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School of Biomedical Sciences, University of Leeds, Leeds LS2 9NQ, UK

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 µM) 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 µM) 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 µM ryanodine and 1 µM 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 µM) and myocytes (40 µM). In fura 2-loaded myocytes, HOE 642 and streptomycin, but not L-NAME, ablated the stretch-induced increase in [Ca²⁺]_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.

(Received 28 May 2004; accepted after revision 29 June 2004; first published online 2 July 2004)
Corresponding author S. Calaghan: School of Biomedical Sciences, University of Leeds, Leeds LS2 9NQ, UK. Email: s.c.calaghan{at}leeds.ac.uk

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