempol injection. Significant differences were detected by Tukey's post hoc test following two-way repeated ANOVA.

Figure 4

Representative recordings from one MI rat of muscle tension, AP, HR and RSNA during intermittent (1–4 s stimulation to relaxation) static contraction before (A) and after (B) intra-arterial injection of tempol into the hindlimb circulation. Eighth, ninth and tenth of 12 repeated contractions are presented in this figure. RSNA responded synchronously as tension was developed. This MI rat, the same as the one shown in Fig. 1, displayed a tendency for the AP to decrease during contraction.

Figure 5

Comparison of TTI and the integrated ΔRSNA in response to intermittent static contraction before and after injection of tempol in 13 healthy controls and 16 MI rats. Values are means ±s.e.m.*P < 0.05 vs. healthy controls. †P < 0.05 vs. before tempol injection. Significant differences were detected by Tukey's post hoc test following two-way repeated ANOVA.