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Load-dependent relaxation was studied in eight conscious dogs by inflating an intra-aortic balloon during late systole. Initially, the balloon was inflated at the aortic dicrotic notch and deflated before the next systole; subsequently, the inflation time was moved progressively earlier in 30-ms steps. This intervention produced an abrupt increment in left ventricular (LV) systolic pressure. The contraction duration was assessed by measuring the time required for LV pressure to fall by 50% of its maximum value (P50). The rate of LV pressure decline was assessed by measuring its peak negative first time derivative (-dP/dt) and the time constant of relaxation (tau). When the balloon was inflated during late systole (50 +/- 5 ms before aortic dicrotic notch), the time to peak -dP/dt fell, P50 fell, peak -dP/dt increased, and tau was unchanged. Thus the initial rate of LV pressure decline was accelerated, and the duration of the contraction was abbreviated. These data indicated that myocardial relaxation in the intact conscious dog is load dependent. Late systolic balloon inflations were performed after treatment with propranolol, verapamil, or caffeine. During propranolol and verapamil, the rate of LV relaxation (peak -dP/dt and tau) was slowed; however, the effects of balloon inflation on LV pressure transients were qualitatively similar to that seen in the baseline state. By contrast, caffeine prevented the abbreviation in the contraction duration caused by late-systolic balloon inflation. Thus LV relaxation remained load dependent when myocardial relaxation was slowed by propranolol or verapamil; load-dependent relaxation was attenuated by caffeine, presumably due to its influence on the sarcoplasmic reticulum.

To determine whether isolated changes in preload (end-diastolic force) can influence myocardial relaxation rate in normal or abnormal (hypoxic or hypertrophic) hearts, isolated LV papillary muscles from normal Wistar-Kyoto (WKY) and spontaneously hypertensive (SHR) rats were studied using physiologically sequenced contractions. While total (systolic) load and late (lengthening) load were held constant, maximum isometric force decline (peak -dT/dt) and maximum isotonic lengthening rate (peak +dL/dt) were measured at seven levels of preload that varied from 115 to 55% of the resting tension at maximum length-tension curves (Lmax). Muscles from normal rats were studied in the oxygenated state (95% O2-5% CO2) and in the hypoxic state (95% N2-5% CO2). Preload did not effect peak -dT/dt or peak +dL/dt in either oxygenated or hypoxic muscles. During hypoxia, peak -dT/dt and peak +dL/dt were 9.5 +/- 1.0 g.mm-2.s-1 and 0.3 +/- 0.1 muscle length/s, respectively, at a preload of 115% compared with 9.0 +/- 1.2 g.mm-2.s-1 and 0.2 +/- 0.1 at a preload of 55%. In separate experiments, the effect of preload on relaxation rate was studied in WKY and SHR rats. In neither group did preload have an independent effect on relaxation rate. In the SHRs, peak -dT/dt and peak +dL/dt were 24.3 +/- 5.3 g.mm-2.s-1 and 0.7 +/- 0.1 muscle length/s, respectively, at a preload of 115% compared with 24.7 +/- 6.6 and 0.8 +/- 0.1 at a preload of 55%. Thus, in hypoxic and hypertrophic myocardium, as in normal muscle, an acute isolated change in preload did not influence the rate of force decline or muscle lengthening.

The hemodynamic determinants of the time constant of left ventricular (LV) isovolumic pressure (P) decline were studied in 32 anesthetized dogs. The time constant, tau (an index of LV relaxation), was determined from the best exponential fit of the equation P = Poe-t/r, to LVP measured at 5-ms intervals during isovolumic relaxation; Po = LVP at maximum negative dP/dt and t = time. At a constant heart rate of 120 beats/min, tau was determined during steady-state increases in preload (volume expansion), increases in afterload (methoxamine infusion), reductions in afterload (nitroprusside infusion), and in variably afterloaded beats at a constant preload (single-beat interventions). tau was directly related to LV systolic pressure and length during the alterations in LV loading conditions, but tau was not closely related to the extent of fiber shortening. During isoproterenol infusion, relaxation was more rapid (tau), and following the administration of propranolol, relaxation was prolonged (tau). While data from the variably afterloaded contractions indicate the presence of systolic load-dependent LV relaxation velocity, the steady-state studies do not exclude the possibility that altered contractility through reflex or other mechanisms contributes to the observed changes in tau.

Peak systolic elastance (Emax) was measured in the intact canine circulation by means of a new experimental technique. In this technique the heart is isolated from the circulation during a single systole and subjected to controlled ventricular loads. An electropneumatic aortic occluder is used to isolate the ventricle, and a servo-controlled syringe pump is used to control the ventricular load. Because the experimental load is applied for a single heartbeat only, ventricular function can be measured without the interference of regulatory feedback mechanisms. In eight dogs, weighing 17-42 kg, the relationship between changes in endsystolic pressure and volume was determined from the single-beat application of purely compliant loads. The end-systolic relations were linear, and their slope, Emax, was inversely related to weight. The observed relation between Emax and body weight allows comparisons to be made between different preparations in which Emax has been determined. Values of Emax obtained from the single-beat preparation were found to be 27-74% above those reported in isolated heart preparations and nearly identical to those reported for in vivo or denervated in situ preparations.

The effects of nitroprusside and cyanide on myocardial relaxation were studied during hypoxia and reoxygenation of isolated rat papillary muscle, and during segmental ischemia and reperfusion in the intact dog heart. Nitroprusside did not affect isolated muscle performance before or during hypoxia. During reoxygenation of hypoxic muscles, the tension prolongation phenomenon (which characterizes abnormal or prolonged relaxation) was only slightly attenuated by the addition of nitroprusside to the muscle bath; in contrast, cyanide (at concentrations that did not prevent the return of tension) abolished tension prolongation during reoxygenation. During reperfusion of ischemic segments in intact hearts, the prolongation of segment tension was not affected by systemic administration of nitroprusside, but was abolished by intracoronary cyanide. Attenuation of the tension prolongation phenomenon by nitroprusside in the isolated muscle may be due to the liberation of cyanide. Inasmuch as nitroprusside did not affect the tension prolongation phenomenon in the intact heart, it is unlikely that the influence of this drug on left ventricular diastolic compliance is mediated through an alteration in the tension prolongation phenomenon.

We studied the effect of left ventricular (LV) asynchrony and alterations in beta-adrenergic tone on the systolic load (pressure) dependency of LV isovolumic relaxation rate in anesthetized dogs. The time constant (T) of isovolumic exponential pressure decline was used as an index of relaxation rate. Variably afterloaded LV contractions resulted in a progressive increase in LV end-systolic pressure from 124 +/- 6 in the control beat to 176 +/- 11 mmHg in the third beat and a progressive lengthening of T from 19 +/- 2 to 30 +/- 4 ms. The direct relation between LV end-systolic pressure and T was nearly linear (r = 0.98), and the slope (k) of this relation was taken to reflect the systolic load dependency of T. Administration of isoproterenol (n = 6) produced a decrease in k from 0.11 +/- 0.02 to 0.08 +/- 0.02 (P less than 0.05); with propranolol (n = 6), k increased from 0.08 +/- 0.02 to 0.27 +/- 0.04 (P less than 0.01). Right ventricular epicardial pacing (n = 6) produced an asynchronous LV contraction and an increase in k from 0.09 +/- 0.02 (atrial pacing) to 0.25 +/- 0.04 (P less than 0.01). These studies confirm the dependency of LV relaxation rate on systolic loads and indicate that this form of load-dependent relaxation can be modified by alterations in beta-adrenergic tone and LV asynchrony. The observed alterations suggest the importance of temporal dispersion of the contraction-relaxation sequence as a mechanism responsible for disturbed relaxation.