Capillary hemodynamics and contracting skeletal muscle oxygen pressures in male rats with heart failure: Impact of soluble guanylyl cyclase activator

Abstract

In heart failure with reduced ejection fraction (HFrEF), nitric oxide-soluble guanylyl cyclase (sGC) pathway dysfunction impairs skeletal muscle arteriolar vasodilation and thus capillary hemodynamics, contributing to impaired oxygen uptake (V̇O₂) kinetics. Targeting this pathway with sGC activators offers a new treatment approach to HFrEF. We tested the hypotheses that sGC activator administration would increase the O₂ delivery (Q̇O₂)-to-V̇O₂ ratio in the skeletal muscle interstitial space (PO₂is) of HFrEF rats during twitch contractions due, in part, to increases in red blood cell (RBC) flux (f_RBC), velocity (V_RBC), and capillary hematocrit (Hct_cap). HFrEF was induced in male Sprague-Dawley rats via myocardial infarction. After 3 weeks, rats were treated with 0.3 mg/kg of the sGC activator BAY 60-2770 (HFrEF + BAY; n = 11) or solvent (HFrEF; n = 9) via gavage b.i.d for 5 days prior to phosphorescence quenching (PO₂is, in contracting muscle) and intravital microscopy (resting) measurements in the spinotrapezius muscle. Intravital microscopy revealed higher f_RBC (70 ± 9 vs 25 ± 8 RBC/s), V_RBC (490 ± 43 vs 226 ± 35 μm/s), Hct_cap (16 ± 1 vs 10 ± 1%) and a greater number of capillaries supporting flow (91 ± 3 vs 82 ± 3%) in HFrEF + BAY vs HFrEF (all P < 0.05). Additionally, PO₂is was especially higher during 12-34s of contractions in HFrEF + BAY vs HFrEF (P < 0.05). Our findings suggest that sGC activators improved resting Q̇O₂ via increased f_RBC, V_RBC, and Hct_cap allowing for better Q̇O₂-to-V̇O₂ matching during the rest-contraction transient, supporting sGC activators as a potential therapeutic to target skeletal muscle vasomotor dysfunction in HFrEF.

Keywords: Exercise; Microcirculation; Nitric oxide; Oxygen transport.

Fig. 1.. Interstitial PO₂ from rest to contractions in spinotrapezius muscle.

Data are means ± SE. Analyzed via two-way ANOVA (Group x Time). Group average spinotrapezius interstitial PO₂ (PO₂is) at rest and during electrically induced contractions for HFrEF + BAY (open circles; n = 10) and HFrEF (filled circles; n = 9); contractions beginning at 0s. *P < 0.05 (shaded area; 12–34 s).

Fig. 2.. Capillary hemodynamics in spinotrapezius muscle at rest.

Data are means ± SE. Analyzed via student’s unpaired t-test. A. RBC flux in skeletal muscle capillaries supporting flow. B. RBC velocity in skeletal muscle capillaries supporting flow. C. Capillary hematocrit in skeletal muscle capillaries. D. Percentage of capillaries supporting RBC flow. HFrEF + BAY n = 9; HFrEF n = 8; all * P < 0.05.

Fig. 3.. Relationship between average RBC velocity and flux in capillaries supporting continuous flow in HFrEF + BAY and HFrEF

(P < 0.05).

Fig. 4.. Western immunoblotting.

Data are means ± SE. A. Normalized protein expression in HFrEF (n = 8) vs HFrEF + BAY (n = 10) (P > 0.05). B. Representative blotting of sGCβ1 expression in HFrEF vs HFrEF + BAY.