Soluble Guanylyl Cyclase Stimulator Improves Contracting Skeletal Muscle Oxygen Pressures in Heart Failure Rats

Abstract

IntroductionImpaired convective and diffusive oxygen (O2) transport is a hallmark of heart failure with reduced ejection fraction (HFrEF), largely attributed to nitric oxide‐soluble guanylyl cyclase (sGC)‐cyclic guanosine monophosphate pathway dysfunction. sGC stimulators were synthesized to independently and synergistically (with endothelial derived‐NO) promote vasodilation, thereby demonstrating the potential to improve skeletal muscle oxygenation in HFrEF. We tested the hypotheses that 2 weeks of administration of sGC stimulator BAY 41‐2272 would increase the O2 delivery (Q̇O2)‐to‐O2uptake (V̇O2) ratio in the skeletal muscle interstitial space (PO2is) of HFrEF rats at rest and during twitch contractions.MethodsHFrEF was induced in adult male Sprague‐Dawley (3‐4 mo. old) rats via myocardial infarction (MI). Following 5 weeks of HFrEF progression, rats were treated with 1.0 mg/kg of BAY 41‐2272 via oral gavage twice per day (HFrEF + BAY; n=6) for 2 weeks prior to the contraction protocol. The control heart failure group (HFrEF; n=5) received vehicle only. Phosphorescence quenching protocols determined the partial pressure of O2 in the spinotrapezius muscle interstitial space at rest and during twitch contractions, reflecting the dynamic relationship between Q̇O2 and V̇O2.ResultsThe degree of HFrEF was not different between groups as evidenced by left ventricular end‐diastolic pressure (16 ± 1 mmHg, both groups) and MI size (27 ± 1 vs. 29 ± 1%) (all P>0.05). There were no differences in blood gases following contractions (P>0.05). Kinetic analyses revealed no difference in PO2is at rest, however immediately following the onset of contractions and throughout the contraction steady‐state, HFrEF+BAY rats maintained a ~5‐7 mmHg higher PO2is (32‐180s of contractions, P<0.05). Furthermore, HFrEF+BAY rats had an attenuated undershoot, decreased tau (time constant), and increased end PO2is (all P<0.05) in comparison to HFrEF rats.ConclusionsDuring the rest‐contraction transient and throughout the contractions steady‐state BAY 41‐2272 increases PO2isin rats with moderate HFrEF. By improving O2delivery and relieving the HF‐induced O2‐dependence of V̇O2 kinetics these findings support the therapeutic potential for sGC stimulators to reduce vasomotor dysfunction and improve exercise tolerance in HFrEF.