The slow force response to stretch in atrial and ventricular myocardium from human heart: functional relevance and subcellular mechanisms

Prog Biophys Mol Biol. 2008 Jun-Jul;97(2-3):250-67. doi: 10.1016/j.pbiomolbio.2008.02.026. Epub 2008 Mar 14.

Abstract

Mechanical load is an important regulator of cardiac force. Stretching human atrial and ventricular trabeculae elicited a biphasic force increase: an immediate increase (Frank-Starling mechanism) followed by a further slow increase (slow force response, SFR). In ventricle, the SFR was unaffected by AT- and ET-receptor antagonism, by inhibition of protein-kinase-C, PI-3-kinase, and NO-synthase, but attenuated by inhibition of Na+/H+- (NHE) and Na+/Ca2+ exchange (NCX). In atrium, however, neither NHE- nor NCX-inhibition affected the SFR. Stretch elicited a large NHE-dependent [Na+]i increase in ventricle but only a small, NHE-independent [Na+]i increase in atrium. Stretch-activated non-selective cation channels contributed to basal force development in atrium but not ventricle and were not involved in the SFR in either tissue. Interestingly, inhibition of AT receptors or pre-application of angiotensin II or endothelin-1 reduced the atrial SFR. Furthermore, stretch increased phosphorylation of atrial myosin light chain 2 (MLC2) and inhibition of myosin light chain kinase (MLCK) attenuated the SFR in atrium and ventricle. Thus, in human heart both atrial and ventricular myocardium exhibit a stretch-dependent SFR that might serve to adjust cardiac output to increased workload. In ventricle, there is a robust NHE-dependent (but angiotensin II- and endothelin-1-independent) [Na+]i increase that is translated into a [Ca2+]i and force increase via NCX. In atrium, on the other hand, there is an angiotensin II- and endothelin-dependent (but NHE- and NCX-independent) force increase. Increased myofilament Ca2+ sensitivity through MLCK-induced phosphorylation of MLC2 is a novel mechanism contributing to the SFR in both atrium and ventricle.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Angiotensin II / metabolism
  • Cardiac Myosins / metabolism
  • Endothelin-1 / metabolism
  • Heart / physiology*
  • Heart Atria / metabolism
  • Humans
  • Myocardial Contraction / physiology*
  • Myocardium / metabolism
  • Myosin Light Chains / metabolism
  • Nitric Oxide Synthase / metabolism
  • Protein Kinase C / metabolism
  • Sarcoplasmic Reticulum / physiology
  • Sodium-Calcium Exchanger / metabolism*
  • Sodium-Hydrogen Exchangers / metabolism*
  • Stress, Mechanical
  • Ventricular Function

Substances

  • Endothelin-1
  • Myosin Light Chains
  • Sodium-Calcium Exchanger
  • Sodium-Hydrogen Exchangers
  • myosin light chain 2
  • Angiotensin II
  • Nitric Oxide Synthase
  • Protein Kinase C
  • Cardiac Myosins