title: Activation of Na+-H+ exchange and stretch-activated channels underlies the slow inotropic response to stretch in myocytes and muscle from the rat heart.
abstract: We present the first direct comparison of the major candidates proposed to underlie the slow phase of the force increase seen following myocardial stretch: (i) the Na(+)-H(+) exchanger (NHE) (ii) nitric oxide (NO) and the ryanodine receptor (RyR) and (iii) the stretch-activated channel (SAC) in both single myocytes and multicellular muscle preparations from the rat heart. Ventricular myocytes were stretched by approximately 7% using carbon fibres. Papillary muscles were stretched from 88 to 98% of the length at which maximum tension is generated (L(max)). Inhibition of NHE with HOE 642 (5 microm) significantly reduced (P < 0.05) the magnitude of the slow force response in both muscle and myocytes. Neither inhibition of phosphatidylinositol-3-OH kinase (PtdIns-3-OH kinase) with LY294002 (10 microm) nor NO synthase with L-NAME (1 mm) reduced the slow force response in muscle or myocytes (P > 0.05), and the slow response was still present in the single myocyte when the sarcoplasmic reticulum was rigorously inhibited with 1 microm ryanodine and 1 microm thapsigargin. We saw a significant reduction (P < 0.05) in the slow force response in the presence of the SAC blocker streptomycin in both muscle (80 microm) and myocytes (40 microm). In fura 2-loaded myocytes, HOE 642 and streptomycin, but not L-NAME, ablated the stretch-induced increase in [Ca(2+)](i) transient amplitude. Our data suggest that in the rat, under our experimental conditions, there are two mechanisms that underlie the slow inotropic response to stretch: activation of NHE; and of activation of SACs. Both these mechanisms are intrinsic to the myocyte.
authors.affiliation: School of Biomedical Sciences, University of Leeds, Leeds LS2 9NQ, UK. s.c.calaghan@leeds.ac.uk
authors.forename: Sarah
authors.initials: S
authors.lastname: Calaghan
authors.forename: Ed
authors.initials: E
authors.lastname: White
mesh_terms: D000818:Animals; D002867:Chromones / Q000494:pharmacology; D006146:Guanidines / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D009025:Morpholines / Q000494:pharmacology; D009200:Myocardial Contraction / Q000187:drug effects / Q000502:physiology*; D009206:Myocardium / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000502:physiology*; D051381:Rats; D017208:Rats, Wistar; D017923:Sodium-Hydrogen Exchangers / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013450:Sulfones / Q000494:pharmacology
chemical_list: D002867:Chromones; D006146:Guanidines; D009025:Morpholines; D017923:Sodium-Hydrogen Exchangers; D013450:Sulfones; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C093373:cariporide