Effects of soluble guanylyl cyclase stimulation on muscle oxygenation and exercise capacity in heart failure with mildly reduced ejection fraction

Abstract Heart failure (HF) with a mildly reduced ejection fraction (HFmrEF; 40%–49%) is present in ≤25% of HF patients. Therapeutic treatment options for HFmrEF‐associated exercise intolerance are limited. Nitric oxide (NO)‐independent stimulation of soluble guanylyl cyclase to improve peripheral vasodilatation offers a novel approach to enhance skeletal muscle oxygenation (interstitial pressure of O 2 ) and exercise capacity. We tested the hypotheses that the soluble guanylyl cyclase stimulator BAY 41‐2272 (BAY41) would increase exercise tolerance, skeletal muscle interstitial pressure of O 2 during contractions and NO sensitivity in rats with HFmrEF. Healthy Sprague–Dawley rats ( n = 20) and rats with experimentally induced HFmrEF ( n = 25) (3–4 months old) were used for this investigation. HFmrEF was confirmed via echocardiography, and rats were randomized and treated with 1.0 mg/kg of BAY41 or vehicle for 2 weeks, followed by exercise testing and spinotrapezius muscle phosphorescence quenching measurements during 1 Hz contractions. The HFmrEF rats had a lower exercise capacity than healthy rats (834 ± 169 vs. 1138 ± 214 s; p < 0.001). BAY41 increased exercise capacity (1158 ± 223 s; p = 0.006) and muscle oxygenation index (1461 ± 427 vs. 1108 ± 239 mmHg·s; p = 0.047) during 1 Hz contractions versus HFmrEF vehicle control rats. Sodium nitroprusside superfusion elicited a faster response time in BAY41‐treated HFmrEF rats versus vehicle‐treated control animals (150 ± 58 vs. 220 ± 50 s; p = 0.022). After sodium nitroprusside superfusion, BAY41‐treated HFmrEF rats had a significantly elevated muscle oxygenation index during steady‐state contractions versus vehicle‐treated control animals (3104 ± 703 vs. 2365 ± 682 mmHg·s; p = 0.027). These data suggest that stimulation with soluble guanylyl cyclase can improve skeletal muscle oxygenation and increase the exercise capacity in HFmrEF rats, potentially via enhanced vascular smooth muscle NO sensitivity.