Nitric oxide increases cross-bridge cycling rate in cardiac muscle but inhibits cycling enhancement due to ß-adrenergic stimulation
Year: 2025
Type: preprint
Abstract: Nitric oxide (NO) has a biphasic effect on cardiac contractility, showing a positive inotropy at a low concentration but a negative inotropy at high concentrations. The effect of NO donor S -nitroso- N -acetyl-penicillamine (SNAP) on the kinetics of cross-bridge cycling in rat papillary muscle was investigated using dynamic stiffness analysis. This analysis yields a stiffness minimum frequency, f min , which reflects cross-bridge cycling rate. The mean control value of f min for rat papillary muscle at 25 0 C was 1.83 ± 0.08 (SEM, n=4) Hz. After treating the papillary muscle with SNAP (60mM), f min significantly increased to 2.27 ± 0.04 Hz, an increase of 24 %. When the papillary muscle was pre-treated with methylene blue (MB), a guanylyl cyclase inhibitor, SNAP no longer induce an increase in f min . Treatment with isoprenaline, a ß-agonist, led to a 65 % increase in f min , which is known to be due to the phosphorylation of cardiac troponin I (c-TnI) by cAMP activated protein kinase A (PKA), but after treatment with both isoprenaline and SNAP, f min shift was significantly reduced to 43%. The results suggest that: (i) NO induced f min enhancement is due to guanylyl cyclase generated cGMP activating protein kinase G (PKG) to phosphorylate c-TnI, (ii) NO induced partial inhibition of ß-agonist mediated cross-bridge cycling enhancement is due to cGMP activated cAMP phosphodiesterase (PDE2) inhibiting the rise in cAMP. PKG phosphorylation of c-TnI compensates for the loss of its PKA phosphorylation, retaining the enhancement of cross-bridge cycling which accelerates ventricular relaxation and facilitates diastolic filling during negative inotropy.
Authors: J.F.Y. Hoh, L. Turnbull, G.H. Rossmanith
Institutions: The University of Sydney, Macquarie University
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
OpenAlex ID: W4413418036