title: The slow force response to stretch in atrial and ventricular myocardium from human heart: functional relevance and subcellular mechanisms.
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.
authors.affiliation: Department of Cardiology, Medical University of Graz, Auenbruggerplatz 15, Graz, Austria.
authors.forename: Jens
authors.initials: J
authors.lastname: Kockskämper
authors.forename: Dirk
authors.initials: D
authors.lastname: von Lewinski
authors.forename: Mounir
authors.initials: M
authors.lastname: Khafaga
authors.forename: Andreas
authors.initials: A
authors.lastname: Elgner
authors.forename: Michael
authors.initials: M
authors.lastname: Grimm
authors.forename: Thomas
authors.initials: T
authors.lastname: Eschenhagen
authors.forename: Philip A
authors.initials: PA
authors.lastname: Gottlieb
authors.forename: Frederick
authors.initials: F
authors.lastname: Sachs
authors.forename: Burkert
authors.initials: B
authors.lastname: Pieske
mesh_terms: D000804:Angiotensin II / Q000378:metabolism; D024722:Cardiac Myosins / Q000378:metabolism; D019332:Endothelin-1 / Q000378:metabolism; D006321:Heart / Q000502:physiology*; D006325:Heart Atria / Q000378:metabolism; D006801:Humans; D009200:Myocardial Contraction / Q000502:physiology*; D009206:Myocardium / Q000378:metabolism; D018994:Myosin Light Chains / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000378:metabolism; D011493:Protein Kinase C / Q000378:metabolism; D012519:Sarcoplasmic Reticulum / Q000502:physiology; D019831:Sodium-Calcium Exchanger / Q000378:metabolism*; D017923:Sodium-Hydrogen Exchangers / Q000378:metabolism*; D013314:Stress, Mechanical; D016276:Ventricular Function
chemical_list: D019332:Endothelin-1; D018994:Myosin Light Chains; D019831:Sodium-Calcium Exchanger; D017923:Sodium-Hydrogen Exchangers; C107184:myosin light chain 2; D000804:Angiotensin II; D019001:Nitric Oxide Synthase; D011493:Protein Kinase C; D024722:Cardiac Myosins