Effects Of Inotropic Interventions Research Articles

Effect of inotropic interventions on the force-frequency relation in the human heart.

In severe human heart failure, an increase in frequency of stimulations is accompanied by a reduced force of contraction in vivo and in vitro. This contrasts the findings in nonfailing human hearts. To investigate influences of inotropic stimulation on the force-frequency relationship in human myocardium, the effects of the cAMP-independent positive inotropic agents ouabain (Na+/K(+)-ATPase inhibitor) and BDF 9148 (Na(+)-channel modulator) as well as of the beta-adrenoceptor agonist isoprenaline on the force-frequency relationship in electrically driven left ventricular papillary muscle strips from nonfailing and terminally failing human myocardium were studied. In nonfailing myocardium, force of contraction increased following an increase in stimulation frequency, whereas in failing human myocardium force of contraction gradually declined following an increase in stimulation frequency. Moderate stimulation of contractility by isoprenaline reversed the negative force-frequency relationship in failing myocardium and preserved the positive force-frequency relationship in nonfailing myocardium. In the presence of ouabain and BDF 9148 the positive force-frequency relationship was completely restored in failing myocardium. In contrast, in the presence of high concentrations of isoprenaline the former positive force-frequency relationship became negative even in nonfailing myocardium. The negative force-frequency relationship in failing human myocardium is accompanied by alterations in the intracellular Ca(2+)-homeostasis. The latter may be due to an impaired function of the sarcoplasmic reticulum (SR) in failing human myocardium. Therefore, the activity of the SR-Ca(2+)-ATPase (SERCA2) of crude membrane preparations was investigated and was significantly reduced in failing compared to nonfailing human myocardium. It is concluded that the negative force-frequency relationship may be due to alterations in the intracellular Ca(2+)-handling caused by an impaired function of the SERCA2 in failing human myocardium. The beneficial effects of cAMP-increasing agents on the force-frequency relationship in failing human hearts could result from an enhanced phosphorylation status of phospholamban in the presence of beta-adrenoceptor-stimulation. The effect of the [Na+]i-modulating agents BDF 9148 and ouabain demonstrates that the intracellular Na(+)-homeostasis influences intracellular Ca(2+)-handling as well. Differences observed in failing compared to nonfailing myocardium may be due to an altered expression or function of the Na+/Ca(2+)-exchanger, Na(+)-channels or the Na+/K(+)-ATPase in addition to the blunted activity of the SERCA2 in failing myocardium.

Reappraisal of the multicellular preparation for the in vitro physiopharmacological evaluation of myocardial performance.

In order to evaluate myocardial performance, single cardiomyocytes suffer from technical problems and from the fact that some basic functional properties vanish when one moves down the hierarchic scale from multicellularity to single cells. The isolated papillary muscle has at present proven to be superior to the isolated intact cardiomyocyte. A large number of major intra- and extracellular features required to describe myocardial performance can be derived from analyzing twitch contraction and relaxation in the multicellular isolated papillary muscle. In addition, the present paper illustrates the possibility to differentiate between effects of inotropic interventions on activating Ca2+ and Ca2+ sensitivity in multicellular preparations, from a grid analysis of isometric twitches in a coordinate system of peak rate of force development (+dF/dt; reflecting the time pattern of twitch contraction) versus time to half relaxation (tHR; reflecting the time pattern of twitch relaxation). The abundance of information about myocardial performance that can be derived from the easily accessible multicellular preparation reflects its physiological kinship with the intact ventricle.

Effect of inotropic interventions on contraction and Ca2+ transients in the human heart.

The present study investigated the influences of inotropic intervention on the intracellular Ca2+ transient (intracellular Ca2+ concentration ([Ca2+]i)) and contractile twitch. Isometric twitch and [Ca2+]i (fura 2 ratio method) were measured simultaneously (1 Hz, 37 degrees C) after stimulation with Ca2+ (0.9-3.2 mM), the cardiac glycoside ouabain (Oua; 0.1 microM), the beta1- and beta2-adrenoceptor-agonist isoprenaline (Iso; 1-10 nM), and the Ca2+ sensitizer EMD-57033 (30 microM) by using isolated human nonfailing right auricular trabeculae (n = 19). Inotropic interventions increased force of contraction and peak rate of tension rise (+T) significantly. Only Iso stimulated peak rate of tension decay (-T) higher than +T (P < 0.05), thereby reducing time of contraction (Ttwitch). EMD-57033 increased +T more effectively than -T and prolonged Ttwitch (P < 0.05). Ca2+, Oua, and Iso, but not EMD-57033, increased systolic Ca2+. Diastolic Ca2+ increased after stimulation with Oua or Ca2+, but not in the presence of EMD-57033. Iso shortened the Ca2+ transient and did not influence diastolic Ca2+. In conclusion, positive inotropic agents differently affect force and [Ca2+]i depending on their mode of action. Inotropic interventions influence diastolic Ca2+ and thus may be less advantageous in a situation with altered intracellular Ca2+ homeostasis (e.g., heart failure due to dilated cardiomyopathy).

Difference in excitation-contraction mechanisms between atrial and ventricular myocardia of hatched chicks

1. 1. Effects of inotropic interventions on contractile force were examined in isolated atrial and ventricular preparations from hatched chicks. 2. 2. The duration of twitch contractions were briefer in the atria than in the ventricle. 3. 3. No difference in the extracellular Ca 2+-contractile force curve was observed between atrial and ventricular preparations. 4. 4. The sensitivity to nicardipine was higher in the ventricular preparations than in atrial preparations while that to ryanodine was higher in atrial preparations. 5. 5. The magnitude of post-rest contraction was larger than the basal contractile force in atrial preparations, while it was smaller than the basal contractile force in ventricular preparations. 6. 6. These results suggested that the atrial myocardium of hatched chick was more dependent on sarcoplasmic reticulum function than its ventricular myocardium, which is similar to the case with mammalian species.

Intramyocardial pressure: interaction of myocardial fluid pressure and fiber stress

Previous measurements of intramyocardial pressure (IMP) have yielded systolic pressures that range from values lower than to far exceeding systolic left ventricular pressure (LVP). This study identifies a possible mechanism underlying these divergent observations by building on established morphology of the ventricular wall. It is hypothesized here that the generation of fiber stress as a manifestation of myocardial contraction increases fluid pressure in the myocytes and the interstitial spaces. This increase in fluid pressure in turn generates the pressure in the ventricular cavity. Thus there are two quantities of interest: intramyocardial fluid pressure (IFP) and intramyocardial fiber stress (IFS). To test the hypothesis, we conducted experiments on conditioned dogs, utilizing a side-mounted catheter-tip strain gauge transducer to sense IMP as the sum of IFP and some component of IFS. In addition, a recessed end-tip fiber-optic transducer with its sensing element shielded from local myocardial fibers was employed to sense IFP. Both IFP and IMP were measured at various depths in the left ventricular free wall. The effects of inotropic interventions by administration of epinephrine and propranolol, mechanical interventions via clamping of the aorta and ligation of the left anterior descending coronary artery, and neural interventions by stimulation of the ansa subclavian of the stellate ganglion and right vagus were recorded. A transmural gradient in the wall for both IMP and IFP was observed. Systolic values of IFP recorded in the endocardium match those of LVP, with peak IMP exceeding both. The results support the hypothesis and offer an interpretation of the long-standing controversy regarding the magnitude of IMP with respect to LVP.

Effects of inotropic interventions on end systolic length-force curve of cat ventricular muscle.

A computer controlled servosystem was used to generate physiological contractions in which cat papillary muscles went through a cycle of force and length changes similar to that undergone by muscle fibres in the heart during systole and diastole, net external work being done during each cardiac cycle. End systolic length-force curves were obtained by varying the setpoint force against which the muscle shortened. The end systolic length-force curve was very similar to the isometric length-force curve obtained under comparable experimental conditions. It was altered in the same way by inotropic interventions (increase in stimulus frequency, increasing the bathing calcium concentration, and exposure to isoprenaline), each of which increased the slope of the curve and decreased its (extrapolated) intercept on the length axis. As these results were obtained from studies of muscles producing physiological contractions at 37 degrees C, they provide evidence for length dependence of activation in the working myocardium.

Measurements of intracellular calcium concentration in heart muscle: The effects of inotropic interventions and hypoxia

The use of aequorin as an intracellular calcium indicator in ventricular muscle is described. If the increase of intracellular calcium concentration associated with each contraction (the calcium transient) is measured during inotropic interventions, it is possible to distinguish two classes of inotropic intervention. One class leads to changes in the calcium transient which parallel the changes in tension. The second class leads to changes in the calcium transient and tension which are different in magnitude or direction. In this latter class, changes in the sensitivity of the contractile proteins to calcium are occurring and represent an important part of the inotropic mechanism. When oxidative phosphorylation is inhibited in an isolated mammalian papillary muscle, tension declines but the amplitude of the calcium transients is unaffected. Intracellular acidosis caused by lactate production associated with the increased rate of glycolysis is the probable mechanism of this decline in tension. When both oxidative phosphorylation and glycolysis are inhibited, both the calcium transient and the developed tension decline rapidly to zero. This profound contractile failure may be a consequence of a decline in the free energy of hydrolysis of ATP so that the sarcoplasmic reticulum can no longer accumulate calcium. Hypoxic contractures occur in the absence of significant increases in resting [Ca2+]i and are probably due to rigor produced by the low [ATP].

Effect of inotropic interventions on rate of change of ventricular diastolic dimensions.

The effects of inotropic interventions upon the maximal rate of change of left ventricular (LV) wall thickness and internal diameter during early diastole were measured in nine open-chest dogs by ultrasonic-dimension gauges. Isoproterenol increased the maximal rate of wall thickening during systole from 28 +/- 3 to 48 +/- 5 (SE) mm/s (P less than 0.001), whereas it had no effect on the maximal rate of wall thinning during early diastole, 40 +/- 4 vs. 42 +/- 4 mm/s [not significant (NS)]. Isoproterenol also increased the maximal rate of reduction of the LV diameter during systole from 87 +/- 6 to 125 +/- 8 mm/s (P less than 0.001), whereas it had little effect on the maximal rate of increase of the diameter during early diastole, 79 +/- 6 vs. 87 +/- 4 mm/s (NS). Similarly, propranolol had a direct effect on the maximal rate of wall thickening and LV diameter reduction during systole, but it had little or no effect on their counterparts during early diastole. These observations support the concept that alterations of the contractile state need not be accompanied by a concomitant effect on relaxation.

Tension development and sarcomere length in rat cardiac trabeculae. Evidence of length-dependent activation.

The slope of the sarcomere length-tension relation in cardiac papillary muscle suggests length-dependent activation of the contractile system (1). However, there are no data on the effect of inotropic interventions on this curve. Only muscle length-tension curves are available, which give conflicting results (1,2,3). The purpose of the present study was to examine the effect of varied calcium concentrations on the sarcomere length-tension relationship, using laser diffraction techniques.

Effects of inotropic interventions on the normal and ischemic myocardium in conscious dogs

Effects of inotropic interventions on the normal and ischemic myocardium in conscious dogs