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Myocardial mechanics in the male spontaneously hypertensive rat (SHR) and Wistar-Kyoto rat (WKY) at 18 months of age were studied. Left ventricular hypertrophy was documented in the SHR by an increase in left ventricle/body weight and left ventricle/tibial length ratios when compared to the WKY (P less than 0.001). Isolated left ventricular papillary muscles were studied at 28 degrees C while contracting 12 times/min at the apex of the length-tension curve. Active and passive length-tension relations were measured at relatively early (65 +/- 3 min) and late (200 +/- 5 min) times following sacrifice. No significant differences in passive length-tension relations between strains were observed. Between early and late measurements, a significant decrease in passive tension within the length spectrum 89-100% Lmax occurred in both SHR and WKY, accompanied by a significant increase in passive stiffness (P less than 0.01, SHR; P less than 0.001, WKY). Isometric performance was measured at relatively early (81 +/- 3 min) and later (190 +/- 5 min) times following sacrifice. Strain differences in active muscle performance were of a greater electromechanical delay time (EMD) (P less than 0.05, early: P less than 0.001, late) and time-to-peak tension (TPT) (P less than 0.001, late) in SHR compared to WKY. Between early and late measurements, decreases in EMD (P less than 0.01, SHR; P less than 0.001, WKY), TPT (P less than 0.001; P less than 0.001), the half-time of relaxation (P less than 0.001; P less than 0.001), and the resting tension (P less than 0.01; P less than 0.001) were observed, and the maximum rate of fall of tension increased (P less than 0.01; P less than 0.01). We conclude that studies must be precisely referenced from the time of sacrifice of the animal in order to accurately evaluate the effects of experimental hypertrophy on isolated muscle performance. No evidence for the depression of papillary muscle isometric performance was seen in the 18-month SHR when compared to the WKY, although prolonged EMD and TPT were observed.

Isolated, blood-perfused dog hearts were subjected to 2 hours of arrest at 27 degrees C and perfused at 15-minute intervals with either a potassium crystalloid cardioplegic solution (KCC) or an identical solution to which washed red blood cells were added (KrbcC). After reperfusion, hearts protected with KCC were easily defibrillated and systolic pressure returned to 62% of prearrest values 90 minutes after reperfusion. In hearts protected with KrbcC, systolic pressures recovered to 103% of prearrest values 15 minutes after reperfusion. Metabolic variables recovered more quickly in hearts perfused with KrbcC. Adenosine triphosphate did not decline with arrest in either group. Creatine phosphate values decreased with KCC and increased with KrbcC. The pH of the myocardial effluent fell to 6.48 during arrest with KCC and to 7.19 with KrbcC (p less than 0.001). Carbon dioxide tension increased with KCC, but decreased with KrbcC (p less than 0.001). Thus, marked improvement in recovery after 2 hours of arrest is seen with KrbcC. Protection beyond that provided by KCC appears solely due to the washed red cells, and may be the result of the buffering action of the red cell improved oxygen delivery.

Using a simple model for cardiac muscle relaxation which takes into account muscle length, activation, elasticity and a rate constant for the decay of activation, we are able to use easily measured mechanical parameters to assess the state of the cardiac relaxing system. In isolated trabeculae carneae from the left ventricle of the rat, performing physiologically sequenced contractions, observations have been made (1) at varying preloads and afterloads, (2) with changes in temperature from 23 degrees to 33 degrees C, (3) with changes in bath Ca2+ concentration and (4) with the addition of isoproterenol. During isometric relaxation, the slope (SIM) of the curve relating maximum rate of decline of force (-dF/dtmax) to end-systolic muscle length is load-independent and sensitive to interventions which directly affect the cardiac relaxing system (e.g., temperature, isoproterenol); it is only slightly sensitive to bath calcium concentration. During isotonic relaxation, the maximum velocity of lengthening (+dL/dtmax) is in negative linear proportion to muscle shortening at a given preload, the slope (SIT) of the curve relating +dL/dtmax to end-systolic length is sensitive to the interventions which directly affect the cardiac relaxing system but insensitive to calcium-mediated inotropic interventions. The model provides a theoretical basis for the use of SIM and SIT as measures of the relaxation process.

The mechanical performance of isolated left ventricular muscle preparations from rats exposed to smoke from Kentucky Reference cigarettes was examined for possible chronic effects. Eight rats were subjected to smoke for periods of 10 min/hr for 5 hr/day for 180 days. Nineteen additional rats served as either sham-smoked controls or weight-matched, food-deprived controls. Rats exposed to tobacco smoke had a significant diminution in body and left ventricular weight compared to sham-smoked controls. When compared to food-deprived rats, no differences in weights were observed. Contraction mechanics were measured for each muscle at the peak of its length tension curve. No significant difference in cardiac muscle performance was found in rats exposed to tobacco smoke when compared to control animals with respect to contractile performance under oxygenated conditions, muscle performance during 60 min of hypoxia or subsequent reoxygenation, or sensitivity of mechanical performance to isoproterenol. Thus, chronic cigarette smoke exposure did not alter the intrinsic mechanical performance of isolated rat ventricular muscle.

The effects of brief periods of graded reductions in perfusion pressure on normally beating and fibrillating hearts were examined. Mechanical and metabolic parameters were studied in the isolated, isovolumic (balloon in left ventricle), blood-perfused dog heart preparation. Experiments were carried out at perfusion pressures of 100, 75, 50, and 25 mm Hg, and comparisons of performance were made at the same ventricular volumes in the beating and fibrillating heart. A fall in perfusion pressure significantly decreased systolic performance in the beating heart. Diastolic pressure-volume relations were not altered by changes in perfusion pressure in the beating heart, but the fibrillating heart became significantly more compliant as perfusion pressure declined. Coronary blood flow and myocardial oxygen consumption were consistently higher during fibrillation than during sinus rhythm, and both parameters declined significantly at decreasing perfusion pressures. The fibrillating heart produced lactate at a perfusion pressure below 65 mm Hg, while the beating heart produced lactate at a perfusion pressure below 35 mm Hg. These studies demonstrate that brief periods of relatively modest decreases in perfusion pressure during ventricular fibrillation alter myocardial energy demand-supply relationships to result in ischemia of the fibrillating heart.

The effects of washed blood or oxygenator-traumatized whole blood as vehicles for sanguinous cardioplegia were studied utilizing the isolated blood-perfused dog heart preparation. Hearts were subjected to 2 hr of potassium-induced arrest at 27 degrees C followed by 90 min of normothermic reperfusion. Washed blood cardioplegia (n = 7) contained blood washed thrice with saline while oxygenator blood cardioplegia (n = 6) contained whole blood which had been exposed to an extracorporeal circuit for 30 to 45 min. Cardioplegic solutions were administered at a perfusion pressure of 100 mm Hg every 15 min during arrest. While the arrest-reperfusion sequence caused minor variations in the mechanical, metabolic, and biochemical parameters tested, generally insignificant differences were found to exist between groups. Differences in coronary washout PCO2 appeared to be due to inherent differences between the two cardioplegic solutions. Thus, while washing blood may be thought to be beneficial and whole blood from the extracorporeal circuit may be theorized to have a deleterious effect on the myocardium, excellent recovery of mechanical function was observed with both cardioplegic solutions. The present study suggests that it is unnecessary to wash the sanguinous cardioplegic solution obtained from the cardiopulmonary circuit.

The effect of hypoxia on contractile performance of left ventricular papillary muscles from 2-week old and 6-month old rats was studied. Left ventricular glycogen concentration was not significantly different between 2-week and 6-month old hearts; however, the lactate dehydrogenase isoenzyme pattern of the left ventricular myocardium from the 2-week old rats demonstrated a shift toward M-type (anaerobic) distribution relative to 6-month-old animals. Papillary muscle performance was studied at 28 degrees C while contracting 12 times/min at the peak of the active tension curve in oxygenated (95% oxygen, 5% carbon dioxide) Krebs-Henseleit solution containing glucose concentrations from 5.5 to 22 mM. In a bath containing 5.5 mM glucose, the decline in developed tension during hypoxia (95% nitrogen, 5% carbon dioxide) of preparations from the 2-week old rats was significantly less (P less than 0.05) than the 6-month old group only at 15 min. Raising the glucose concentrations of the bath to 11 and 16.5 mM resulted in improved performance throughout 60 min of hypoxia in preparations from 2-week compared with 6-month old animals. Practolol (5 X 10(-5)M) did not prevent the increased tolerance to hypoxia observed in preparations from 2-week animals. Thus, increasing anaerobic substrate has differential effects on the performance of 2-week and 6-month myocardium during hypoxia. The data suggests that in contrast to 6-month old heart muscle, myocardium from 2-week old rats is capable of modulating its active mechanical activity during hypoxia in accordance with the availability of glycolyptic substrate.

Heat and liver lactate dehydrogenase (LDH) and isoenzyme distributions were studied in rats with experimental thiamine deficiency. No change in total heart LDH activity was observed on days 24 and 40 of a thiamine deficient diet. At the time of symptoms (average 53 days on diet), total heart muscle LDH was slightly decreased in thiamine deficient rats (248 +/- 12 U/g tissue, Mn +/- SE) compared to ad lib fed controls (293 +/- 12, p less than 0.05), but did not differ from pair fed controls (273 +/- 15). Heart muscle LDH isoenzyme distribution showed a relative increase in the H4 band and a decrease in the H2M2 and HM3 bands in thiamine deficiency on day 24. This pattern became more promient by day 40. Calculated total M-LDH activity of heart muscle in thiamine deficient rats was significantly decreased at day 40 (44 +/- 3) compared to pair fed controls (57 +/- 5, p less than 0.05) and ad lib fed controls (85 +/- 7 p less than 0.001). Further changes were not observed in the symptomatic stage. Total H-LDH in heart muscle did not change during the period of study, while total liver LDH activity was reduced in thiamine deficient rats at the symptomatic stage (137 +/- 15) compared with pair fed controls (193 +/- 12, p less than 0.05) and ad lib fed controls (407 +/- 50, p less than 0.01). Liver isoenzyme electrophoresis showed an almost 100% distribution to the M4 band. The present investigation demonstrates a decrease in cardiac muscle M-LDH in experimental thiamine deficiency. Differences in LDH isoenzyme distribution in chronic hypoxia and thiamine deficiency are discussed.

The contractile performance of isolated muscle preparations from the left ventricle of rats receiving a 3% casein protein deficient diet for two to three weeks was compared with the performance of muscle preparations from animals receiving a normal diet. The right and left ventricular weights from protein deficient animals were significantly decreased, but left ventricle/body weight and right ventricular/body weight ratios did not differ from control animals. The performance of the isolated muscle preparations revealed no differences in the following parameters measured at the apex of the length tension curve: peak active tension, resting tension, maximum rate of tension development and time to peak tension. RT1/2, an index of relaxation, and maximum rate of tension decline indicated relaxation rate was increased in preparations from protein deficient animals. We conclude that, while a protein deficient diet of two to three weeks duration results in proportionate decreases in body and cardiac chamber weight in comparison to control animals, no evidence for impaired contractile activity is seen.

The mechanical performance of isometrically contracting papillary muscle was studied in rats sacrificed by decapitation or anesthetized with sodium pentobarbital or chloralose before decapitation. The purpose was to evaluate which maneuver would be the more adequate to ve used, when performance of papillary muscle mechanics must be evaluated later. The data suggest that either anesthetic agents used in this experiment and/or decapitation have the same effects on isolated muscle performance in the three groups. The results may be a consequence of the time elapsed between animal decapitation and the recording of cardiac parameters: this fact would attenuate the many factors that could promote mechanical performance dysfunction or isolated papillary muscles.

The preformance of isolated left ventricular muscle preparations during 60 min of hypoxia (95 percent N-2, 5% CO-2) and 30 min of reoxygenation (95% O-2, 5% CO2) was examined at differing stimulation rates (1, 12 and 60 stimuli/min). Since a change in inotropic state accompanies a change in cardiac rate, studies were carried out in two species with different force-frequency relationships over the heart rate range examined the rat and the guinea pig. Preparations were studied at the apices of their length tension curves while contracting isometrically 12 times a min at 28 degrees. At increasing stimulation rates, under oxygenated conditions, isometric tension fell in rat ventricular muscle while the reverse is true in the guinea pig. Despite the differing force-frequency responses, both species demonstrated progressively poor performance during hypoxia at increasing stimulation rates. This was manifested by a more rapid and greater decline in mechanical activity, more severe contracture during hypoxia and and slower recovery upon reoxygenation.

To document the independent effects of acute changes in preload, afterload and inotropic state on the systolic time intervals, 10 isolated rat left ventricular muscle preparations were studied. Experiments were performed using physiologically sequenced contractions that simulate the loading conditions of the intact left ventricle. The preshortening period was measured from the time of the electrical stimulus to the onset of muscle shortening, and the isotonic contraction time was measured as the duration of shortening. These variables are analogous to the preejection period and the left ventricular ejection time in the intact heart. It was found that an isolated increase in preload shortened the preshortening period and prolonged the isotonic contraction time, whereas an increase in afterload prolonged the former and shortened the latter. Isoproterenol shortened both the preshortening period and the isotonic contraction time, while an increase in calcium shortened the preshortening period and lengthened the isotonic contraction time. All changes were significant (p less than 0.01) by analysis of variance. Thus, the similar dependence of preshortening period, isotonic contraction time and clinical systolic time intervals on changes in preload, afterload and inotropic state supports the derivation of systolic time intervals from fundamental principles of myocardial mechanics. These data provide an improved basis for the rational interpretation of systolic time intervals in patients with and without heart disease.

An application language for the control and analysis of isolated cardiac muscle experiments is described. It is defined using an extensible language, STOIC (derived from FORTH), which consists of a set of basic operations called words. The basic words are readily combined to form higher level words which perform more complex operations. A suitable set of higher level words forms an application language. The resulting language takes full advantage of system hardware capabilities, is easily used by those with little programming experience, and provides flexibility in a research environment where experimental protocols frequently change.

To examine the effects of hypertrophy and fibrosis on myocardial mechanics, we studied isolated left ventricular papillary muscles from 6-month-old male SHR and allylamine-fed rats. In SHR, the peak developed tension (DT) and the maximum rate of tension development (dT/dt) were higher compared to control male Wistar-Kyoto rats (WKY). With 15 min of hypoxia, the DT and the dT/dt declined similarly in both groups and the ratios of DT and dT/dt to their prehypoxic values after 15 min of hypoxia were not different in the two groups. From allylamine-fed rats, only 4 papillary muscles had more than 25% interstitial fibrosis by point-counting (AL-B group), but 9 muscles had no fibrotic involvement and their left ventricular hydroxyproline concentration was normal (AL-A group). The myocardial diameters, the passive stiffness constant and the duration of isometric contractions at Lmax were increased in AL-B group, but the resting tension, the DT at Lmax and the force-velocity relations did not differ from controls. The mechanical properties of the AL-A group muscles were not different from controls. However, when pumping function was examined in the intact heart from the AL-A group, the LVEDP was increased and the peak cardiac output normalized by body weight was decreased. Thus, hypertrophied muscle from SHR shows hyperfunction without an increase in susceptibility to hypoxic stress. Even if fibrosis progresses, hypertrophy can compensate for the reduction in contractile component up to a certain degree.(ABSTRACT TRUNCATED AT 250 WORDS)

An inverse linear relationship between normalized tension development (T/mm2) and muscle cross-sectional area (range 0.32-1.68 mm2) is seen in fully oxygenated rat papillary and columnar carnease muscles studied while contracting isometrically at the apex of the length-tension curve. The data demonstrate progressively poorer performance with thicker preparations, presumatic blockade) is added to fully oxygenated muscle preparations, no significant change in performance is seen even with the thickest preparations, suggesting that no portion of mechanical activity is supported by anaerobic glycolysis. With progressive lowering of the muscle bath PO2, the relative contributions of aerobic and glycolytic activity to mechanical performance are demonstrated. Viewed from the Hill model of oxygen and lactic acid distribution in a cylindrical section of muscle, the data that suggest the presence of a hypoxic core appear contrary to the evidence that indicates the absence of tension supported by glycolytic activity. A possible solution to this apparent contradiction is presented. The findings of these experiments emphasize limitations of isolated muscle studies and help define the relationship between oxygenation and mechanical activity of cardiac muscle.

The effects of isoproterenol, glucose, and pH on the responses of isolated rat cardiac muscle to hypoxia (95% N2, 5% CO2) were examined while the muscles were contracting isometrically 12 times a minute at 28 degrees C. In the presence of 5.5 mM glucose, 10(-5) M isoproterenol and alkaline pH (7.8) improved the performance of cardiac muscle during early hypoxia. This was followed by a premature decline in developed tension, and contracture appeared. Recovery of function following reoxygenation with 95% O2 and 5% CO2 after a 60-min period of hypoxia was poor. Acid pH (6.8) resulted in an early decline of mechanical activity during hypoxia; but contracture did not appear, and full recovery of developed tension was seen upon reoxygenation after 60 min of hypoxia. When 22 mM glucose was used as substrate, the early responses to hypoxia were not altered; but late performance was improved, contracture did not appear, and full recovery after 60 min of hypoxia was seen. If additional glucose was added to the bath after 30 min of hypoxia (concentration 22 mM), little effect on developed tension was evident; but contracture diminished and recovery after 60 min of hypoxia was improved. Addition of 22 mM glucose allowed isoproterenol to exert its inotropic effect in the absence of late deleterious changes. The data support the concept that factors tending to increase the utilization of limited stores of anaerobic substrate during hypoxia facilitate deterioration. By increasing exogenous glucose, the support of inotropic activity without late adverse effects appears possible, and recovery is improved upon reoxygenation.

The mechanism of myocardial protection provided by red blood cells was studied with a preparation of isolated, blood-perfused dog heart. Myocardial function, metabolism, and high-energy phosphate stores were determined before and at the end of cardioplegic arrest and after reperfusion. Cardioplegic solutions containing NaCl, KCl, and dextran (crystalloid; C) were compared, at 27 degrees C, with an identical solution containing 20% washed red cells (R) and a third solution in which the red cells were treated with 0.02M NaNO2, resulting in methemoglobin (M) formation or red cells able to buffer pH but unable to transport oxygen. Solutions were delivered at 15 min intervals during 2 hr of arrest and coronary effluent pH, PCO2, and lactate were measured. Both R and M solutions prevented the increases in effluent PCO2 and decreases observed in pH with C. On the other hand, mechanical, metabolic, and high-energy phosphate determinations revealed that marked protection was provided by R but not by M or C. Thus, myocardial protection provided by R at 27 degrees C is not the result of buffering but appears to be primarily the result of oxygen delivery by the red cells to the myocardium.

Oxygen-derived free radicals (OFR) have been implicated as mediators of tissue injury in various disease states. Their participation in myocardial injury due to ischemia-reperfusion has also been suggested. To characterize the mechanical dysfunction associated with OFR-induced injury, we studied alterations in isometric contractions of rat papillary muscle at 28 degrees C. A purine-xanthine oxidase system was used to generate OFR. Neither purine nor xanthine oxidase alone had significant effects on rest or active tension, duration of the contraction, or peak rates of tension development or decline. In contrast, their combination resulted in a reduction of active tension to 38% of base-line values without alteration in rest tension. This reduction was largely due to a decline in the peak rate of tension development. When catalase or superoxide dismutase was introduced into the bath prior to the generation of OFR, catalase but not superoxide dismutase offered essentially complete functional protection. These results substantiate that impaired myocardial function can result from exposure to OFR. In this case the active radicals appear to be either peroxides or hydroxyl and not superoxide. These observations provide a basis for understanding the functional protection afforded ischemic myocardium by OFR scavenging enzymes.

High speed oscilloscopic recordings (4000 mm/sec) of left ventricular pressure (micromanometer) and its first derivative were used to calculate contractile element velocity (Vce) during the isovolumic period of auxotonic beats in anesthetized dogs. At 0.5-2.0 msec intervals of isovolumic systole, Vce was derived as (dP/dt)/kP, where k = 24 cm(-1). Plots of Vce and P yielded inverse curves from peak Vce to aortic valve opening pressure which averaged 27 msec in controls, and 11 msec during norepinephrine administration. Extrapolated Vmax, in muscle lengths/second, averaged 3.6 (controls), 3.6 (volume load), and 6.6 (norepinephrine). In each experimental state, Vmax was also determined from force-velocity relations of isovolumic beats (abrupt aortic occlusion) analyzed at 10 msec intervals from conventional pressure recordings. Vmax by both methods correlated well (r = 0.88). While good correlations were also noted between Vmax and maximum dP/dt, (max dP/dt)/integrated isovolumic pressure, (max dP/dt)/peak isovolumic pressure, and (max dP/dt)/kP, only the last two of these successfully distinguished changes between volume load and inotropic stimulation. Thus, assuming an unchanged series elasticity, the contractile state of the auxotonic ventricle may be determined utilizing a single high-fidelity catheter system and high speed recordings of isovolumic pressure.

The mechanical behavior of isolated cat, rat, and dog ventricular muscle was examined during hypoxia and after reoxygenation. During hypoxia, an early abbreviation of tension duration was followed by a decline in the rate of tension development. After reoxygenation, a marked, early prolongation of tension development and relaxation time was invariably observed with little, if any, increase in peak tension. As recovery progressed, the duration of contraction gradually shortened as tension returned to control levels. This phenomenon was also observed in the intact dog heart after release of a coronary artery ligature. Isometric tension gauges sewn to ischemic portions of the left ventricle demonstrated that after reinstitution of coronary flow, segment tension duration "outlasts" the duration of left ventricular pressure development and is associated with ventricular irritability. Epicardial electrograms showed shortening of the QT interval within the ischemic segment with prolongation of the QT interval after release of the coronary ligature. Prolongation of tension development during recovery from hypoxia was not observed in experiments with rat skeletal muscle. These observations identify localized mechanical abnormalities during recovery from myocardial ischemia which may be important in the syndrome of acute coronary heart disease.

The mechanical performance of hypoxic heart muscle is further depressed by an acid pH. In contrast to preparations at normal or alkaline pH. however, hypoxic preparations at acid pH do not develop contracture and exhibit full recovery of mechanical activity upon reoxygenation.