In a limited number of cells, I(to) in human ventricular myocytes shows no dramatic differences between cells derived from failing and non-failing hearts. The characteristics of I(to) in human cells were similar though not identical to I(to) in rat heart cells. This current may be a potential target for antiarrhythmic drug action.

We have studied the responses to a brief interruption of a train of steady state beats, namely: (1) a single prolonged depolarisation within the train; (2) a single short interval within the train; (3) a single long interval within the train. These responses are predicted by a two compartment model of intracellular calcium handling. They are characterised by the following phenomena. (1) Prolongation of one depolarisation/action potential in the steady state train causes potentiation of the following beat. We postulate on the basis of the published evidence that this may be due to "reversed" sodium/calcium exchange during late systole leading to extra calcium entry during the prolonged depolarisation. (2) Postextrasystole potentiation is postulated to share this mechanism when a depolarisation (extrasystole) is introduced immediately after one of the steady state depolarisations (single short interval). The postextrasystolic beat is then potentiated. (3) A single short interval during the steady state train also leads to attenuation of contractile force on the beat immediately after the short interval, that is, the extrasystole. Mechanical restitution is the term applied to the recovery of this force with increasing interval. This consists of two phases. The initial rapid phase is ryanodine and caffeine insensitive, indicating possible independence of sarcoplasmic reticular function. We postulate that a "membrane compartment" of internal calcium may be responsible. The second, slower, phase of mechanical restitution is ryanodine and caffeine sensitive, indicating that it is likely to be a property of the sarcoplasmic reticulum.(ABSTRACT TRUNCATED AT 250 WORDS)

The effects of various inotropic interventions on post-rest potentiation and its decay were investigated in isolated cardiac muscle. The inotropic interventions studied were: reduced extracellular Na+ and elevated extracellular Ca2+ concentration; exposure to ouabain, monensin, isoprenaline, phenylephrine and cirazoline. Force of contraction (stimulation frequency 2 Hz) was measured isometrically in left atria and right ventricular strips of rat hearts. Maximum post-rest potentiation was reached after 10 sec. of rest and amounted to 245 +/- 26% of pre-rest control in ventricle and 192 +/- 15% in atria. Ca(2+)-recirculation fraction was calculated from the decay of post-rest potentiation after resumption of regular stimulation, it was 0.77 +/- 0.01 in 11 control ventricular strips. High concentrations of caffeine (3 mmol/l) completely abolished post-rest potentiation in both tissues. The development of post-rest potentiation was accelerated in the presence of most of the inotropic agents. However, with the exception of ouabain and only in atrial muscle, none of the inotropic interventions produced higher post-rest contraction amplitudes than during controls. In rat heart muscle, the inotropic interventions studied are not any more effective in augmenting force of contraction than prolonged stimulation intervals. This suggests that (1) the distribution of Ca2+ into the sarcoplasmic reticulum is at a maximum during post-rest potentiation; (2) modifications of signal transduction pathways cannot further increase post-rest potentiation; and therefore that (3) shifts in Ca2+ distribution act as a limiting factor.

Abstract; Force of contraction (F,) of isolated human and rat atrial myocardium shows characteristic patterns of mechanical restitution when single test intervals are interposed in regular stimulation. With several pharmacological agents that modify the function of the sarcoplasmic reticulum we have investigated the role of the sarcoplasmic reticulum in mechanical restitution in these two species. Caffeine, thapsigargin and 2,5-di-(terr-butyl)-l ,4-benzohydroquinone (BHQ) were used to reduce Ca'+ uptake, ryanodine to open Ca2+ release channels, and forskolin to stimulate Ca'+ uptake. Under control conditions, F, recovered rapidly with test intervals shorter than steady-state. and was potentiated with longer than steadystate intervals. In human atrial tissue the maximum potentiation factor was 1.2620.03 after a mean test interval of 9.70% 1.55 s (n=43) as compared to 3.07%0.45 after 30 sec. in rat atria (n=48). Caffeine (3 mM) did not significantly affect steady-state F, but abolished post-rest potentiation in human and rat preparations. Forskolin ( I pM) enhanced and accentuated the mechanical restitution curve in particular for short test intervals. In the presence of thapsigargin (10 pM), steady-state F, and mechanical restitution could not be distinguished from time-matched controls exposed to solvent only.indicating that this agent is ineffective in human and rat atrial tissue. In contrast, the putative Ca2+ uptake inhibitor BHQ (100 pM) strongly reduced steady-state F, and decreased potentiation at all intervals in human muscle, but shifted the mechanical restitution curve in parallel to lower values in rat atria. Ryanodine (10 nM) induced post-rest decay in human and depressed both steady-state F, and post-rest potentiation in rat atrial muscle. From these results it is concluded that human and rat atrial muscle differ in the Ca2+ handling by the sarcoplasmic reticulum during mechanical restitution.In heart muscle, Ca2+ entry via L-type Ca2+ channels triggers the release of further Ca2+ from the sarcoplasmic reticulum. The increase in cytosolic C2+concentration activates contractile proteins for force production. During relaxation, Ca*+ is taken up again into the sarcoplasmic reticulum by the ATP-dependent Ca2+ pump and an amount equivalent to the systolic Ca" entry is transported out of the cell mainly via the Na+/Ca'+ exchanger. When regular pacing is disturbed by a single test pulse of variable interval, force of contraction (F,) changes in a characteristic pattern. The relationship between force of an interposed contraction and the preceding test interval is referred to as mechanical restitution. It consists of three phases (Schouten 1990): The initial one is a short and rapid phase of recovery for intervals shorter than steady-state. The second phase during which F, is potentiated with longer than regular intervals is followed by a third phase of force decline (post-rest decay).The adaptive changes in F, during mechanical restitution are considered to represent a physiological correlate of cellular Ca...

No abstract

No abstract