Minimal force-frequency modulation of inotropy and relaxation of in situ murine heart

I The normal influence of heart rate (HR) on cardiac contraction and relaxa tion in the mouse remains uncertain despite its importance in interpreting many genetically engineered models. Prior in vivo data have repeatedly show n positive effects only at subphysiological heart rates, yet depressed basa l conditions and use of load-dependent parameters probably have an impact o n these results. 2. Open-chest mice of various strains (n = 16, etomidate/urethane anaesthes ia) were instrumented with a miniaturized pressure-volume catheter employin g absolute left ventricular (LV) volume calibration. HR was slowed (< 400 b eats min(-1)) using ULFS-49, and atrial or ventricular pacing was achieved via an intra-oesophageal catheter. Pressure-volume data yielded cardiac-spe cific contractile indexes minimally altered by vascular load. 3. At a resting HR of 600 beats min(-1), peak pressure-rise rate (dP/dt(max )) was 16871 +/- 2941 mmHg s(-1) (mean +/- S.D.) and the relaxation time co nstant was 3.9 +/- 0.8 ms, similar to values in conscious animals. Within t he broad physiological range (500-850 beats min(-1)), load-insensitive cont ractile indexes and relaxation rate varied minimally, whereas dP/dt(max) pe aked at 600 +/- 25 beats min(-1) and decreased at higher rates due to prelo ad sensitivity. Contraction and relaxation were enhanced modestly (13-15 %) at HRs of between 400 and 500 beats min(-1). 4. The minimal force-frequency dependence was explained by rapid calcium cy cling kinetics, with a mechanical restitution time constant of 9 +/- 2.7 in s, and by dominant sarcoplasmic reticular buffering (recirculation fraction of 93 +/- 1 %). 5. The mouse normally has a very limited force-frequency reserve at physiol ogical HRS, unlike larger mammals and man. This is important to consider wh en studying disease evolution and survival of genetic models that alter cal cium homeostasis and SR function.