© 1998 by European Society of Cardiology
Copyright © 1998, European Society of Cardiology
The role of cAMP in the frequency-dependent changes in contraction of guinea-pig cardiomyocytes
aImperial College School of Medicine at the National Heart and Lung Institute, London, SW3 6LY, UK
bDepartment of Cardiac Medicine, John Radcliffe Hospital, Oxford, OX3 9DU, UK
* Corresponding author. Tel.: (+44-171) 352 8121X3311; fax: (+44-171) 823 3392; e-mail: sian.harding@ic.ac.uk
Objectives: β-Receptor desensitisation, low basal cAMP, and a negative force–frequency relationship are characteristic changes in human heart failure. Isolated cardiomyocytes from noradrenaline-treated guinea pigs also show these features. We tested the hypothesis that low basal cAMP underlies the loss of contractile response to increasing stimulation frequency in this model. Methods: Isolated cardiomyocytes were obtained from noradrenaline-treated (NA) and sham-operated (SHAM) guinea pigs. They were stimulated from 0.1–2 Hz and contraction amplitude was monitored with a video edge-detection system. Results: NA cells had less positive amplitude–frequency responses (AFR) compared to SHAMs at 2 mM (P=0.002, n=17), or midrange Ca2+ concentrations (EC40-EC60) (P<0.001, n=13). When the cAMP agonist, 8-CPT-cAMP (CPT, 10 µM) or high Ca2+ (above EC75) was added to NA cells the AFR was normalised to that of SHAM myocytes (NA vs. SHAM P=ns). In control experiments the cAMP antagonists, Rp-cAMPS (Rpc) and Rp-8-CPT-cAMPS (Rp8, 100 µM), blocked the positive inotropic effects of CPT at 0.5 Hz (control pD2=4.36±0.06, Rp8 pD2=3.68±0.08, P<0.0001, n=6 paired). Rpc (100 µM) completely but reversibly blocked the effect of maximal isoprenaline in control experiments (P<0.0001). Neither antagonist reduced the AFR compared to time-matched controls (P=ns, n=6). Blockade of SERCA2a with thapsigargin resulted in a significant reduction in the AFR (ANOVA P<0.0001). Conclusions: The results are consistent with sarcoplasmic reticulum (SR) function being a more important determinant of the amplitude–frequency relationship than tonic levels of cAMP under basal conditions. Reversal of AFR depression by CPT may result from stimulation of SR Ca2+ uptake.
KEYWORDS Heart failure; Myocyte; Basal cAMP; Contractile function; Guinea pig; Rp-cAMPS
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