Peak Developed Pressure Research Articles

Nitric oxide–generating β-adrenergic blocker nipradilol preserves postischemic cardiac function

Background. Preconditioning protects the heart from ischemic injury, but some of its effects are reversed by β-adrenergic blockade. We hypothesize that because nitric oxide is known to precondition the heart, the nitric oxide–generating β-blocker nipradilol may simultaneously precondition and provide clinically relevant β-blockade. Methods. Isolated, crystalloid-perfused rabbit hearts underwent 1 hour of left anterior descending coronary artery ischemia followed by 1 hour of reperfusion. Before ischemia, six hearts received nipradilol, six received the nitric oxide donor l-arginine, four hearts received the nitric oxide synthase inhibitor N G-nitro- l-arginine methyl ester before l-arginine, nine underwent ischemic preconditioning, and six received β-blockade by esmolol before ischemic preconditioning. Seven hearts received no pretreatment (control). Action potential duration and ventricular pressure were measured. Infarct size was determined at the end of reperfusion. Results. Both l-arginine and ischemic preconditioning prolonged action potential duration significantly at 60 minutes of reperfusion. Compared with control, infarct size was reduced by ischemic preconditioning (26% ± 4% versus 49% ± 3%, IPC versus control; p < 0.01), l-arginine (24% ± 2%; p < 0.01 versus control), and nipradilol (24% ± 2%; p < 0.01 versus control). Only nipradilol preserved peak developed pressure during reperfusion. Conclusions. Despite its properties as a β-adrenergic blocking agent, nipradilol was able to precondition the heart, probably as a result of its ability to produce nitric oxide.

Increased myocardial calcium cycling and reduced myofilament calcium sensitivity in early endotoxemia

Background: Mechanisms of cardiac dysfunction during endotoxemia are multiple and their targets uncertain. This study tested the hypothesis that endotoxin (LPS) induces abnormal calcium-activated contractile force in the heart. Methods: Adult rabbits were given LPS intravenously; 2 hours later hearts were studied in the Langendorff mode. Measurements included peak developed pressure (PDP), myocardial oxygen consumption (MVO2), high-energy phosphates by 31P-NMR, and beat-to-beat intracellular calcium (Cai) by fluorescence spectroscopy. Myofibrillar calcium sensitivity was assessed from the relationship of PDP to Cai and the rate of diastolic Cai removal (τCa) was quantified. Results: Force-calcium relationships were markedly depressed in LPS hearts despite increased Cai. MVO2 was increased in parallel with increased Cai. Taken together, these data denote myofilament calcium insensitivity and mechanical inefficiency. τCa was markedly prolonged in LPS hearts, indicating impaired calcium reuptake and/or extrusion. High-energy phosphates and intracellular pH were unaffected by LPS; however, inorganic phosphate (Pi) was significantly increased. Dobutamine further increased Cai and MVO2 in LPS hearts without significantly improving calcium-activated force. Pyruvate, an inotrope that reduces Pi, significantly improved contractility in LPS hearts. Conclusions: Endotoxemia rapidly induced futile calcium cycling and reduced myofibrillar calcium sensitivity. This state was resistant to β-agonist inotropic stimulation; inotropes that normalize the calcium-force relationship may be more effective. (Surgery 1999;126:231-8.)

Increased myocardial calcium cycling and reduced myofilament calcium sensitivity in early endotoxemia

Background: Mechanisms of cardiac dysfunction during endotoxemia are multiple and their targets uncertain. This study tested the hypothesis that endotoxin (LPS) induces abnormal calcium-activated contractile force in the heart. Methods: Adult rabbits were given LPS intravenously; 2 hours later hearts were studied in the Langendorff mode. Measurements included peak developed pressure (PDP), myocardial oxygen consumption (MVO 2), high-energy phosphates by 31P-NMR, and beat-to-beat intracellular calcium (Ca i) by fluorescence spectroscopy. Myofibrillar calcium sensitivity was assessed from the relationship of PDP to Ca i and the rate of diastolic Ca i removal (τCa) was quantified. Results: Force-calcium relationships were markedly depressed in LPS hearts despite increased Ca i. MVO 2 was increased in parallel with increased Ca i. Taken together, these data denote myofilament calcium insensitivity and mechanical inefficiency. τCa was markedly prolonged in LPS hearts, indicating impaired calcium reuptake and/or extrusion. High-energy phosphates and intracellular pH were unaffected by LPS; however, inorganic phosphate (P i) was significantly increased. Dobutamine further increased Ca i and MVO 2 in LPS hearts without significantly improving calcium-activated force. Pyruvate, an inotrope that reduces P i, significantly improved contractility in LPS hearts. Conclusions: Endotoxemia rapidly induced futile calcium cycling and reduced myofibrillar calcium sensitivity. This state was resistant to β-agonist inotropic stimulation; inotropes that normalize the calcium-force relationship may be more effective. (Surgery 1999;126:231-8.)

Flanking proline residues identify the L-type Ca2+ channel binding site of calciseptine and FS2.

Calciseptine and FS2 are 60-amino acid polypeptides, isolated from venom of the black mamba (Dendroaspis polylepis polylepis), that block voltage-dependent L-type Ca2+ channels. We predicted that these polypeptides contain an identical functional site between residues 43 and 46 by searching for proline residues that mark the flanks of protein-protein interaction sites [Kini, R. M., and Evans, H. J. (1966) FEBS Lett. 385, 81-86]. The predicted Ca2+ channel binding site also occurs in closely related toxins, C10S2C2 and S4C8. Therefore, it is likely that these toxins also will block L-type Ca2+ channels. To test the proposed binding site on calciseptine and FS2, an eight-residue peptide, named L-calchin (L-type calcium channel inhibitor), was synthesized and examined for biological activity. As expected for an L-type Ca2+ channel blocker, L-calchin reduced peak systolic and developed pressure in isolated rat heart Langendorff preparations without affecting diastolic pressure or heart rate. Furthermore, L-calchin caused a voltage-independent block of L-type Ca2+ channel currents in whole-cell patch-clamped rabbit ventricular myocytes. Thus the synthetic peptide exhibits the L-type Ca2+ channel blocking properties of the parent molecules, calciseptine and FS2, but with a lower potency. These results strongly support the identification of a site in calciseptine and FS2 that is important for binding to L-type Ca2+ channels and reinforce the importance of proline brackets flanking protein-protein interaction sites.

The effect of sarcoplasmic reticulum blockade on the force/frequency relationship and systolic contraction patterns in the newborn pig heart.

We investigated the relationship between heart rate and contractility in seven anaesthetized young piglets by measuring contractility at different atrial pacing rates. To study the origin of this relationship we repeated the measurements after blocking the sarcoplasmic reticulum calcium release channel with ryanodine. We assessed contractility using indices derived from instantaneous left ventricular pressure and volume measured by micromanometric and conductance catheters during rapid inferior vena cava occlusion, thus generating the end-systolic pressure-volume relationship, which was characterized by its slope Ees, and the maximum rate of change of ventricular pressure (dP/dtmax)/end-diastolic volume relationship, also characterized by its slope. All animals showed an increase in contractility with increasing heart rate (intact force/frequency relationship) which was abolished after ryanodine. The most striking effect of ryanodine on baseline haemodynamics was the dramatic decrease of dP/dtmax to about 50% of its original value, while peak developed pressure and Ees did not change. We conclude that the young piglet, despite its immaturity, has a functional sarcoplasmic reticulum, illustrated by an intact force/frequency relationship. In addition, blockade of the sarcoplasmic reticulum in vivo has profoundly different effects during early and late systole, indicating that indices of contractility derived during different parts of the cardiac cycle represent different aspects of systole.

Dopaminergic responses in the Fischer 344 rat heart: preserved chronotropic and dromotropic responses with aging.

Marked decreases in cardiac responses to beta-adrenergic stimuli have been found in cellular, animal, and human models of physiologic aging. As another probe of receptor-regulated cardiovascular changes with aging, responses to dopamine were studied. Responses were studied with and without depletion of myocardial catecholamines to eliminate effects secondary to myocardial catecholamine release. Responses of heart rate (A-A intervals), atrioventricular conduction (AV intervals and AV Wenckebach block cycle length) to 0-50 microM dopamine were studied in Langendorff perfused hearts from 10 mature (6.2 +/- 0.8 mo, mean +/- SD) and 9 senescent (23.6 +/- 0.7 mo) Fischer 344 rats and in hearts from 10 mature (5.3 +/- 0.4 mo) and 8 senescent (23.9 +/- 0.8) Fischer 344 rats after myocardial catecholamine depletion by reserpine (0.25 mg/kg i.p. x 5 days). Dopamine decreased A-A (p < .0001) and AV conduction intervals (p < .0001) and increased peak developed pressure (p < .0001) and dP/dt (p < .001) in hearts from nonreserpine treated mature and senescent rats. Greater decreases in A-A intervals and AV conduction were seen in senescent compared to mature hearts (p < .0001). Contractile responses were greater in mature hearts (p < .001). After reserpine, A-A interval and paced AV conduction dose vs response relationships shifted rightward (p < .0001), but peak responses and age-related differences in responses were not significantly affected. In contrast, increases in peak developed pressure were greatly reduced in mature hearts (p < .0001) and age-related differences in contractile responses to dopamine were eliminated in hearts from reserpine-treated rats. (a) A-A interval and AV conduction responses to dopamine were greater in senescent hearts even after catecholamine depletion, suggesting age-related differences in sinus and AV nodal responses to direct dopaminergic stimuli exist. (b) Age-related differences in contractile responses to dopamine were eliminated by reserpine suggesting basal age-related differences in response were secondary to age-related differences in responses to myocardial catecholamine release.

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.

Survival after myocardial infarction in rats: captopril versus losartan

Objectives. This study sought to compare the effects of angiotension-converting enzyme inhibition versus angiotensin II receptor blockade on survival in rats with myocardial infarction.Background. The effects of speciifc nonpeptide angiotensin receptor blocking agents on survival after myocardial infarction are unknown.Methods. Rats with a moderate to large myocardial infarction were treated with captpril (2 g/liter drinking water, n= 87) or losartan (2 g/liter drinking water, n= 96). Therapy was initiated immediately after coronary artery ligation and continued for 1 years.Results. Uncensored median survival in captopril-treated rats that survived at least 48 h was 201.5 days versus 236.0 days for losartan-treated rats (p = 0.066). Median survival censored for rats with lung infections was 201.5 days in captopril-treated rats versus 243.0 days for losartan-treated rats (p = 0.028). Conscious hemodynamic measurements and remodeling data obtained at 1 year in the surviving rats (n = 5 for captopril; n = 9 for losartan) revealed no differences in heart weight, left ventricular pressure, dP/dt, cardiac index, time constant of relaxation or any variable of left ventricular remodeling. The only differences (mean ± SD) were an increase in heart rate (293 ± 19 vs. 260 ± 15 beats/min, p < 0.05) and a decrease in peak developed pressure (153 ± 21 vs. 180 ± 16 mm Hg, p < 0.05) in the losartan-treated rats.Conclusions. We conclude that in this experimental model of heatr failure, there was no difference between survival after angiotensin II receptor blockade with losartan and with angiotensin-converting enzyme inhibition with captopril.

965-46 Survival After Large Myocardial Infarction in Rats: Comparison of ACE Inhibition with Captopril Versus Direct Angiotensin II Blockade with Losartan

To compare the effects of angiotensin converting enzyme (ACE) inhibition vs angiotensin II (A-II) receptor blockade on survival, rats with large myocardial infarctions were treated with captopril (N = 46) or losartan (N = 51) a specific A-II antagonist, at a dose of 2 g/L drinking water. Therapy was initiated immediately after coronary artery ligation and continued for one year. Median survival in captopril treated rats was 191.4 ± 14.1 days vs 246.4 ± 15.7 days for losartan treated rats (P &lt; 0.03). Measurements of myocardial function and LV geometry were obtained at one year in surviving rats (N = 5 for captopril; 9 for losartan). No differences were noted in heart weight, LV pressures, dPldt, cardiac index, time constant of relaxation, or LV volume and dimensions. In losartan-treated rats, however, heart rate was increased 1293 ± 19 vs 266 ± 15 beatslmin, P &lt; 0.05) and peak developed pressure was decreased (153 ± 21 vs 180 ± 16 mmHg, P &lt; 0.05). Thus, in the rat model of heart failure, survival was prolonged with losartan compared to captopril, suggesting that the major benefit of ACE inhibition is attenuation of responses mediated through the A-II receptor.

Ischemic preconditioning improves preservation with crystalloid cardioplegia

Ischemic preconditioning has not been investigated in a clinically relevant model of hypothermic multidose cardioplegia arrest. Using isolated rabbit hearts perfused on a Langendorff apparatus, ischemic preconditioning was investigated as an adjunct to crystalloid cardioplegia during a 2.5-hour ischemic period at 15 °C. After baseline functional data were obtained, ischemic preconditioning was induced with either 1 minute or 5 minutes of normothermic ischemia, followed by 5 minutes of reperfusion before the arrest period. Control hearts underwent no ischemic preconditioning. The control hearts exhibited a decrement in both the peak developed pressure and diastolic function, as measured by the slope of the diastolic pressure-volume relationship, of from 107 ± 2 to 68 ± 7 mm Hg ( p < 0.005) and from 0.99 ± 0.2 to 2.95 ± 0.44 mm Hg/0.1 mL ( p < 0.005), respectively. Hearts exposed to either 1 or 5 minutes of normothermic ischemia showed no significant change in the slope of the diastolic pressure-volume relationship. Hearts exposed to 1 or 5 minutes of normothermic ischemia also had a significant decrease in the peak developed pressure of from 107 ± 6 to 92 ± 2 mm Hg and from 102 ± 3 to 85 ± 4 mm Hg, respectively ( p < 0.05). However, ischemic preconditioning brought about a significant improvement in the postischemic peak developed pressure, as opposed to that seen for the control hearts ( p < 0.05). Creatine kinase washout was significantly higher in the control hearts only. High-energy phosphate levels, lactate levels, the percentage wet weight, and tissue creatine phosphate levels were not significantly different among the groups. Our findings suggest ischemic preconditioning may be useful in cases with an anticipated prolonged cross-clamp period, if this effect is validated by future investigations.

Myocardial Oxygen Consumption After Reversible Ischemia

There is a marked dissociation between return of contractile function and oxidative metabolism in stunned myocardium. Initial observations in isovolumically contracting hearts demonstrated that postischemically, the MVO2 to generate a given peak-developed pressure was augmented compared to preischemia. This metabolic inefficiency was independent of coronary hyperemia and myocellular oxygen extraction and not evident in the vented, empty beating state. In an ejecting heart model, the highly linear relationship between external mechanical work (integrated area of dynamic pressure-volume loops) increased non-working oxygen needs not to the efficiency of ejecting a given stroke volume. More sophisticated mathematical modeling to further compartmentalize chemomechanical transduction in the globally stunned heart has confirmed deranged energetics, but ascribing specific work components to inefficient oxygen need is predicated on the biological validity of each model. The findings in regionally stunned myocardium are more uniform, demonstrating paradoxically normal oxygen consumption despite persistent systolic bulging or markedly decreased systolic shortening. The relatively increased MVO2 in stunned hearts is not due to uncoupling of oxidative phosphorylation, but inefficient cellular ATP utilization.

Myocardial glutathione depletion impairs recovery of isolated blood-perfused hearts after global ischaemia

This study was performed to determine whether depletion of myocardial glutathione would impair recovery of left ventricular function of blood-perfused, isolated hearts after reversible ischaemic injury. Cats were treated with either vehicle or buthionine sulfoximine (BSO), an inhibitor of gamma-glutamylcysteine synthetase, the rate-limiting enzyme in the synthesis of glutathione. The feline isolated hearts were perfused with the blood of normal donor cats before and after 40 min of global myocardial ischaemia. The myocardial concentration of glutathione of the BSO group, 178±38 ng/mg tissue, was significantly less than that of the control group, 292±38 ng/mg tissue ( P<0.05). The peak left ventricular developed pressure (LVDP) 1 h after reperfusion, expressed as a fraction of the peak LVDP before ischaemia, was 0.87±0.10 for the control group and 0.64±0.08 for the BSO group ( P=0.05 vs. control). The peak left ventricular dP dt after reperfusion, expressed as a fraction of the peak dP dt before ischaemia, was 1.08±0.14 for the control group and 0.78±0.09 for the BSO group ( P=0.05 vs. control). The myocardial creatine kinase activity of the BSO group, 1046±46 U/g tissue, was not significantly different from that of the control group, 1038±17 U/g tissue ( P=0.87). Thus, depletion of myocardial glutathione resulted in impaired post-ischaemic contractile function that cannot be attributed to a greater extent of irreversible cell injury.

Effects of probucol on impaired cardiac performance and lipid metabolism in streptozotocin-induced diabetic rats.

Plasma lipids and cardiac performance were studied in diabetic rats treated with probucol. Male Wistar rats were rendered diabetic with a single intraperitoneal injection of streptozotocin (STZ, 75 mg/kg). Nondiabetic control rats received the vehicle alone. Two weeks after STZ or vehicle injection, control and diabetic rats were randomly assigned to probucol-treated or untreated groups. The rats in the two probucol-treated groups (control- and diabetic-probucol groups) were fed a diet containing 1% probucol (w/w) for 4 weeks. Blood was drawn, and then cardiac performance was assessed by the isolated perfused working heart technique. Probucol treatment had no effect on the cardiac performance of the nondiabetic control rats. The peak left ventricular developed pressure and maximum rate of change in left ventricular pressure during systole were significantly greater in the probucol-treated diabetic rats than in the untreated diabetic rats (p less than 0.05), although cardiac performance did not improve to the level in the nondiabetic rats. Plasma cholesterol, free fatty acid, and phospholipid were significantly elevated in the untreated diabetic rats, and probucol treatment decreased significantly the plasma cholesterol and free fatty acid concentrations (p less than 0.05). These data suggest that probucol treatment improves plasma lipids and cardiac performance in rats with experimental diabetes and may prevent diabetic cardiomyopathy.

Age-related differences in cardiac susceptibility to ischemia/reperfusion injury

Age-related differences in susceptibility to ischemia/reperfusion injury and the response to the iron chelator deferoxamine during reperfusion were studied in isolated nonworking rabbit hearts subjected to 30 or 40 minutes of ischemia at 37 degrees C followed by 30 minutes of reperfusion. In the experimental group, hearts received a bolus of deferoxamine just before the moment of reflow, followed by a continuous infusion during the first 10 minutes of reperfusion. Isovolumic systolic (peak developed pressure) and diastolic (diastolic pressure versus balloon volume relationship) function was assessed with an intracavity balloon and incremental volume changes. In separate groups of hearts, adenine nucleotide content (adenosine triphosphate, diphosphate, and monophosphate) was measured before ischemia, at end-ischemia, and 30 minutes after reperfusion. The cardiac function measurements showed that after 30 minutes of ischemia and 30 minutes of reperfusion, peak developed pressure in newborn hearts recovered to 89% +/- 5% of preischemic levels; this recovery was significantly better than that of adult hearts, which exhibited 67% +/- 6% (p less than 0.01) recovery. Deferoxamine significantly improved cardiac function only in adult hearts (p less than 0.01). However, after 40 minutes of ischemia and 30 minutes of reperfusion, peak developed pressure in newborn hearts was reduced to 61% +/- 3% and was not significantly better than that of adult hearts (54% +/- 5%). Deferoxamine significantly improved systolic function in both newborn and adult hearts (p less than 0.01) exposed to 40 minutes of ischemia. Myocardial adenosine triphosphate content fell markedly by the end of 30 and 40 minutes of ischemia in both groups. After 30 minutes of ischemia, newborn but not adult hearts were able to completely recover adenosine triphosphate content by 30 minutes of reperfusion. This advantage was lost after 40 minutes of ischemia. Deferoxamine had no effect on recovery of adenosine triphosphate content in any group. We conclude that (1) newborn hearts recover postischemic function and metabolism faster than adult hearts after shorter periods of ischemia; (2) this advantage is lost as the ischemic period is prolonged; (3) deferoxamine improved postischemic cardiac function after longer ischemic periods, in both age groups, but failed to improve the recovery of myocardial adenosine triphosphate content.

Efficacy of a hydroxyl radical scavenger (VF 233) in preventing reperfusion injury in the isolated rabbit heart

We tested the hypothesis that 3,4,5,-trihydroxybenzamidoxime (VF 233), a demonstrated hydroxyl radical scavenger and an effective Fe 3+ chelator, attenuates reperfusion injury and improves isovolumic left ventricular function. Eighteen isolated, perfused rabbit hearts with intracavitary balloons were subjected to normothermic, global ischemia until the initiation of ischemic contracture. Effects on the adenine nucleotide pool metabolites were determined by high-pressure liquid chromatography from right ventricular biopsy specimens before ischemia and at 15-minute intervals throughout reperfusion. In the experimental group (n = 9), a 5-mL bolus of 1 mol/L VF 233 was given immediately before reperfusion and followed by a continuous infusion (0.125 μmol/ min). Tin control group (n = 9) received the vehicle solution at identical times. Rabbits treated with VF 233 had significant improvement in left ventricular function (expressed as percent return of left ventricular peak developed pressure) within 15 minutes of reperfusion (55.0 ± 3.0 versus 66.2 ± 4.1; p < 0.05 by analysis of variance) after global ischemia and remained significantly improved throughout the reperfusion period. Myocardial adenine nucleotide pool intermediates were not significantly different between groups. These results demonstrate that administration of VF 233 significantly improves ventricular function but does not affect adenine nucleotide metabolism after ischemia and reperfusion.

Triiodothyronine-enhanced left ventricular function after ischemic injury

Hypothyroidism is associated with profound left ventricular dysfunction. Brain-dead organ donors and patients undergoing cardiopulmonary bypass are chemically hypothyroid with significantly reduced circulating free triiodothyronine (T 3). To test the hypothesis that T 3 enhances left ventricular function in a hormonally deficient environment a total of 36 healthy New Zealand White rabbit hearts were studied using a modified Langendorff preparation with Krebs-Henseleit perfusate and intraventricular balloon. In 9 normal rabbit hearts a cumulative dose-response curve with logarithmically increasing doses of T 3 was obtained. The vehicle solution for T 3 dissolution served as control (n = 9). Left ventricular function was assessed from peak developed pressure at baseline and after T 3 administration. Triiodothyronine had no effect in normal hearts on peak developed pressure or end-diastolic pressure. In 18 rabbits, the acute effect of T 3 administration after ischemia was investigated. Preischemic left ventricular function was measured to serve as baseline, and hearts were subjected to 37 °C global ischemia. Triiodothyronine (n = 9) or vehicle (n = 9) was infused during reperfusion, and left ventricular peak developed pressure was measured at 30 and 60 minutes of reperfusion. Recovery of function (expressed as percent return of left ventricular peak developed pressure) was significantly improved within 15 minutes of reperfusion (65.0% ± 2.1% versus 80.2% ± 4.1%) and remained significantly improved throughout the reperfusion period ( p < 0.05 by analysis of variance). These data suggest that although T 3 possesses no inotropic properties, it significantly improves postischemic left ventricular function. The rapidity of the functional improvement suggests that these effects may be due to plasma membrane-mediated mechanisms.

Skeletal Muscle Powered Ventricle: Comparison of Double-Layered Small Ventricle and Single-Layered Large Ventricle

Canine left latissimus dorsi (LD) muscles were used to construct two kinds of skeletal muscle powered ventricles (SMPV): a double layered small size (10-17 mL) SMPV (A), and a single-layered large size (40-70 mL) SMPV (B). The same muscle was used sequentially for the construction of both SMPV. A mock circulation system was used for testing. This allowed for change of the preload (10-60 mmHg) and afterload (40-160 mmHg) independently. The peak developed pressure (PDP) and stroke volume (SV) were measured, and the stroke work (SW) was analyzed on line by a computer. The isovolumic PDP was 93.3 +/- 11.8 mmHg at 10 mmHg preload, and 157.7 +/- 20.2 mmHg at 60 mmHg for A, and 37.8 +/- 5.5 mHg and 107.8 +/- 8.5 mmHg for B. The SV and SW at 50 mmHg preload and 80 mmHg afterload were 18.30 +/- 1.25 mL and 1.06 +/- 0.10 x 10(6) erg for A, and 34.18 +/- 2.36 mL and 2.51 +/- 0.28 x 10(6) erg for B. The SV and SW at 20 mmHg preload and 160 mmHg afterload were 2.65 +/- 0.31 mL and 0.27 +/- 0.05 x 10(6) erg for A, and 1.03 +/- 0.23 mL and 0.04 +/- 0.01 x 10(6) erg for (B). The SW generated by the large single-layered SMPV is similar to that reported for the canine left ventricle but requires a high preload. The large single-layered SMPV showed a higher dependence on pre- and afterload changes than the double layered small SMPV, which generates a higher pressure even at low preloads.

Diastolic dysfunction of perfused rat hearts induced by hydrogen peroxide. Protective effect of selenium

Oxidant substances such as hydrogen peroxide are postulated to cause cardiac dysfunction and injury in a number of pathological conditions. Selenium is an essential nutrient which serves as an oxidant defense through the selenoenzyme glutathione peroxidase. This enzyme metabolizes hydrogen peroxide; its activity in rat heart is reduced to 5% of control by selenium deficiency. Left ventricular function of selenium-deficient and control rat hearts was studied in a Langendorff preparation under isovolumic conditions. A stabilization period of 20 min was followed by a 70 min infusion of hydrogen peroxide at 375 or 1500 nmol/min. When no hydrogen peroxide was infused, perfusion for 90 min had no effect on systolic or diastolic function and no effect of selenium deficiency was detected. Hydrogen peroxide infusion into selenium-deficient hearts at 375 nmol/min led to impaired isovolumic relaxation and a substantial increase in end-diastolic pressure after 45 min which worsened progressively until the experiment was terminated. By contrast no effect was observed on systolic contractile function as assessed by peak pressure or developed pressure. Infusion of this dose of hydrogen peroxide into control hearts had no significant effect on diastolic or systolic function. However, infusion of 1500 nmol hydrogen peroxide/min into control hearts caused diastolic dysfunction after 30 min without affecting systolic function. These results indicate that hydrogen peroxide injury to the perfused rat heart is manifested by diastolic dysfunction before systolic dysfunction occurs. Selenium deficiency lowers the dose of hydrogen peroxide needed to cause diastolic dysfunction. This suggests that the selenoenzyme glutathione peroxidase protects the heart against hydrogen peroxide injury.

Cardiac Performance and Plasma Lipids of Omega-3 Fatty Acid–Treated Streptozocin-Induced Diabetic Rats

We studied the effect of omega-3 fatty acid (omega 3FA) treatment on plasma lipids and cardiomyopathy in the diabetic rat. The omega 3FA preparation used was Promega. Male Wistar rats (250-275 g) were rendered diabetic by streptozocin (STZ; 55 mg.kg-1). Nondiabetic control rats received the vehicle alone. Two weeks after STZ or vehicle injection, control and diabetic rats were randomly assigned to either a treated or untreated group. Promega was administered at a dose of 0.5 ml.kg-1.day-1 by oral gavage for 4 wk, after which the rats were decapitated, plasma collected, and isolated working heart performance studied. Promega treatment did not affect plasma glucose, triglyceride, or cholesterol concentrations of either the control or diabetic rats. Cardiac performance was assessed by measuring the left ventricular response to changing left atrial filling pressures (7.5-20 cm H2O). The treatment had no effect on peak left ventricular developed pressure (LVDP) or maximal rate of change of left ventricular pressure during systole (+dP/dtmax) or diastole (-dP/dtmax) in the nondiabetic control rats. LVDP and +/- dP/dt were significantly improved (P less than .05) in the treated diabetic rats compared with untreated diabetic rats, although cardiac performance did not improve to the nondiabetic level. Cardiac sarcoplasmic reticulum (SR) calcium transport activity was not affected by the treatment in the control rats but was significantly improved (P less than .05) in the treated diabetic rats. These data suggest that omega 3FA treatment partially blocks the development of experimental diabetic cardiomyopathy, possibly by affecting SR calcium transport activity.

Left ventricular function and collagen content after regression of hypertensive hypertrophy.

To determine whether regression of hypertensive hypertrophy through blood pressure control also involves left ventricular collagen and consecutive alterations in left ventricular diastolic and systolic function, antihypertensive treatment with the calcium channel blocker nifedipine (30 mg/kg.day) was employed in 20-week-old spontaneously hypertensive rats (n = 15) for a period of 20 weeks. Age-matched (40 weeks old) untreated (n = 13) and 20-week-old spontaneously hypertensive rats representing the state before therapy (n = 14) were used for comparison. Myocardial stiffness was described by the tangent modulus Km of the elastic stiffness-stress relation. Left ventricular collagen was determined by means of hydroxyproline (OH-proline) concentration. Myocardial working capacity of the left ventricle was measured as the peak developed systolic pressure per weight unit muscle mass and systolic peak pump function as the maximum achievable cardiac output under volume loading. After the 20-week course of nifedipine treatment, systolic aortic pressure dropped from 187 +/- 11 to 144 +/- 6 mm Hg (p less than 0.001). Regression of hypertrophy was shown by a left ventricular muscle/body weight ratio of 2.13 +/- 0.18 mg/g (p less than 0.01) in the 40-week-old nifedipine-treated hypertensive rats, whereas the ratios of the 20-week-old and 40-week-old untreated spontaneously hypertensive rats were 2.3 +/- 0.30 and 2.34 +/- 0.18 mg/g, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)