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Eur J Pharmacol. 2004 Oct 1;500(1-3):73-86.

Force-frequency relationship in intact mammalian ventricular myocardium: physiological and pathophysiological relevance.

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Department of Cardiovascular Pharmacology, Yamagata University School of Medicine, 2-2-2 Iida-nishi, Yamagata 990-9585, Japan.


The force-frequency relationship (FFR) is an important intrinsic regulatory mechanism of cardiac contractility. The FFR in most mammalian ventricular myocardium is positive; that is, an increase in contractile force in association with an increase in the amplitude of Ca(2+) transients is induced by elevation of the stimulation frequency, which reflects the cardiac contractile reserve. The relationship is different depending on the range of frequency and species of animal. In some species, including rat and mouse, a 'primary-phase' negative FFR is induced over the low-frequency range up to approximately 0.5-1 Hz (rat) and 1-2 Hz (mouse). Even in these species, the FFR over the frequency range close to the physiological heart rate is positive and qualitatively similar to that in larger mammalian species, although the positive FFR is less prominent. The integrated dynamic balance of the intracellular Ca(2+) concentration ([Ca(2+)](i)) is the primary cellular mechanism responsible for the FFR and is determined by sarcoplasmic reticulum (SR) Ca(2+) load and Ca(2+) flux through the sarcolemma via L-type Ca(2+) channels and the Na(+)-Ca(2+) exchanger. Intracellular Na(+) concentration is also an important factor in [Ca(2+)](i) regulation. In isolated rabbit papillary muscle, over a lower frequency range (<0.5 Hz), an increase in duration rather than amplitude of Ca(2+) transients appears to be responsible for the increase in contractile force, while over an intermediate frequency range (0.5-2.0 Hz), the amplitude of Ca(2+) transients correlates well with the increase in contractile force. Over a higher frequency range (>2.5 Hz), the contractile force is dissociated from the amplitude of Ca(2+) transients probably due to complex cellular mechanisms, including oxygen limitation in the central fibers of isolated muscle preparations, while the amplitude of Ca(2+) transients increases further with increasing frequency ('secondary-phase' negative FFR). Calmodulin (CaM) may contribute to a positive FFR and the frequency-dependent acceleration of relaxation, although the role of calmodulin has not yet been established unequivocally. In failing ventricular myocardium, the positive FFR disappears or is inverted and becomes negative. The activation and overexpression of cardiac sarcoplasmic reticulum Ca(2+) ATPase (SERCA2a) is able to reverse these abnormalities. Frequency-dependent alterations of systolic and diastolic force in association with those of Ca(2+) transients and diastolic [Ca(2+)](i) levels are excellent indicators for analysis of cardiac excitation-contraction coupling, and for evaluating the severity of cardiac contractile dysfunction, cardiac reserve capacity and the effectiveness of therapeutic agents in congestive heart failure.

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