Exercise training and losartan improve endothelial function in heart failure rats by different mechanisms

Figures & data

Table I. Experimental interventions.

A; Group assignment
		Heart failure	Losartan	Exercise training
SH SED PL		-	-	-
SH EX PL		-	-	+
HF SED PL		+	-	-
HF SED LOS		+	+	-
HF EX PL		+	-	+
HF EX LOS		+	+	+
B; Pharmacological interventions during recordings of vascular function
	Pre-incubation	Contraction	Relaxation	2nd Pre-incubation
A	3 mM L-Arg, 10 ^− 5 M Indo	3∙10 ^− 7 M Phe	10 ^− 9–3∙10 ^− 5 M Ach	10 ^− 5 M ODQ
B	250 IU SOD, 10 ^− 5 M Indo	3∙10 ^− 7 M Phe	10 ^− 9–3∙10 ^− 5 M Ach	10 ^− 4 M LNNA
C	250 IU SOD	3∙10 ^− 7 M Phe	10 ^− 9–3∙10 ^− 5 M Ach	10 ^− 5 M ODQ
D	10 ^− 5 M Indo	3∙10 ^− 7 M Phe	10 ^− 9–3∙10 ^− 5 M Ach	10 ^− 4 M LNNA
E	Vehicle	3∙10 ^− 7 M Phe	10 ^− 9–3∙10 ^− 5 M Ach	10 ^− 4 M LNNA
F	Vehicle	3∙10 ^− 7 M Phe	10 ^− 9–3∙10 ^− 5 M SNP	10 ^− 5 M ODQ

SH: sham operation; SED: sedentary; PL: placebo; EX: exercise training; HF: heart failure; LOS: losartan; L-Arg: L-arginine; Indo: indomethacin; SOD: superoxide dismutase; Phe: phenylephrine; Ach: acetylcholine; SNP: Na⁺ nitroprusside; ODQ: 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one; LNNA: N^G-nitro-L-arginine.

Table II. Left ventricular pressure recordings and infarct sizes.

	Sham		HF
	SED-PL	EX-PL	SED-PL	SED-LOS	EX-PL	EX-LOS
LVEDP (mmHg)	4 ± 1*	4 ± 2*	26 ± 2	19 ± 1‡	22 ± 1	17 ± 1†
LVPSP (mmHg)	114 ± 5*	120 ± 6*	100 ± 3	87 ± 5	98 ± 3	88 ± 5
MI/LV (%)			43 ± 3	46 ± 5	36 ± 3	40 ± 3

Pressures were measured at the end of the intervention period, whereas infarct size was measured one week after surgery. LVEDP: left ventricular end-diastolic pressure; LVPSP: left ventricular peak-systolic pressure; MI/LV: size of myocardial infarction (MI relative to the left ventricle (LV). HF: heart failure; SED: sedentary; PL: placebo; EX: exercise training; LOS: losartan. Sham vs. HF: *p < 0.01; HF-EX-LOS vs. HF-SED-PL: †p < 0.01; HF-SED-LOS vs. HF-SED-PL: ‡p < 0.05.

Figure 1. Maximal oxygen uptake (VO_2max) as a measure of exercise capacity. VO_2max in sham-operated (SH) rats was 40% higher (*p < 0.01) than in those with heart failure (HF) before the exercise training program (pre-test). Post-tests indicated that VO_2max increased 40% by exercise training (EX) in SH and HF rats; † (p < 0.01), and by 20% in losartan (LOS)-treated sedentary (SED) HF rats compared to placebo (PL)-controlled HF rats; ≠ (p < 0.01), respectively. Note that HF EX PL and HF EX LOS curves sit on top of each other. Also, SH SED PL and HF SED PL rats decreased VO_2max from pre-to post-tests; # (p < 0.05).

Figure 2. A: Heart failure (HF) reduced the acetylcholine (Ach)-mediated vasorelaxation of aorta as indicated by the right shifted dose-response curve of sedentary (SED) HF rats on placebo (PL), whereas exercise training and losartan corrected for this dysfunction. B: Sensitivity to acetylcholine (EC₅₀); note the y-axis has a logarithmic scale. Aorta segments of the SED HF rats relaxed less than all the other groups (*p < 0.05). Interventions with exercise training (EX), losartan (LOS) or a combination of both (EX LOS) improved endothelial sensitivity to Ach to levels comparable with SED sham-operated (SH) rats, whereas SH EX rats exceeded SED SH rats (†p < 0.01). C: Maximal vasorelaxation was increased in LOS-treated SED HF rats compared to PL-controlled SED HF rats (*p < 0.05). D: EC₅₀-values of Ach-mediated vasorelaxation (white and black bars), with delta EC₅₀-values (grey bars) indicating difference in Ach-mediated vasorelaxation after addition of 3 mM L-arginine; this maneuver increased the response in HF-SED-PL (*p < 0.05). E: EC₅₀-values of Ach-mediated vasorelaxation (white and black bars), with delta EC₅₀-values (grey bars) indicating difference in Ach-mediated vasorelaxation after addition of 250 IU superoxide dismutase (SOD); this maneuver increased the responses in SH-SED-PL and HF-SED-PL (*p < 0.05 and †p < 0.01).

Figure 3. A: Acetylcholine (Ach)-mediated vasorelaxation in the presence of 10 ^{− 5} M indomethacin (Indo). B: Ach-mediated vasorelaxation in the presence of 10 ^{− 4} M LNNA and 10 ^{− 5} M Indo, with a trend (p = 0.12) toward an increase in vasorelaxation in the heart failure (HF) rats on losartan (LOS) vs. placebo (PL)-controlled sedentary (SED) or exercise training (EX) HF or sham-operated (SH) rats. C: Ach-mediated vasorelaxation in the presence of 10 ^{− 5} M ODQ and 10 ^{− 5} M Indo. D: Vasorelaxation due to nitric oxide (NO) was calculated by subtracting the area under curve (AUC) of the graphs in panels B and C from the AUC of panel A (A-(B + C)). HF-EX-LOS vs. HF-SED-PL and HF-SED-LOS: *p < 0.05; SH-EX-PL and HF-EX-PL vs. HF-SED-LOS, HF-SED-PL and SH-SED-PL: †p < 0.01.