Changes in arterial, mixed venous and intraerythrocytic ion concentrations during prolonged exercise.

REASONS FOR PERFORMING STUDY: Prolonged equine exercise can cause hypochloraemic alkalosis and hypokalaemia secondary to the loss of hypertonic sweat. Movement of ions in and out of erythrocytes during exercise may help regulate acid-base balance and changes in plasma ion concentrations. The extent to which this happens during prolonged equine exercise has not been reported. OBJECTIVES: To measure changes in blood gases and major plasma and intraerythrocytic (iRBC) ion concentrations of horses undergoing prolonged submaximal exercise. METHODS: Six horses were trotted at ∼ 30% VO2max on a treadmill for 105 min. Arterial ((a)) and mixed venous ((v)) blood samples were collected every 15 min, and pre- and post exercise. Blood gases and plasma (pl) concentrations of sodium, potassium, chloride and protein were measured and their iRBC concentrations calculated and compared (P < 0.05). RESULTS: P(a)CO(2) decreased in all horses. pl[Cl(-)]v decreased and [HCO(3)(-)]v increased. Due to the exhalation of CO(2) and chloride shifting, [HCO(3)(-)]a<[HCO(3)(-)]v, pl[Cl(-)]a>pl[Cl(-)]v)and iRBC[Cl(-)]aiRBC[K(+)]v. Conversely, iRBC[Na(+)]a

Dynamic myocardial contractile parameters from left ventricular pressure-volume measurements.

A new dynamic model of left ventricular (LV) pressure-volume relationships in beating heart was developed by mathematically linking chamber pressure-volume dynamics with cardiac muscle force-length dynamics. The dynamic LV model accounted for >80% of the measured variation in pressure caused by small-amplitude volume perturbation in an otherwise isovolumically beating, isolated rat heart. The dynamic LV model produced good fits to pressure responses to volume perturbations, but there existed some systematic features in the residual errors of the fits. The issue was whether these residual errors would be damaging to an application where the dynamic LV model was used with LV pressure and volume measurements to estimate myocardial contractile parameters. Good agreement among myocardial parameters responsible for response magnitude was found between those derived by geometric transformations of parameters of the dynamic LV model estimated in beating heart and those found by direct measurement in constantly activated, isolated muscle fibers. Good agreement was also found among myocardial kinetic parameters estimated in each of the two preparations. Thus the small systematic residual errors from fitting the LV model to the dynamic pressure-volume measurements do not interfere with use of the dynamic LV model to estimate contractile parameters of myocardium. Dynamic contractile behavior of cardiac muscle can now be obtained from a beating heart by judicious application of the dynamic LV model to information-rich pressure and volume signals. This provides for the first time a bridge between the dynamics of cardiac muscle function and the dynamics of heart function and allows a beating heart to be used in studies where the relevance of myofilament contractile behavior to cardiovascular system function may be investigated.

Nonlinear myofilament regulatory processes affect frequency-dependent muscle fiber stiffness.

To investigate the role of nonlinear myofilament regulatory processes in sarcomeric mechanodynamics, a model of myofilament kinetic processes, including thin filament on-off kinetics and crossbridge cycling kinetics with interactions within and between kinetic processes, was built to predict sarcomeric stiffness dynamics. Linear decomposition of this highly nonlinear model resulted in the identification of distinct contributions by kinetics of recruitment and by kinetics of distortion to the complex stiffness of the sarcomere. Further, it was established that nonlinear kinetic processes, such as those associated with cooperative neighbor interactions or length-dependent crossbridge attachment, contributed unique features to the stiffness spectrum through their effect on recruitment. Myofilament model-derived sarcomeric stiffness reproduces experimentally measured sarcomeric stiffness with remarkable fidelity. Consequently, characteristic features of the experimentally determined stiffness spectrum become interpretable in terms of the underlying contractile mechanisms that are responsible for specific dynamic behaviors.

Myofilament kinetics in isometric twitch dynamics.

To better understand the relationship between kinetic processes of contraction and the dynamic features of an isometric twitch, studies were conducted using a mathematical model that included: (1) kinetics of cross bridge (XB) cycling; (2) kinetics of thin filament regulatory processes; (3) serial and feedback interactions between these two kinetic processes; and (4) time course of calcium activation. Isometric twitch wave forms were predicted, morphometric features of the predicted twitch wave form were evaluated, and sensitivities of wave form morphometric features to model kinetic parameters were assessed. Initially, the impulse response of the XB cycle alone was analyzed with the findings that dynamic constants of the twitch transient were much faster than turnover number of steady-state XB cycling, and, although speed and duration of the twitch wave form were sensitive to XB cycle kinetic constants. parameters of wave shape were not. When thin filament regulatory unit (RU) kinetics were added to XB cycle kinetics, the system impulse response was slowed with only little effect on wave shape. When cooperative neighbor interactions between RU and XB were added, twitch wave shape (as well as amplitude, speed and duration) proved to be sensitive to variation in cooperativity. Importantly, persistence and shape of the falling phase could be strongly modified. When kinetic coefficients of XB attachment were made to depend on sarcomere length, changes in wave shape occurred that did not occur when only sliding filament mechanisms were operative. Indeed, the force-length relationship proved to be highly sensitive to length-dependent XB attachment in combination with cooperative interactions. These model findings are the basis of hypotheses for the role of specific kinetic events of contraction in generating twitch wave form features.

Overall cardiac functional effect of positive inotropic drugs with differing effects on relaxation.

Recent interest in so-called calcium-sensitizing positive inotropic drugs has highlighted the potential problem of a positive effect on force development being offset, at least partially, by the negative effect that many of these drugs have on relaxation. The purpose of this study was to examine the interplay of contraction and relaxation in determining the overall cardiac effect of different positive inotropic drugs. Using a buffer-perfused isolated rabbit heart preparation, we studied four drugs (calcium, dobutamine, EMD 57033, and CGP 48506) that were given at doses sufficient to increase similarly left ventricular pressure-generating capability by approximately 20%. We show that, even though they produce equivalent changes in pressure-generating capability, these four agents produce dissimilar changes in relaxation capability, with dobutamine speeding relaxation, EMD 57033 slowing relaxation, and calcium and CGP 48506 having little effect of relaxation. Similar relative effects were observed for drug-induced changes in the timing of pressure-generation events. These effects combine to produce different drug-induced changes in overall cardiac pump function judged by the relation between cardiac output and heart rate. Dobutamine shifted the maximal cardiac output to a higher heart rate. In contrast, both calcium sensitizers shifted the maximum in cardiac output to a lower heart rate, whereas calcium had no effect. Thus even though positive inotropic drugs may have similar effects on left ventricular pressure generation, the overall benefit of such drugs on ventricular pump function will depend on how the drug also affects ventricular relaxation and ejection capabilities.

Angiotensin IV has mixed effects on left ventricle systolic function and speeds relaxation.

OBJECTIVE: A novel angiotensin receptor has been described and named AT4. Ligands for this receptor include the angiotensin II (Ang II) metabolite Ang II (3-8), known as angiotensin IV (Ang IV). There is 10-fold more AT4 receptor than AT1 receptor in rabbit myocardium. The AT4 receptor has a high affinity for Ang IV (Ki in rabbit myocardium < 2 x 10(-9)) and similar ligands, but very low affinity for Ang II (Ki in rabbit myocardium > 10(-6)). Although several functions have been attributed to the novel Ang IV peptide/AT4 receptor system, the effect of this system on left ventricular (LV) function has not been studied. We hypothesized (1) that Ang IV would affect LV function and (2) that any effects would be opposite to those of Ang II. METHODS: Using the buffer-perfused (30 degrees C) isolated rabbit heart, we studied the effect of the AT4 agonist Nle1-Ang IV on LV systolic function, quantified using both Frank-Starling and end-systolic pressure-volume relationships, and relaxation. We also studied the effect of the AT1/AT2 agonist, Sar1-Ang II on LV function. Finally, because the profile of effect of Nle1-Ang IV was similar to the reported effect of nitric oxide (NO), we also studied the effect of Nle1-Ang IV in the presence of the NO synthase inhibitor NG-monomethyl-L-arginine. RESULTS: Nle1-Ang IV reduced LV pressure-generating capability at any volume but increased the sensitivity of pressure development to volume change. Nle1-Ang IV reduced LV ejection capability. Sar1-Ang II had the opposite effect-increasing both pressure generation and ejection capability. Finally, both Sar1-Ang II and Nle1-Ang IV speeded LV relaxation. Inhibition of NO synthase did not alter the effect of Nle1-Ang IV on LV systolic function or relaxation. CONCLUSIONS: AT4 receptor agonism has mixed effects on LV systolic function, depressing pressure-generation and ejection capabilities, but enhancing the sensitivity of pressure development to volume change. It also speeds relaxation. The effect of Ang IV on systolic function is generally opposite to the effect of Ang II, whereas the Ang IV influence on relaxation is similar to the effect of Ang II.

Contribution of vasomotion to vascular resistance: a comparison of arteries from virgin and pregnant rats.

Intrinsic oscillatory activity, or vasomotion, within the microcirculation has many potential functions, including modulation of vascular resistance. Alterations in oscillatory activity during pregnancy may contribute to the marked reduction in vascular resistance. The purpose of this study was 1) to mathematically model the oscillatory changes in vessel diameter and determine the effect on vascular resistance and 2) to characterize the vasomotion in resistance arteries of pregnant and nonpregnant (virgin) rats. Mesenteric arteries were isolated from Sprague-Dawley rats and studied in a pressurized arteriograph. Mathematical modeling demonstrated that the resistance in a vessel with vasomotion was greater than that in a static vessel with the same mean radius. During constriction with the alpha1-adrenergic agonist phenylephrine, the amplitude of oscillation was less in the arteries from pregnant rats. We conclude that vasomotor activity may provide a mechanism to regulate vascular resistance and blood flow independent of static changes in arterial diameter. During pregnancy the decrease in vasomotor activity in resistance arteries may contribute to the reduction in peripheral vascular resistance.

The statistics of synergism.

Biological scientists often want to determine whether two agents or events, for example, extracellular stimuli and/or intracellular signaling pathways, act synergistically when eliciting a biological response. When setting out to study whether two experimental treatments act synergistically, most biologists design the correct experiment--they administer four treatment combinations consisting of (1) the first treatment alone, (2) the second treatment alone, (3) both treatments together, and (4) neither treatment (i.e. the control). Many biologists are less clear about the correct statistical approach to determining whether the data collected in such an experimental design support a conclusion regarding synergism, or lack thereof. The non-additivity of two experimental treatments that is central to the definition of synergism leads to an algebraic formulation corresponding to the statistical null hypothesis appropriate for testing whether or not there is synergism. The resulting complex contrast among the four treatment group means is identical to the interaction effect tested in a two-way analysis of variance (ANOVA). This should not be surprising, because synergism, by definition, occurs when two treatments interact, rather than act independently, to influence a biological response. Hence, in the most readily implemented approach, the correct statistical analysis of a question of synergism is based on testing the interaction effect in a two-way ANOVA. This review presents the rationale for this correct approach to analysing data when the question is of synergism, and applies this approach to a recent published example. In addition, a common incorrect approach to analysing data with regards to synergism is presented. Finally, several associated statistical issues with regard to correctly implementing a two-way ANOVA are discussed.

Myocardial contractile depression from high-frequency vibration is not due to increased cross-bridge breakage.

Experiments were conducted in 10 isolated rabbit hearts at 25 degrees C to test the hypothesis that vibration-induced depression of myocardial contractile function was the result of increased cross-bridge breakage. Small-amplitude sinusoidal changes in left ventricular volume were administered at frequencies of 25, 50, and 76.9 Hz. The resulting pressure response consisted of a depressive response [delta Pd(t), a sustained decrease in pressure that was not at the perturbation frequency] and an infrequency response [delta Pf(t), that part at the perturbation frequency]. delta Pd(t) represented the effects of contractile depression. A cross-bridge model was applied to delta Pf(t) to estimate cross-bridge cycling parameters. Responses were obtained during Ca2+ activation and during Sr2+ activation when the time course of pressure development was slowed by a factor of 3. delta Pd(t) was strongly affected by whether the responses were activated by Ca2+ or by Sr2+. In the Sr(2+)-activated state, delta Pd(t) declined while pressure was rising and relaxation rate decreased. During Ca2+ and Sr2+ activation, velocity of myofilament sliding was insignificant as a predictor of delta Pd(t) or, when it was significant, participated by reducing delta Pd(t) rather than contributing to its magnitude. Furthermore, there was no difference in cross-bridge cycling rate constants when the Ca(2+)-activated state was compared with the Sr(2+)-activated state. An increase in cross-bridge detachment rate constant with volume-induced change in cross-bridge distortion could not be detected. Finally, processes responsible for delta Pd(t) occurred at slower frequencies than those of cross-bridge detachment. Collectively, these results argue against a cross-bridge detachment basis for vibration-induced myocardial depression.

Left ventricular pressure response to small-amplitude, sinusoidal volume changes in isolated rabbit heart.

The objective was to determine the dynamics of contractile processes from pressure responses to small-amplitude, sinusoidal volume changes in the left ventricle of the beating heart. Hearts were isolated from 14 anesthetized rabbits and paced at 1 beats/s. Volume was perturbed sinusoidally at four frequencies (f) (25, 50, 76.9, and 100 Hz) and five amplitudes (0.50, 0.75, 1.00, 1.25, and 1.50% of baseline volume). A prominent component of the pressure response occurred at the f of perturbation [infrequency response, delta Pf(t)]. A model, based on cross-bridge mechanisms and containing both pre- and postpower stroke states, was constructed to interpret delta Pf(t). Model predictions were that delta Pf(t) consisted of two parts: a part with an amplitude rising and falling in proportion to the pressure around that which delta Pf(t) occurred [Pr(t)], and a part with an amplitude rising and falling in proportion to the derivative of Pr(t) with time. Statistical analysis revealed that both parts were significant. Additional model predictions concerning response amplitude and phase were also confirmed statistically. The model was further validated by fitting simultaneously to all delta Pf(t) over the full range of f and delta V in a given heart. Residual errors from fitting were small (R2 = 0.978) and were not systematically distributed. Elaborations of the model to include noncontractile series elastance and distortion-dependent cross-bridge detachment did not improve the ability to represent the data. We concluded that the model could be used to identify cross-bridge rate constants in the whole heart from responses to 25- to 100-Hz sinusoidal volume perturbations.

The AT4 receptor agonist [Nle1]-angiotensin IV reduces mechanically induced immediate-early gene expression in the isolated rabbit heart.

Angiotensin II (ANG II), acting principally at the AT1 receptor, modulates mechanically-induced cardiac growth. The ANG II metabolite Angiotensin IV (ANG IV) has been shown to inhibit ANG II-induced mRNA and protein synthesis in chick cardiomyocytes. This effect did not involve the AT1 receptor, but was likely an action at the AT4 receptor. To determine if ANG IV also modulates a mechanically-induced cardiac growth response, we studied the effects of two AT4 receptor ligands, [Nle1]-ANG IV and [divalinal]-ANG IV, on mechanically-induced immediate-early gene expression (c-fos, egr-1, and c-jun) in the buffer perfused (30 degrees C), ejecting, isolated rabbit heart. Mechanical load alone (high systolic pressure and high end-diastolic volume) induced approximately 23-, 49- and 5-fold increases in c-fos, egr-1 and c-jun mRNA (in comparison to control hearts). Perfusion with [Nle1]-ANG IV (10[-10] mol/l) reduced the mechanically-induced expression of c-/fos and egr-1 by 42% and 48%, respectively (P < 0.05). Mechanically-induced c-jun expression was not significantly reduced. Perfusion with [divalinal]-ANG IV (10[-8] mol/l) had no effect on mechanically-induced immediate-early gene expression. We conclude that AT4 receptor agonism influences mechanical immediate-early gene expression, and propose the hypothesis that AT1 and AT4 receptors initiate opposing effects on mechanically-induced immediate-early gene expression in the isolated rabbit left ventricle.

Relaxation effect of CGP-48506, EMD-57033, and dobutamine in ejecting and isovolumically beating rabbit hearts.

Because it is not known whether ejection influences the negative effect of the Ca(2+)-sensitizing drugs on ventricular relaxation, we extended our previous analysis of stress-dependent relaxation in isovolumic beats to encompass ejecting beats and evaluated the relationships between both the time of onset of relaxation and the rate of relaxation and wall stress in a broader analysis framework. Furthermore, because the sites of action of the Ca(2+)-sensitizing drugs CGP-48506 and EMD-57033 may be different, and thus CGP-48506 may have fewer adverse effects on resting muscle length or force, we compared these two drugs to test the hypothesis that CGP-48506 would have less effect than EMD-57033 on relaxation in the isolated buffer-perfused rabbit heart. This analysis of stress-dependent relaxation in both ejecting and isovolumic beats readily differentiates between the negative lusitropic effect of 2 x 10(-6) M EMD-57033, the negligible lusitropic effect of 6 x 10(-6) M CGP-48506, and the positive lusitropic effect of 1.25 x 10(-6) M dobutamine. Furthermore, comparison of the effect of the two Ca(2+)-sensitizing drugs in ejecting versus isovolumic contractions shows that CGP-48506 affects relaxation differently in ejecting contractions than it does in isovolumic contractions, whereas EMD-57033 affects relaxation similarly in both ejecting and isovolumic contractions.

Immediate-early gene responses to different cardiac loads in the ejecting rabbit left ventricle.

Clinical and experimental observations in humans and animals have shown that different cardiac adaptations occur in response to different types of hemodynamic overload. However, very little is known about how different hemodynamic loads lead to these different cardiac adaptations. Accordingly, we studied the acute response of ejecting isolated rabbit hearts to independently varied systolic and diastolic mechanical loads at constant coronary perfusion pressure. We studied the combined effects of low end-diastolic volume (EDV) and low systolic ejection pressure (Pej), compared to low EDV and high Pej, high EDU and low Pej, and high EDV and high Pej, on the expression of c-fos, c-jun, and egr-1. Further, although we did not seek to clarify the role of these immediate-early genes in cardiac hypertrophy, we hypothesized that they should not all respond in the same manner to these different mechanical loads. In these ejecting hearts we found that the expression of these immediate-early genes did not all respond alike to the different mechanical loads: both c-fos and egr-1 were strongly induced at both 30 and 60 min. However, at 30 min only c-fos depended on the level of EDV (P = 0.01). Neither c-fos nor egr-1 was influenced by EDV at 60 min. The expression of c-jun was largely insensitive to all loading conditions. We conclude that EDV, independent of Pej, influences the pattern and time course of expression of some immediately-early genes and that these different immediate-early genes do not respond in parallel to changes in cardiac loading.

Previous-beat contraction history is not influenced by mechanosensitive ion channel blockade.

OBJECTIVES: Prior studies have shown that the performance of the left ventricle on any one beat is influenced by the mechanical events of the previous beat, a phenomenon called "previous-beat contraction history". This previous-beat contraction history, which appears to be an interplay between the mechanical events of one contraction and the activation state of the next contraction, could depend, at least in part, on mechanosensitive ion channels. The purpose of this study, therefore, was to test the hypothesis that mechanosensitive ion channels contribute to previous-beat contraction history: If previous-beat contraction history depends on mechanosensitive ion channels, the magnitude of its effect should be decreased by blocking mechanosensitive ion channels. METHODS: We performed experiments in buffer-perfused isolated rabbit hearts in which left ventricular pressure and volume were controlled with a servo-motor system. We evaluated the pulse interval-dependent expression of previous-beat contraction history under control conditions (no drug) and in the presence of 100 and 500 microM streptomycin, a blocker of mechanosensitive ion channels. RESULTS: Under control conditions, previous-beat contraction history nor its dependence on pulse interval was influenced significantly by either concentration of streptomycin. CONCLUSION: Mechanosensitive ion channels do not play a role in the expression of previous-beat contraction history in the left ventricle of the isolated rabbit heart.

Functional effects of EMD-57033 in isovolumically beating isolated rabbit hearts.

The results of isolated myocyte and cardiac muscle experiments indicate that inotropic agents that increase responsiveness of myofilaments to Ca2+ (so-called Ca2+ sensitizers) may prolong myocardial contraction and increase diastolic tone, but the importance of these effects in the whole heart is unclear. Therefore, we studied the effects of the Ca2+ sensitizer EMD-57033 (EMD) on left ventricular (LV) contractile events and passive properties in isovolumically beating isolated rabbit hearts that were buffer perfused at 30 degrees C. Several LV pressure and timing variables were evaluated, including the passive pressure-volume relationship, the Frank-Starling relationship, and the wall stress dependence of the duration of relaxation during perfusion with 0, 2, and 4 microM EMD. EMD (2 microM) increased average peak developed pressure of the Frank-Starling relationship by approximately 18%. In contrast, the peak developed pressure of the Frank-Starling relationship decreased toward control with 4 microM EMD, and therefore all the results presented pertain to 2 microM EMD. The maximum developed pressure at baseline volume was increased by approximately 19% by 2 microM EMD, and this was accompanied by an increase in contraction duration of approximately 13%, due exclusively to slowed relaxation. The relative contributions of maximal wall stress (sigma max) versus an independent negative lusitropic effect of EMD were determined at three LV volumes. At baseline volume, just less than one-half of the effect to slow relaxation was ascribable to an increase in sigma max, whereas the remainder was due to an independent EMD effect. LV passive properties were unchanged by perfusion with 2 microM EMD. We conclude that EMD is a potent inotrope in our isolated rabbit heart preparation, which has no effect on diastolic tone and causes a modest prolongation of contraction duration due to slowed relaxation. At baseline volume, approximately 50% of the slowed relaxation was ascribable to positive inotropy leading to increased sigma max, whereas the remaining approximately 50% was ascribable to a direct negative lusitropic effect of EMD. We discuss our results in terms of the current hypotheses regarding the mechanism of action of the Ca2+ sensitizers.

Characterization of chronotropic and dysrhythmogenic effects of atropine in dogs with bradycardia.

OBJECTIVE: To characterize the magnitude, character, and time course of chronotropic and dysrhythmogenic responses of dogs with vagally mediated bradycardia to atropine sulfate. DESIGN: Latin square design. ANIMALS: Seven clinically normal adult mixed-breed dogs. PROCEDURE: Vagally mediated bradycardia was induced with morphine and fentanyl citrate. Atropine (0.02 mg/kg of body weight) was administered i.v., s.c., or i.m.. Electrocardiograms were recorded continuously for 5 minutes before and for 35 minutes after atropine administration or until a sustained parasympatholytic response was observed. Data were digitized, analyzed independently for changes in atrial and ventricular rate, and compared between different routes of administration. RESULTS: All dogs developed second-degree atrioventricular (AV) block after i.v. administration of atropine, and 71% of dogs developed AV block after s.c. or i.m. administration. The AV block arose and resolved more rapidly with i.v. administration than with s.c. or i.m. administration. The AV block was principally attributable to an increase in the atrial rate prior to increases in the ventricular rate. Atropine, regardless of route of administration, potentiated baseline ventricular bradycardia in 62% of the experiments (mean heart rate decrease of 16 beats/min; decreased to < 20 beats/min in 2 dogs for < or = 10 seconds). Duration of the bradycardic potentiation was longer with s.c. administration (9.1 minutes, s.c., vs 1.4 minutes, i.v., and 4.6 minutes, i.m.). Parasympatholytic rate was higher for i.v. than s.c. or i.m. administration (128 beats/min vs 92 beats/min and 101 beats/min). Two dogs given atropine s.c. failed to resolve the AV block and attain sinus rhythm. CONCLUSIONS: Administration of 0.02 mg of atropine/kg by i.v., i.m., and s.c. routes for vagally mediated bradycardia in dogs consistently induces AV block and occasional brief potentiation of ventricular bradycardia. CLINICAL RELEVANCE: Parasympathomimetic effects occur and resolve most rapidly and consistently, and the stable parasympatholytic effect is of greatest magnitude after i.v. administration. Thus, vagally mediated bradycardia in clinically normal dogs appears to be best abolished by i.v. administration of atropine.

Mechanical determinants of left ventricular relaxation in isovolumically beating hearts.

Both pressure and volume have been proposed to determine the speed of left ventricular (LV) relaxation, but their relative importance is not known. Accordingly, we used isolated, buffer-perfused, isovolumically beating ferret hearts to study the effects of maximal developed pressure (Pdmax) and LV volume (V) on the speed of LV relaxation. Experiments were performed at 30 degrees C, and the hearts were paced at a baseline interbeat interval (BI) of 800 ms. Pdmax was varied independently of V by use of seven BI (75 to 133% of baseline BI), which resulted in test beats that developed a range of Pdmax due to varying degrees of restitution. Pdmax was also varied by setting V at five levels (80 to 120% of baseline V) during the test beats. Speed of relaxation was quantified as the time period of pressure decay from 75 to 25% Pdmax (T75-25). Data were analyzed by multiple linear regression. Increases in both Pdmax and V independently prolonged T75-25, and T75-25 was 1.45 times more sensitive to Pdmax than to V. However, when Pdmax and V were combined to estimate maximal wall stress (sigma max), the effects of Pdmax and V, as well as relative circumferential muscle length (estimated by V1/3), were not important determinants, and T75-25 depended on sigma max alone. Thus we conclude that 1) Pdmax and V are both determinants of the speed of LV relaxation and that Pdmax is approximately 1.5 times more important than V, and 2) the effects of Pdmax and V on relaxation act via the common mechanism of sigma max.

Beta-adrenergic blockade reduces myocardial injury during experimental cardiopulmonary resuscitation.

OBJECTIVES: We attempted to determine the effects of beta-adrenergic blockade during cardiopulmonary resuscitation (CPR) on defibrillation rates and postresuscitation left ventricular function. BACKGROUND: The results of previous studies suggest that propranolol administration can both reduce myocardial oxygen requirements and increase coronary perfusion pressure during CPR. METHODS: Left ventricular pressure and segment length were measured before and after 5 min of CPR in 22 dogs either given epinephrine (0.015 mg/kg body weight at the onset and after 4 min) or pretreated with propranolol (2 mg/kg) and given epinephrine during CPR. RESULTS: Despite identical epinephrine doses, coronary perfusion pressure during CPR was higher in the epinephrine plus propranolol group (p < 0.05), and defibrillation was successful in 9 of 11 dogs given both epinephrine and propranolol versus 6 of 11 dogs given epinephrine alone (p = NS). Peak and developed left ventricular pressures, left ventricular end-diastolic pressure and the peak rate of left ventricular pressure development (+dP/dt) did not differ between study groups when measured either 5 or 15 min after successful defibrillation. However, when survivors in the epinephrine group were given propranolol after CPR to eliminate compensatory sympathetic stimulation, left ventricular developed pressure and peak +dP/dt were lower (p < 0.05) despite trends toward higher left ventricular end-diastolic pressures and normalized end-diastolic segment lengths compared with dogs given propranolol before CPR. CONCLUSIONS: These findings suggest that beta-adrenergic blockade reduces myocardial injury during CPR without decreasing the likelihood of successful defibrillation or compromising spontaneous postresuscitation left ventricular function.

Previous beat contraction history alters mechanical restitution in the isolated left ventricle.

OBJECTIVE: The aim was to test directly the hypothesis that the magnitude of previous beat contraction history will be greatest for short pulse intervals, will become smaller as pulse interval is lengthened, and will vanish when pulse interval is long enough to allow complete restitution. METHODS: Experiments were performed in isolated rabbit and ferret left ventricles in which pressure and volume were controlled with a servo-motor system. Two restitution curves were generated, each constructed from isovolumetric beats that were preceded by a beat with differing amounts of ejection: one curve was constructed from isovolumetric beats preceded by non-ejecting beats, while the other was constructed from isovolumetric beats preceded by a beats that had a high level of ejection (ejection fraction approximately 50%). RESULTS: When the isovolumetric beats used to construct a restitution curve were preceded by ejecting beats, the restitution curve was shifted upward (that is, higher activation at a given interval between beats) when compared to a restitution curve constructed from isovolumetric beats that were preceded by non-ejecting beats. CONCLUSIONS: Mechanical restitution is affected by the mechanical events of preceding contractions, implying that previous beat contraction history and restitution share a common mechanism and that restitution sets the stage for previous beat contraction history. Hence restitution is not simply a useful tool for assessing calcium cycling or interval dependent behaviour and should be viewed more broadly as a fundamental process in the beat to beat regulation of cardiac contraction.

Effects of free wall ischemia and bundle branch block on systolic ventricular interaction in dog hearts.

Systolic direct ventricular interaction is thought to occur via the ventricular septum and the coordinated contraction of common fibers shared by both ventricles. The purpose of the present study was to evaluate the effects of transient free wall ischemia and bundle branch block, which disrupt the coordinated contraction of shared common fibers, on left-to-right systolic ventricular interaction. We produced transient right and left ventricular free wall ischemia by 2-min coronary artery occlusions and bundle branch block by ventricular pacing in nine in situ dog hearts. To eliminate any confounding effect of series interaction, we used an abrupt hemodynamic perturbation (aortic constriction), and we measured systolic interaction gain (IG) as delta right ventricular peak systolic pressure/delta left ventricular peak systolic pressure (IG(peak)) and instantaneous delta right ventricular pressure/delta left ventricular pressure at matched data sampling times (IG(inst)), along with changes in right ventricular stroke volume and stroke work before and on the beat immediately after the aortic constriction. To achieve equivalence of the interventricular septal pressure transmission contribution to ventricular interaction, the delta left ventricular peak systolic pressure produced by the aortic constriction was matched under all experimental conditions [average increase: 64 +/- 19 (SD) mmHg]. Control IG(peak) was 0.12 +/- 0.05, and control IG(inst) was 0.11 +/- 0.05. These values did not change with either free wall ischemia or ventricular pacing, with or without an intact pericardium. The changes in right ventricular stroke volume and stroke work produced by the aortic constriction were not different from zero, during either ischemia or ventricular pacing, with or without an intact pericardium.(ABSTRACT TRUNCATED AT 250 WORDS)