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Contracting Skeletal Muscle Oxygen Pressures in Rats with Heart Failure: Impact of Soluble Guanylyl Cyclase Activator
Author(s) -
Weber Ramona,
Schulze Kiana,
Colburn Trenton,
Horn Andrew,
Hageman K. Sue,
Ade Carl,
Sandner Peter,
Musch Timothy,
Poole David
Publication year - 2021
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2021.35.s1.04903
Subject(s) - heart failure , ejection fraction , medicine , soluble guanylyl cyclase , skeletal muscle , cardiology , cyclic guanosine monophosphate , activator (genetics) , nitric oxide , chemistry , endocrinology , guanylate cyclase , receptor
Heart failure with reduced ejection fraction (HFrEF) causes impaired convective and diffusive oxygen (O 2 ) transport, in part, by nitric oxide ‐soluble guanylyl cyclase (sGC)‐ cyclic guanosine monophosphate pathway dysfunction. sGC activators were developed to selectively target oxidized, heme‐free sGC and promote vasodilation, thereby demonstrating potential for improving skeletal muscle oxygenation in HFrEF. We tested the hypotheses that 5 days of administration of sGC activator BAY 60‐2770 would increase the O 2 delivery (Q̇O 2 )‐to‐V̇O 2 ratio in the skeletal muscle interstitial space (PO 2 is, pressure driving O 2 into the contracting myocyte) of HFrEF rats at rest and during twitch contractions. Methods HFrEF was induced in adult male Sprague‐Dawley (3‐4 mo. old) rats via myocardial infarction (MI) and the development of HFrEF was monitored via transthoracic echocardiography. Following 3 weeks of HFrEF progression, rats were treated with 0.3 mg/kg of BAY 60‐2770 via oral gavage twice per day (HFrEF + BAY; n =10) for 5 days prior to the contraction protocol. The control heart failure group (HFrEF; n = 9) received vehicle only. Phosphorescence quenching protocols determined the partial pressure of O 2 in the spinotrapezius muscle interstitial space at rest and during twitch contractions. Results The degree of HFrEF was not different between groups as evidenced by ejection fraction (44.7 ± 5.1 vs. 46.3 ± 4.8%), left ventricular end‐diastolic pressure (16 ± 1 vs. 14 ± 1 mmHg), and MI size (29 ± 2 vs. 28 ± 3%) (all P > 0.05) . Despite no difference either at rest or during the contracting steady‐state, across the on transient (14‐22 seconds of contractions) there was a ~30% increase in PO 2 is in HFrEF + BAY vs HFrEF (P ≤ 0.05), demonstrating a greater pressure head driving oxygen to the contracting myocyte. There was also a decrease in arterial blood lactate in HFrEF + BAY vs HFrEF (P < 0.05). Conclusions These data support that during the rest‐contraction transient, BAY 60‐2770 increases PO 2 is in rats with moderate HFrEF at the transition from rest to exercise, which may speed V̇O 2 kinetics, thereby reducing lactate accumulation. This supports sGC activators as a therapeutic targeting vasomotor dysfunction in chronic heart failure which has the potential to increase exercise capacity and quality of life in this patient population.