Rosiglitazone treatment improves cardiac efficiency in hearts from diabetic mice.

Isolated perfused hearts from type 2 diabetic (db/db) mice show impaired ventricular function, as well as altered cardiac metabolism. Assessment of the relationship between myocardial oxygen consumption (MVO(2)) and ventricular pressure-volume area (PVA) has also demonstrated reduced cardiac efficiency in db/db hearts. We hypothesized that lowering the plasma fatty acid supply and subsequent normalization of altered cardiac metabolism by chronic treatment with a peroxisome proliferator-activated receptor-gamma (PPARgamma) agonist will improve cardiac efficiency in db/db hearts. Rosiglitazone (23 mg/kg body weight/day) was administered as a food admixture to db/db mice for five weeks. Ventricular function and PVA were assessed using a miniaturized (1.4 Fr) pressure-volume catheter; MVO(2) was measured using a fibre-optic oxygen sensor. Chronic rosiglitazone treatment of db/db mice normalized plasma glucose and lipid concentrations, restored rates of cardiac glucose and fatty acid oxidation, and improved cardiac efficiency. The improved cardiac efficiency was due to a significant decrease in unloaded MVO(2), while contractile efficiency was unchanged. Rosiglitazone treatment also improved functional recovery after low-flow ischemia. In conclusion, the present study demonstrates that in vivo PPARgamma-treatment restores cardiac efficiency and improves ventricular function in perfused hearts from type 2 diabetic mice.

Cardiovascular effects of epinephrine during rewarming from hypothermia in an intact animal model.

Rewarming from accidental hypothermia is often complicated by "rewarming shock," characterized by low cardiac output (CO) and a sudden fall in peripheral arterial pressure. In this study, we tested whether epinephrine (Epi) is able to prevent rewarming shock when given intravenously during rewarming from experimental hypothermia in doses tested to elevate CO and induce vasodilation, or lack of vasodilation, during normothermia. A rat model designed for circulatory studies during experimental hypothermia and rewarming was used. A total of six groups of animals were used: normothermic groups 1, 2, and 3 for dose-finding studies, and hypothermic groups 4, 5, and 6. At 20 and 24 degrees C during rewarming, group 4 (low-dose Epi) and group 5 (high-dose Epi) received bolus injections of 0.1 and 1.0 microg Epi, respectively. At 28 degrees C, Epi infusion was started in groups 4 and 5 with 0.125 and 1.25 microg/min, respectively. Group 6 served as saline control. After rewarming, both CO and stroke volume were restored in group 4, in contrast to groups 5 and 6, in which both CO and stroke volume remained significantly reduced (30%). Total peripheral resistance was significantly higher in group 5 during rewarming from 24 to 34 degrees C, compared with groups 4 and 6. This study shows that, in contrast to normothermic conditions, Epi infused during hypothermia induces vasoconstriction rather than vasodilation combined with lack of CO elevation. The apparent dissociation between myocardial and vascular responses to Epi at low temperatures may be related to hypothermia-induced myocardial failure and changes in temperature-dependent adrenoreceptor affinity.

Characterization of fresh yard trimmings for agricultural use.

Direct application of yard trimmings to agricultural land can benefit soils and crop production, while providing an outlet for handling high volumes of materials at compost facilities. Variability in the composition of yard trimmings can make it difficult to determine appropriate application rates. Our objective was to characterize the chemical composition and variability of yard trimmings generated throughout the spring and summer season at facilities in the Puget Sound region of Washington State. Yard trimmings were sampled from four composting facilities on five dates between April and August 1999. One material contained mostly grass clippings and had higher mean total N (3.2%) than mixed grass and woody materials (1.5-2%). Mean C:N was lower in the grass-rich material (12:1 vs. 15 to 21:1), while mean ammonium concentrations were similar (0.18-0.28%). Variation among facilities was greater than variation over time. The amount of variation observed with other nutrients, pH, EC, or trace elements would not affect use of the yard trimmings in agriculture. Our results suggest that it is possible to characterize yard trimmings adequately for agricultural use.

A non-immune interaction between the light chain of human immunoglobulin and a surface component of a Peptococcus magnus strain.

The immunoglobulin-binding capacity of a Peptococcus magnus strain was studied in a sensitive binding assay using purified human immunoglobulin preparations. The P. magnus strain 312 was capable of binding 48% of polyclonal IgG. Twenty-four of 40 purified myeloma proteins (60%) representing immunoglobulin classes A, G and M showed definite reactivity with an uptake level ranging from 45 to 90%. The remaining 16 monoclonal proteins were non-reactive, binding less than 15%. One myeloma protein with antistaphylolysin and two with antistreptolysin O specificity, i.e. monoclonal proteins with defined antigen specificity, were highly reactive. Binding capacity was observed in all four IgG subclasses and in Ig classes A and M. Twenty-three of 27 myeloma proteins of kappa type were reactive but only one of 13 myeloma proteins of lambda type interacted with the P. magnus strain. Isotope-labelled Fab gamma, F(ab')2 gamma and F(ab')2 alpha fragments were effectively bound by the strain. IgG Fc fragments were completely non-reactive. Isolated light immunoglobulin chains inhibited in a dose-dependent way the uptake of intact IgG to bacteria. Purified heavy chains were non-inhibitory. Isotope-labelled antistaphylolysin IgG F(ab')2 fragments preincubated with staphylolysin were as reactive as free antibody fragments, suggesting that the bacterial binding structure is located outside the antibody-combining site. The immunoglobulin reactivity of P. magnus was not affected by heating the bacteria to 80 degrees C for 5 min nor by treatment with trypsin or sodium metaperiodate. Digestion of 2 X 10(9) organisms with 100 micrograms of pepsin and papain reduced the binding by 58 and 90%, respectively. These data indicate that the binding of immunoglobulin to P. magnus is a non-immune reactivity mediated by a heat-stable surface protein interacting with specific sites on the light chain of the immunoglobulin molecule.

Streptococcal protein G has affinity for both Fab- and Fc-fragments of human IgG.

We have analyzed the binding of IgG and fragments of IgG [Fc, F(ab')2, and Fab] to group C and G streptococci and to protein G, the IgG binding cell wall protein of these bacteria. A direct correlation (r = 0.87, P less than 0.0001) was observed when the binding of radiolabelled, polyclonal IgG F(ab')2- and Fc-fragments to 23 group C and G streptococcal strains was compared. One strain (G-148) was treated with increasing amounts of pepsin, trypsin or papain and the Fab-binding structure was found to be much more sensitive to the enzymes as compared to the Fc-binding. A 35 K fragment of protein G was coupled to Sepharose, and both radiolabelled IgG F(ab')2- and Fc-fragments bound to the Sepharose beads. Binding of IgG fragments was inhibited by intact IgG or by the homologous IgG fragment, whereas Fc-fragments did not inhibit Fab binding or vice versa. Two radiolabelled protein G-fragments (28 and 35 K) showed different binding to polyclonal IgG, IgG F(ab')2-, IgG Fab- and IgG Fc-fragments. Thus, in a dot binding assay the 35 K fragment bound all IgG fragments tested, whereas the 28 K protein G fragment bound only intact IgG and IgG Fc-fragments. These results indicate two independent and separate binding sites for Fab- and Fc-fragments on protein G. Different binding sites on protein G were also indicated by Western blot analysis of four different protein G-fragments (28, 35, 42 and 65 K). In these experiments the 28 K fragment showed affinity only for Fc-fragments, while the higher mol. wt protein G preparations bound both IgG Fab- and Fc-fragments.

Fractionation of rat IgG subclasses and screening for IgG Fc-binding to bacteria.

The four IgG subclasses of the rat, IgGl, IgG2a, IgG2b and IgG2c, were purified from normal serum by a combination of protein A-affinity chromatography and DEAE-cellulose chromatography. Purified, radiolabelled preparations of IgG were tested for binding to Gram-positive bacteria representing five different Fc-receptor (FcR) types. Distinct rat subclass-specific Fc-binding was noted to bacterial species belonging to different Fc-receptor types. Staphylococcus aureus (FcR I) strains bind IgGl and IgG2c as shown by others. Group C and G Streptococci (FcR III) bind all four subclasses of rat IgG. Streptococcus zooepidemicus strains (FcR V) also bind all four subclases but only to a lower degree. Human group A Streptococci (FcR II) and bovine group G Streptococci (FcR IV) do not bind any of the rat IgG subclasses. Elution studies on two strains. Staphylococcus aureus, Cowan I, and human group G Streptococcus, G 148, showed that both thiocyanate and pH-elution might be useful for the fractionation of IgG subclasses bound to bacterial cells. The present work indicates the possible use of bacterial cells as solid-phase absorbents in immunological studies of rat IgG.

Hypertrophic cardiomyopathy characterised by beta-adrenoceptor density, relative amount of beta-adrenoceptor subtypes and adenylate cyclase activity.

The total quantity of beta-adrenoceptors and the relative amount of beta 1 and beta 2 receptor subtypes were determined in heart biopsies of 10 patients with various heart diseases and 5 patients suffering from hypertrophic cardiomyopathy (HOCM). In membrane particle preparations from the same patients we also examined the activity of the adenylate cyclase (AC), and its response to isoprenaline, terbutaline, histamine and sodium fluoride (NaF). The high affinity ligand [125I] (1)-cyanopindolol (CYP) was used in the binding assays, and the highly beta 2-selective antagonist ICI 118 551 for the determination of beta-adrenoceptor subtypes. No differences were found in total beta-adrenoceptor density between patients with HOCM and "controls" (27.6 +/- 14.2 vs 26.5 +/- 10.7 fmol . mg-1 protein). The relative amounts of beta 1 and beta 2 receptor subtypes were similar, patients with HOCM had 82.1 +/- 4.9% of beta 1 and 14.4 +/- 3.9% of the beta 2 receptor subtype, compared with 76.3 +/- 11.5% of beta 1 and 20.7 +/- 11.0% of the beta 2 subtype in the "control" patients. Both absolute activity of AC (pmol . mg-1 protein . min) as well as the relative responses to the various stimulators were not significantly different between the two groups. Thus, this study does not support the hypothesis that HOCM is a disorder with altered beta-adrenoceptor number or adenylate cyclase response to adrenergic agonists. Furthermore, HOCM is not associated with altered response of the AC system to histamine or NaF.

Effects of highly purified eicosapentaenoic acid and docosahexaenoic acid on hemodynamics in humans.

The hemodynamic effects of highly purified eicosapentaenoic acid (EPA, 20:5n-3) and docosahexaenoic acid (DHA, 22:6n-3) have not been evaluated in humans. We therefore conducted a randomized, double-blind, parallel-design intervention study to assess possible separate effects of EPA and DHA on blood pressure, heart rate, and cardiac mechanics. Healthy, nonsmoking men aged 36-56 y (n = 224) were randomly assigned to dietary supplementation with 4 g/d of ethyl ester concentrates of DHA or EPA or 4 g corn oil/d (control). Mean blood pressure at baseline was 122/77 mm Hg and was positively associated with concentrations of serum phospholipid saturated fatty acids. Blood pressure did not change during the intervention. Mean heart rate at baseline was 63.4 beats/min; it decreased 2.2 beats/min in the DHA group (P = 0.006 compared with control), increased 1.9 beats/min in the EPA group (P = 0.04 compared with control), and remained practically unchanged in the control group. In a pooled analysis, changes in heart rate were independent of baseline heart rate and were associated with changes in concentrations of serum phospholipid DHA and docosapentaenoic acid (22:5n-3). Echocardiography in a subsample of 52 men showed improved left ventricular diastolic filling in the marine oil groups compared with the corn oil group (P = 0.02). In contrast, an increase in plasma concentrations of saturated fatty acids was associated with delayed diastolic filling. We conclude that dietary DHA and EPA influence heart rate and that the fatty acid composition of plasma phospholipids may affect cardiac mechanics in humans.

Different protein A immunosorbents may have different binding specificity for rat immunoglobulins.

Purified polyclonal immunoglobulin preparations representing the 4 rat IgG subclasses were tested for binding to Staphylococcus aureus protein A attached to 3 different solid phases (Staphylococcus aureus Cowan I bacteria, Sepharose CL4B and Sepharose 6MB). Protein A Sepharose CL4B showed higher reactivity with IgG1 and IgG2b than the staphylococci, whereas protein A Sepharose 6MB showed a lower uptake of these subclasses. No differences were seen for IgG2a and IgG2c. Protein A on different solid phases cannot be used interchangeably without confirmation of binding specificity.

Serial complement studies in a patient with Goodpasture's syndrome treated with bilateral nephrectomy and renal transplantation.

A young male patient with Goodpasture's syndrome was treated with bilateral nephrectomy and when antiglomerular basement membrane antibodies could no longer be detected he received a cadaveric renal homograft. Fifteen months later he is in good health and without signs of pulmonary disease. Renal function is satisfactory, and there are no findings indicating recurrence of the nephritis. Serial complement studies during the entire course revealed varying degrees of activity in the sequence in the different phases: a high degree of in vivo activation of complement was found in the period before the nephrectomy, there was a moderate degree of activation in the period between the nephrectomy and transplantation and, finally, there were no signs of activity in the system after transplantation. This investigation strongly suggests that the complement system is of definite pathogenetic significance in this human equivalent to experimental nephrotoxic nephritis.

The effect of a thromboxane synthetase inhibitor, dazoxiben, and acetylsalicylic acid on platelet function and prostaglandin metabolism.

Twenty-four men received either placebo, 0.1 g of the thromboxane synthetase inhibitor dazoxiben, 0.25 or 1.0 g of acetylsalicylic acid (ASA). Dazoxiben reduced the maximal rate of collagen-induced platelet aggregation, but less than did ASA. ASA abolished secondary, ADP-induced aggregation, dazoxiben not. Both drugs prolonged the bleeding-time. Plasma thromboxane B2 (TxB2) levels did not change significantly after dazoxiben, whereas the prostacyclin metabolite 6-keto-PGF1 alpha rose. The larger dose of ASA reduced both TxB2 and 6-keto-PGF1 alpha in plasma. Whole blood was allowed to clot in order to estimate prostaglandin metabolism. Both drugs prevented thromboxane production effectively. Formation of 6-keto-PGF1 alpha decreased by 95 per cent after ASA but was more than doubled after dazoxiben. Dazoxiben is a selective and effective thromboxane synthetase inhibitor, but has a weaker effect on platelet reactivity than ASA, possibly because endoperoxide formation is not prevented.

Clinical pharmacokinetics of methyldopa.

Absorption of methyldopa from the gastrointestinal tract is incomplete and variable; bioavailability after oral administration is about 25% (range 8 to 62%). The average time to reach maximum plasma concentration (tmax) [chemically determined] is 2 hours, when the maximum plasma concentration of active drug accounts for 50% of the radioactivity, the remainder representing various metabolites. Physicochemical determination of methyldopa shows that bi-phasic elimination occurs after both intravenous and oral administration, the half-life of the alpha-phase being 0.21 hours (range 0.16 to 0.26 hours) and of the beta-phase 1.28 hours (range 1.02 to 1.69 hours) in normal subjects. Methyldopa is less than 15% protein bound, whereas the primary metabolite, which most probably is the O-sulphate, is about 50% protein bound. The apparent volume of distribution in the central compartment is about 0.23L/kg (range 0.19 to 0.32L/kg), and the total volume of distribution (calculated as Vdarea) is about 0.60L/kg (range 0.41 to 0.72L/kg) in healthy volunteers. Acid-labile conjugates are formed after oral administration. These acid-labile conjugates, in particular the O-sulphate, are probably formed in the intestinal cells, since they are detected in very small amounts after intravenous administration. Additionally, there is a rapid formation of partly unidentified metabolites after both intravenous and oral administration. After intravenous administration the quantitatively most prominent metabolites are methyldopamine and the glucuronide of dihydroxyphenylacetone, but traces of 5 or 6 other metabolites have also been found and identified. These metabolites are probably formed in the liver, but the complete metabolic pattern is still unknown. The renal clearance of methyldopa (95 ml/min/m2) is more than 50% higher than the endogenous creatinine clearance. Renal excretion of some metabolites is slower. Extrarenal elimination accounts for about 50% of the total body clearance of the drug. Renal excretion is very low in patients with renal failure, resulting in accumulation of both active drug and, in particular, its metabolites. There is a marked accumulation of unidentified metabolites in renal failure patients, which possibly explains the strong and prolonged hypotensive action of methyldopa in these patients.

Effects of a selective thromboxane synthetase inhibitor, dazoxiben, and of acetylsalicylic acid on myocardial ischemia in patients with coronary artery disease.

Thromboxane A2 (TxA2) may aggravate myocardial ischemia by inducing vasoconstriction and platelet aggregation in small coronary vessels, whereas prostacyclin (PGI2) counteracts these effects. Acetylsalicylic acid (ASA) inhibits the formation of TxA2 as well as PGI2, whereas dazoxiben, a thromboxane synthetase inhibitor, reduces TxA2 formation selectively. In 25 patients with coronary artery disease, 2 identical atrial pacing stress tests were performed: before and after the administration of dazoxiben (200 mg) in 15 patients and before and after ASA (250 mg) in 10. The ischemic response, quantified by coronary sinus and aortic lactate levels and by ST depression, was significantly reduced after administration of dazoxiben (p less than 0.02) but not after ASA. Heart rate at rest, myocardial extraction of free fatty acids and the arteriovenous oxygen difference was unaffected by medication. Both drugs reduced TxB2 levels to the same extent, whereas collagen-induced aggregation was more reduced after ASA than after dazoxiben. The effect of dazoxiben on ischemia was probably a result of inhibited TxA2 and preserved PGI2 production, which increased blood flow to ischemic regions.

Reproducibility of cardiac stroke volume estimated by Doppler echocardiography.

Doppler echocardiography was used to measure cardiac stroke volume in 10 patients with coronary artery disease who were treated with cardioactive drugs. Stroke volume estimates were determined at the aortic orifice by multiplying area by systolic velocity integral measured both from the suprasternal and the apical approach. Recordings were done independently by 2 experienced observers on the same day and repeated once after 1 to 21 days. Analysis of variance showed that no systematic differences were introduced by the 2 observers and Doppler approaches or by measuring on different days. The coefficient of variation between any pair of measurements in each patient was 9%. This variability is probably a result of the method or spontaneous fluctuations of the stroke volume and not of the varying recording conditions. The ultrasonic method detects day-to-day changes of cardiac stroke volume larger than 20% with a probability greater than 0.95.

Non-immune Fab- and Fc- mediated interactions of avian Ig with S. aureus and group C and G streptococci.

Serum samples from 19 avian species representing 8 orders were tested for their capacity to inhibit the Fab- and Fc-mediated immunoglobulin binding to protein A-carrying S. aureus and protein G-carrying group C and G streptococci. Four species (mallard, dunlin, starling and blackbird) belonging to three different orders showed a high degree of Fc-mediated protein A- and protein G-reactivity. Five species demonstrated a high level and nine species exhibited a low level of Fab-mediated protein A-reactivity. The four species identified as Fc-reactive were capable of Fab-mediated immunoglobulin binding with streptococcal surface proteins but incapable of Fab-mediated protein A binding. SDS-PAGE analysis confirmed that the protein A-Sepharose affinity purified material contained proteins corresponding to immunoglobulin chains. Inhibition results by avian sera were confirmed by direct binding of protein A-reactive proteins to bacteria, by precipitation in gel and by Western blot analysis of binding to protein A and protein G, respectively.

Haemodynamic effects of selective positive end-expiratory pressure after unilateral pulmonary hydrochloric acid-aspiration in dogs.

We investigated 1) the effects of HCl-mediated acute left lung injury on regional juxtacardiac pressures and 2) the haemodynamic effects of different modes of ventilation before and after induction of left lung injury. The study was done in 7 mechanically ventilated, anaesthetized dogs. Juxtacardiac pressures and haemodynamic variables were recorded during 1) differential ventilation (DV) with zero positive end-expiratory pressure (PEEP = 0) and 2) DV with general (G) PEEP and selective right (R) and left (L) lung PEEP. Left lung injury increased left, but not right pleural pressure of pericardial pressure. Pulmonary vascular resistance (PVR) and pulmonary artery pressure (PAP) were increased moderately. Cardiac output (CO) did not change. GPEEP reduced LV filling and cardiac output markedly and by approximately the same degree before and after lung injury. The haemodynamic effects of LPEEP were minor before as well as after the induction of lung injury. RPEEP, which had only moderate haemodynamic effects during control, caused a marked reduction in cardiac function after the induction of left lung injury. The transmission of airway pressure to the pleura was reduced in the diseased lung. These results suggest that serious haemodynamic side effects may be avoided by applying PEEP selectively to the diseased lung.

Effects of NO inhalation on pulmonary leukocyte sequestration and blood volume in porcine endotoxaemia.

OBJECTIVE: Sequestration and migration of activated neutrophils plays a major role in the pulmonary injury typical of septic shock and the adult respiratory distress syndrome. Inhaled NO may counteract alveolar-capillary damage attributed to activated neutrophils. The present study describes a method to directly demonstrate the effects of NO inhalation on endotoxin-induced sequestration of 99mTc-labelled leukocytes [As(t)] in the lungs of pigs. DESIGN: Prospective controlled study. SETTING: Laboratory for experimental surgery at a university medical centre. SUBJECTS: Anaesthetised and ventilated pigs. INTERVENTIONS: To induce inflammatory shock 26 animals received a continuous endotoxin infusion. Thirteen animals inhaled NO from the start of the experiments, while 13 served as controls. In 13 animals from both groups, leukocytes were labelled in vitro and reinjected, while in the 13 others erythrocytes were labelled in vivo to provide corrections for changes in blood volume. MEASUREMENTS AND RESULTS: The pulmonary distribution of 99mTc-labelled leukocytes or erythrocytes was studied dynamically for 180 min. After correction for changes in pulmonary and heart blood volume (PBV, HBV), leukocyte sequestration curves were generated. Endotoxin induced pulmonary vasoconstriction, reduced PBV, impaired oxygenation, and caused a maximum increase in As(t) of 30% in the lungs. NO inhalation attenuated pulmonary vasoconstriction and the reduction in PBV. The maximum increase in As(t) was reduced to 15% of baseline. CONCLUSIONS: Inhaled NO exerts its main vascular effects in the pulmonary microvasculature, the primary site of physiological neutrophil margination and pathological adhesion of activated leukocytes. Early use of NO inhalation may offer protection against the development of more lasting pulmonary failure in septic shock by reducing leukocyte sequestration in the lungs.

Effect of the pericardium on atrial systolic function.

The effect of pericardial constraint on atrial systolic function was investigated in nine acutely instrumented anesthetized dogs. Left and right atrial pressures were recorded by high-fidelity catheters; auricular diameters and free wall segment lengths were measured by sonomicrometry. Atrial function curves were constructed by relating atrial systolic dimensional shortening to atrial end-diastolic pressure during progressive volume loading. With the pericardium closed, the function curves were shifted markedly downward and rightward, such that atrial systolic shortening was reduced at any given pressure. There was a concomitant leftward and upward shift of the atrial end-diastolic pressure-dimension relationship. The relationship between atrial systolic shortening and atrial end-diastolic dimension was not shifted. These results suggest that the apparent depression of atrial systolic function with the pericardium closed is due to a restrictive effect of the pericardium on atrial filling. In conclusion, in the acutely dilated heart, the pericardium restricts atrial filling and thus causes a reduction in atrial systolic contribution to ventricular filling.

Selective positive end-expiratory pressure and intracardiac dimensions in dogs.

Effects of differential ventilation with general vs. selective right (R) and left (L) positive end-expiratory pressure (PEEP) on left (LV) and right ventricular (RV) end-diastolic dimensions were compared in seven pentobarbital-anesthetized dogs. All three modes of PEEP reduced LV cross-sectional area: general PEEP more than RPEEP and RPEEP more than LPEEP. General PEEP and, to a lesser degree, RPEEP decreased both the LV anteroposterior diameter and LV septum-free wall diameter, whereas LPEEP reduced the LV septum-free wall diameter only. Cardiac output was unaffected by LPEEP, whereas general PEEP (20 cmH2O) reduced cardiac output by 48%, and RPEEP (20 cmH2O) reduced it by 23%. RV septum-free wall diameter was not changed by any mode of PEEP. In conclusion, cardiac output was better maintained with selective PEEP than with general PEEP because LV filling was less impeded with selective PEEP. During LPEEP LV assumed a different configuration than during RPEEP and general PEEP, probably reflecting a different pattern of heart-lung interaction.

Left ventricular dysfunction following rewarming from experimental hypothermia.

This study was aimed at elucidating whether ventricular hypothermia-induced dysfunction persisting after rewarming the unsupported in situ dog heart could be characterized as a systolic, diastolic, or combined disturbance. Core temperature of 8 mongrel dogs was gradually lowered to 25 degreesC and returned to 37 degreesC over a period of 328 min. Systolic function was described by maximum rate of increase in left ventricular (LV) pressure (dP/dtmax), relative segment shortening (SS%), stroke volume (SV), and the load-independent contractility index, preload recruitable stroke work (PRSW). Diastolic function was described by the isovolumic relaxation constant (tau) and the LV wall stiffness constant (Kp). Compared with prehypothermic control, a significant decrease in LV functional variables was measured at 25 degreesC: dP/dtmax 2,180 +/- 158 vs. 760 +/- 78 mmHg/s, SS% 20.1 +/- 1.2 vs. 13.3 +/- 1.0%, SV 11.7 +/- 0.7 vs. 8.5 +/- 0.7 ml, PRSW 90.5 +/- 7.7 vs. 29.1 +/- 5.9 J/m. 10(-2), Kp 0.78 +/- 0.10 vs. 0.28 +/- 0.03 mm-1, and tau 78.5 +/- 3.7 vs. 25.8 +/- 1.6 ms. After rewarming, the significant depression of LV systolic variables observed at 25 degreesC persisted: dP/dtmax 1,241 +/- 108 mmHg/s, SS% 10.2 +/- 0.8 J, SV 7.3 +/- 0.4 ml, and PRSW 52.1 +/- 3.6 m. 10(-2), whereas the diastolic values of Kp and tau returned to control. Thus hypothermia induced a significant depression of both systolic and diastolic LV variables. After rewarming, diastolic LV function was restored, in contrast to the persistently depressed LV systolic function. These observations indicate that cooling induces more long-lasting effects on the excitation-contraction coupling and the actin-myosin interaction than on sarcoplasmic reticulum Ca2+ trapping dysfunction or interstitial fluid content, making posthypothermic LV dysfunction a systolic perturbation.