Nitric Oxide Increases Myocardial Cross-Bridge Cycling Rate and Reduces the Loss of Rapid Relaxation During Its Inhibition of β-Adrenergic Stimulation
Joseph F.Y. Hoh1*, Lynne Turnbull2, Gunther H. Rossmanith2
1Discipline of Physiology and Institute for Biomedical Research, University of Sydney, NSW 2006, Australia.
2Biomedical Systems Research Group, Division of Information and Communication Sciences, Macquarie University, NSW 2109, Australia.
*Corresponding Author: Joseph Foon Yoong Hoh, A2 Garnet St, Killara, NSW, 2071, Australia.
DOI: https://doi.org/10.58624/SVOAMR.2026.04.013
Received: May 08, 2026
Published: May 28, 2026
Citation: Hoh JFY, Turnbull L, Rossmanith GH. Nitric Oxide Increases Myocardial Cross-Bridge Cycling Rate and Reduces the Loss of Rapid Relaxation During Its Inhibition of β-Adrenergic Stimulation. SVOA Medical Research 2026, 4:3, 124-135. doi: 10.58624/SVOAMR.2026.04.013
Abstract
Objective: The positive inotropy induced by β-agonist on the myocardium is associated with enhanced relaxation rate due increased cross-bridge cycling rate resulting from cAMP-induced phosphorylation of cardiac troponin I (c-TnI) by protein kinase A (PKA). Nitric oxide (NO) at a high level is negatively inotropic and inhibits β-agonist induced positive inotropy. We investigated the effects of NO and a β-agonist, and both agents acting concurrently, on cross-bridge cycling rate in rat papillary muscle.
Methods: We used dynamic stiffness analysis in the frequency domain to investigate cross-bridge cycling kinetics in rat papillary muscle during a sustained contracture induced by Ba2+ ions. This technique yields a characteristic parameter, fmin , the frequency at which stiffness is a minimum which reflects the cross-bridge cycling rate. We use S-nitroso-N-acetyl-penicillamine (SNAP) as NO donor and isoprenaline as a β-agonist.
Results: The mean control fmin at 250C was 1.83 ± 0.08 (SEM, n=4) Hz. After SNAP (60 μM) treatment, fmin significantly increased to 2.27 ± 0.04 Hz, an increase of 24% over the control value. After pre-treatment with methylene blue, a guanylyl cyclase inhibitor, SNAP had no influence on fmin . Treatment with β-agonist isoprenaline (2 μM) led to a 65% increase in fmin . However, after pre-treatment with both isoprenaline and SNAP, fmin enhancement was significantly reduced to 43%.
Conclusions: In the light of the current literature, we propose that (i) NO/guanylyl cyclase generated cGMP activated protein kinase G (PKG) to phosphorylate c-TnI, leading to the enhancement of fmin and cross bridge cycling rate, (ii) the effect of NO and isoprenaline acting concurrently on fmin is due to two opposing mechanisms: cGMP activated cAMP phosphodiesterase (PDE2) hydrolysing cAMP, thereby reducing PKA phosphorylation of c-TnI, and cGMP activated PKG enhancing the phosphorylation of c-TnI, (iii) The functional significance of NO/cGMP/PKG-induced cross-bridge cycling rate enhancement is that, during endogenous NO induced inhibition of β-agonist mediated positive inotropy, which occurs in failing hearts, it moderates the cross-bridge cycling rate reduction due to PDE2 hydrolysis of cAMP, thereby enhancing myocardial relaxation rate and improving diastolic function.
Keywords: Nitric oxide, β-agonist, Myocardium, Protein kinase G, Cross-bridge cycling, cAMP phosphodiesterases