Depressed Cardiac Contractility Research Articles

Identification of biochemical adaptations in hyper- or hypocontractile hearts from phospholamban mutant mice by expression proteomics.

Phospholamban (PLN) is a critical regulator of cardiac contractility through its binding to and regulation of the activity of the sarco(endo)plasmic reticulum Ca2+ ATPase. To uncover biochemical adaptations associated with extremes of cardiac muscle contractility, we used high-throughput gel-free tandem MS to monitor differences in the relative abundance of membrane proteins in standard microsomal fractions isolated from the hearts of PLN-null mice (PLN-KO) with high contractility and from transgenic mice overexpressing a superinhibitory PLN mutant in a PLN-null background (I40A-KO) with diminished contractility. Significant differential expression was detected for a subset of the 782 proteins identified, including known membrane-associated biomarkers, components of signaling pathways, and previously uninvestigated proteins. Proteins involved in fat and carbohydrate metabolism and proteins linked to G protein-signaling pathways activating protein kinase C were enriched in I40A-KO cardiac muscle, whereas proteins linked to enhanced contractile function were enriched in PLN-KO mutant hearts. These data demonstrate that Ca2+ dysregulation, leading to elevated or depressed cardiac contractility, induces compensatory biochemical responses.

The efficacy of nicorandil, calcium chloride and nitroglycerin in treatment of ropivacaine-induced cardiotoxicity

Background and objective: The amide-linked local anaesthetics, bupivacaine and ropivacaine, can cause depression of cardiac contractility and dysrhythmias. In a previous study, we observed decreased contractility and ST segment depression following ropivacaine administration in anaesthetized dogs. The efficacy of intravenous (i.v.) and intracoronary nicorandil (30 and 100 μg kg−1), i.v. nitroglycerin (glyceryl trinitrate) (5 μg kg−1) and calcium chloride (1, 2 and 4 mmol) in reversing the cardiotoxic effects of intracoronary ropivacaine were studied following the administration of intracoronary ropivacaine. Methods: Six dogs were studied. The dogs were anaesthetized with i.v. pentobarbital (30 mg kg−1). A left-sided thoracotomy was performed and the left circumflex coronary was cannulated. For each dog, the dose of ropivacaine was identified, which produced measurable cardiotoxicity. In each case, ropivacaine was followed by one of the three resuscitation drugs. The effects of each resuscitation drug on ST segments and left ventricular contractility (dP/dt) produced by ropivacaine alone were compared with those produced by ropivacaine followed by each of the three resuscitation drugs using Fisher's exact test. Results: The doses of ropivacaine required to produce depression of left ventricular dP/dt and ST segments ranged from 1 to 8 mg. Ropivacaine-induced depression of left ventricular contractility (dP/dt) was more rapidly and completely reversed by calcium chloride than by either nitroglycerin or nicorandil (P = 0.008). Conclusions: Calcium chloride may be effective in the treatment of inadvertent intravascular administration of amide local anaesthetic agents.

Phosphoinositide 3-kinase gamma-deficient hearts are protected from the PAF-dependent depression of cardiac contractility.

Following an ischemic insult, cardiac contractile recovery might be perturbed by the release of autacoids, like platelet-activating factor (PAF), that depress heart function by acting through G protein-coupled receptors (GPCRs). The signaling events downstream the PAF receptor that lead to the negative inotropic effect are still obscure. We thus investigated whether the GPCR-activated phosphoisositide 3-kinase gamma (PI3Kgamma) could play a role in the cardiac response to PAF. The negative inotropic effect of PAF was studied ex vivo, in isolated electrically driven atria and in Langendorff-perfused whole hearts derived from wild-type and PI3Kgamma-null mice. Postischemic recovery of contractility was analyzed in normal and mutant whole hearts subjected to 30 min of ischemia and 40 min of reperfusion in the presence or absence of a PAF receptor antagonist. While wild-type hearts stimulated with PAF showed increased nitric oxide (NO) production and a consequent decreased cardiac contractility, PI3Kgamma-null hearts displayed reduced phosphorylation of nitric oxide synthase 3 (NOS3), blunted nitric oxide production and a complete protection from the PAF-induced negative inotropism. In addition, Langendorff-perfused PI3Kgamma-null hearts showed a better contractile recovery after ischemia/reperfusion, a condition where PAF is known to be an important player in depressing contractility. In agreement with a role of PI3Kgamma in this PAF-mediated signaling, postischemic contractile recovery in PI3Kgamma-null mice appeared overlapping with that of normal hearts treated with the PAF receptor antagonist WEB 2170. These data indicate a novel PAF-dependent signaling pathway that, involving PI3Kgamma and NOS3, contributes to postischemic contractile depression.

Effects of simulated microgravity on nitric oxide level in cardiac myocytes and its mechanism

The depression of cardiac contractility induced by space microgravity is an important issue of aerospace medicine research, while its precise mechanism is still unknown. In the present study, we explored effects of simulated microgravity on nitric oxide (NO) level, inducible nitric oxide synthase (iNOS) expression and related regulative mechanism using electron spin resonance (ESR) spectroscopy, immunocytochemistry and in situ hybridization. We found a remarkable increase of NO level and up-regulation of iNOS and iNOS mRNA expression in rat cardiac myocytes under simulated microgravity. Staurosporine (a nonselective protein kinase inhibitor), calphostin C (a selective protein kinase C inhibitor), partially inhibited the effect of simulated microgravity. Thus regulative effect of simulated microgravity on iNOS expression is mediated at least partially via activation of protein kinase C. These results indicate that NO system in cardiac myocytes is sensitive to simulated microgravity and may play an important role in the depression of cardiac contractility induced by simulated microgravity.

Experimental Assessment of the Role of Acetaldehyde in Alcoholic Cardiomyopathy.

Alcoholism is one of the major causes of non-ischemic heart damage. The myopathic state of the heart due to alcohol consumption, namely alcoholic cardiomyopathy, is manifested by cardiac hypertrophy, compromised ventricular contractility and cardiac output. Several mechanisms have been postulated for alcoholic cardiomyopathy including oxidative damage, accumulation of triglycerides, altered fatty acid extraction, decreased myofilament Ca2+ sensitivity, and impaired protein synthesis. Despite intensive efforts to unveil the mechanism and ultimate toxin responsible for alcohol-induced cardiac toxicity, neither has been clarified thus far. Primary candidates for the specific toxins are ethanol, its first and major metabolic product - acetaldehyde (ACA) and fatty acid ethyl esters. Evidence from our lab suggests that ACA directly impairs cardiac function and promotes lipid peroxidation resulting in oxidative damage. The ACA-induced cardiac contractile depression may be reconciled with inhibitors of Cytochrome P-450 oxidase, xanthine oxidase and lipid peroxidation Unfortunately, the common methods to investigate the toxicity of ACA have been hampered by the fact that direct intake of ACA is toxic and unsuitable for chronic study, which is unable to provide direct evidence of direct cardiac toxicity for ACA. In order to overcome this obstacle associated with the chemical properties of ACA, our laboratory has used the chronic ethanol feeding model in transgenic mice with cardiac over-expression of alcohol dehydrogenase (ADH) and an in vitro ventricular myocyte culture model. The combination of both in vivo and in vitro approaches allows us to evaluate the role of ACA in ethanol-induced cardiac toxicity and certain cellular signaling pathways leading to alcoholic cardiomyopathy.

Influence of gender on ethanol-induced ventricular myocyte contractile depression in transgenic mice with cardiac overexpression of alcohol dehydrogenase

Acute ethanol exposure depresses ventricular contractility and contributes to alcoholic cardiomyopathy in both men and women chronically consuming ethanol. However, a gender-related difference in the severity of myopathy exists with female being more sensitive to ethanol-induced tissue damage. Acetaldehyde (ACA), the major oxidized product of ethanol, has been implicated to play a role in the pathogenesis and gender-related difference of alcoholic cardiomyopathy, possibly due to its direct cardiac effect and interaction with estrogen. This study was designed to compare the effects of cardiac overexpression of alcohol dehydrogenase (ADH), which converts ethanol into ACA, on the cardiac contractile response to ethanol in ventricular myocytes isolated from age-matched adult male and female transgenic (ADH) and wild-type (FVB) mice. Mechanical properties were measured with an IonOptix SoftEdge system. ACA production was assessed by gas chromatography. The ADH myocytes from both genders exhibited similar mechanical properties but a higher efficacy to produce ACA compared to FVB myocytes. Exposure to ethanol (80–640 mg/dl) for 60 min elicited concentration-dependent decrease of cell shortening in both FVB and ADH groups. The ethanol-induced depression on cell shortening was significantly augmented in female but not male ADH group. ADH transgene did not exacerbate the ethanol-induced inhibition of maximal velocity of shortening/relengthening in either gender. In addition, neither ethanol nor ADH transgene affect the duration of shortening and relengthening in male or female mice. These data suggest that females may be more sensitive to ACA-induced cardiac contractile depression than male, which may attribute to the gender-related difference of alcoholic cardiomyopathy.

Influence of genetically predisposed diabetes on ethanol-induced depression of cardiac contraction in adult rat ventricular myocytes.

Diabetes mellitus and alcohol (ethanol) intake are two positively correlated major risk factors for cardiovascular abnormalities. However, the interaction of the two on cardiac function is largely unknown. The purpose of the present study was to examine the impact of genetically predisposed diabetes on acute ethanol exposure-induced cardiac contractile depression at the myocyte level. Ventricular myocytes from spontaneously biobreeding diabetes-prone (BBDP) rats and their diabetes-resistant littermates (BBDR) were stimulated to contract at 0.5 Hz. Contractile properties analysed include: peak shortening amplitude (PS), time-to-PS (TPS), time-to-90 % relengthening (TR(90)) and maximal velocities of shortening/relengthening (+/- dL/dt). BBDP rats displayed hyperglycaemia, reduced body weight gain and increased cardiac, hepatic and renal size. Myocytes isolated from BBDP rat hearts exhibited prolonged TPS and TR(90) associated with normal PS and +/- dL/dt, compared with myocytes from the BBDR group. Acute ethanol exposure (80-640 mg dl(-1)) caused a concentration-dependent inhibition of PS in both BBDR and BBDP myocytes. However, the degree of inhibition of PS was significantly reduced in BBDP myocytes compared to that of BBDR myocytes. The maximal inhibition was 52.9 % and 28.4 % in BBDR and BBDP groups, respectively. Ethanol significantly depressed +/- dL/dt in both BBDR and BBDP myocytes. In addition, ethanol did not affect TPS or TR(90) in either the BBDR or BBDP group. Collectively, these results suggest that the ethanol-induced depression in cardiac myocyte contraction may be 'shadowed' by genetically predisposed diabetes.

Effect of L-canavanine, an Inhibitor of inducible nitric oxide synthase, on myocardial dysfunction during septic shock.

Overproduction of nitric oxide (NO) by inducible NO synthase (iNOS) plays a role in the pathophysiology of septic shock. The depression of cardiac contractility in such situations is mediated by proinflammatory cytokines, including interleukin-1beta (IL-1beta), and tumor necrosis factor-alpha (TNF-alpha). The effects of two NOS inhibitors with different isoform selectivity were compared in isolated working rat hearts. The depression of contractility by IL-1beta and TNF-alpha was prevented by administration of a nonselective nitric oxide synthase inhibitor, N(G)-nitro-L-arginine methyl ester (L-NAME) or an inhibitor of inducible nitric oxide synthase, L-canavanine. In contrast, when L-NAME was administered in the absence of IL-1beta and TNF-alpha, it depressed contractility over the 2h perfusion period by significantly reducing coronary flow. These results support current thinking that the depression of myocardial function by IL-1beta and TNF-alpha is mediated, at least in part, by an intracardiac increase in inducible nitric oxide synthase, and that in contrast to L-NAME, the decline in coronary conductance seen in cytokine-treated is not prevented by L-canavanine hearts. L-canavanine shows selective inhibition of inducible nitric oxide synthase unlike the vasopressor action of L-NAME in cytokine-treated hearts.

Gender Influences on Sarcoplasmic Reticulum Ca2+-handling in Failing Human Myocardium

Gender has recently been implicated as an important modulator of cardiovascular disease. However, it is not known how gender may specifically influence the Ca2+-handling deficits that characterize the depressed cardiac contractility of human heart failure. To elucidate the contributory role of gender to sarcoplasmic reticulum (SR) Ca2+cycling alterations, the protein levels of SR Ca2+-ATPase (SERCA), phospholamban, and calsequestrin, as well as the site-specific phospholamban phosphorylation status, were quantified in a mixed gender population of failing (n=14) and donor (n=15) myocardia. The apparent affinity (EC50) and the maximal velocity (Vmax) of SR Ca2+-uptake were also determined to lend functional significance to any observed protein alterations. Phospholamban and calsequestrin levels were not altered; however, SERCA protein levels were significantly reduced in failing hearts. Additionally, phospholamban phosphorylation (serine-16 and threonine-17 sites) and myocardial cAMP content were both attenuated. The alterations in SR protein levels were also accompanied by a decreased Vmaxand an increased EC50(diminished apparent affinity) of SR Ca2+-uptake for Ca2+in failing myocardia. Myocardial protein levels and Ca2+uptake parameters were then analyzed with respect to gender, which revealed that the decreases in phosphorylated serine-16 were specific to male failing hearts, reflecting increases in the EC50values of SR Ca2+-uptake for Ca2+, compared to donor males. These findings suggest that although decreased SERCA protein and phospholamban phosphorylation levels contribute to depressed SR Ca2+-uptake and left ventricular function in heart failure, the specific subcellular alterations which underlie these effects may not be uniform with respect to gender.

RGS4 Reduces Contractile Dysfunction and Hypertrophic Gene Induction in Gα qOverexpressing Mice

The intrinsic GTPase activity of Gα qis low, and RGS proteins which activate GTPase are expressed in the heart; however, their functional relevance in vivo is unknown. Transgenic mice with cardiac-specific overexpression of Gα qin myocardium exhibit cardiac hypertrophy, enhanced PKCξ membrane translocation, embryonic gene expression, and depressed cardiac contractility. We recently reported that transgenic mice with cardiac-specific expression of RGS4, a Gα qand Gα iGTPase activator, exhibit decreased left ventricular hypertrophy and ANF induction in response to pressure overload. To test the hypothesis that RGS4 can act as a Gα q-specific GTPase activating protein (GAP) in the in vivo heart, dual transgenic Gα q-40xRGS4 mice were generated to determine if RGS4 co-expression would ameliorate the Gα q-40 phenotype. At age 4 weeks, percent fractional shortening was normalized in dual transgenic mice as was left ventricular internal dimension and posterior and septal wall thicknesses. PKC ξ membrane translocation and ANF and α -skeletal actin mRNA levels were also normalized. Compound transgenic mice eventually developed depressed cardiac contractility that was evident by 9 weeks of age. These studies establish for the first time a role for RGS4 as a GAP for Gα qin the in vivo heart, and demonstrate that its regulated expression can have pathophysiologic consequences.

Phosphorylation-dependent alteration in myofilament ca2+ sensitivity but normal mitochondrial function in septic heart.

The subcellular mechanisms responsible for myocardial depression during sepsis remain unclear. Recent data suggest a role for impaired energy generation and utilization, resulting in altered contractile function. Here, we studied the energetic and mechanical properties of skinned fibers isolated from rabbit ventricle in a nonlethal but hypotensive model of endotoxemia. Thirty-six hours after lipopolysaccharide (LPS) injection (in the presence of altered myocardial contractility), mitochondrial respiration, coupling between oxidation and phosphorylation, and creatine kinase function were similar in preparations from endotoxemic (LPS) and control animals. The maximal Ca2+-activated force was similar in LPS and control preparations. However, the Ca2+ concentration corresponding to half-maximal force (pCa50, where pCa = -log10[Ca2+]) was 5.55 +/- 0.01 (n = 11) in LPS fibers versus 5.61 +/- 0.01 (n = 10) in control fibers (p < 0.01). Both protein kinase A (PKA) and alkaline phosphatase treatment led to the disappearance in the difference between control and LPS pCa50 values. Incubation of control fibers with the nitric oxide donor S-nitroso-N-acetylpenicillamine (SNAP) did not change the Ca2+ sensitivity after subsequent skinning, whereas isoproterenol decreased pCa50 from 5.62 +/- 0.01 to 5.55 +/- 0.01 (p < 0.01). These data suggest that during sepsis, cardiac mitochondrial and creatine kinase systems remain unaltered, whereas protein phosphorylation decreases myofibrillar Ca2+ sensitivity and may contribute to the depression of cardiac contractility.

Brain derived neurotrophic factor is an endothelial cell survival factor required for intramyocardial vessel stabilization.

Brain derived neurotrophic factor, BDNF, is a neurotrophin best characterized for its survival and differentiative effects on neurons expressing the trk B receptor tyrosine kinase. Although many of these neurons are lost in the BDNF(-)(/)(- )mouse, the early postnatal lethality of these animals suggests a wider function for this growth factor. Here, we demonstrate that deficient expression of BDNF impairs the survival of endothelial cells in intramyocardial arteries and capillaries in the early postnatal period, although the embryonic vasculature can remodel into arteries, capillaries and veins. BDNF deficiency results in a reduction in endothelial cell-cell contacts and in endothelial cell apoptosis, leading to intraventricular wall hemorrhage, depressed cardiac contractility and early postnatal death. Vascular hemorrhage is restricted to cardiac vessels, reflecting the localized expression of BDNF and trk B by capillaries and arterioles in this vascular bed. Conversely, ectopic BDNF overexpression in midgestational mouse hearts results in an increase in capillary density. Moreover, BDNF activation of endogenous trk B receptors supports the survival of cardiac microvascular endothelial cells cultured from neonatal mice. These results establish an essential role for BDNF in maintaining vessel stability in the heart through direct angiogenic actions on endothelial cells.

Transgenic replacement of type V adenylyl cyclase identifies a critical mechanism of β-adrenergic receptor dysfunction in the G αq overexpressing mouse

Chronic activation of G q coupled receptors, or overexpression of G αq, in cardiomyocytes results in hypertrophy, enhanced expression of fetal genes, decreased basal and β-adrenergic receptor (βAR) stimulated adenylyl cyclase (AC) activities, and depressed cardiac contractility in vivo. Among several abnormalities of the βAR-Gs-AC pathway that occur in G αq overexpressing transgenic mice, we have investigated whether the observed ∼45% decrease in type V AC expression and function compared to non-transgenic (NTG) is the basis of the above phenotype. Transgenic mice were generated that overexpressed by ∼50% the rat type V AC in the heart using the α-myosin heavy chain promoter. These mice were mated with the G αq transgenics resulting in animals (ACV/G αq) that had restored levels of forskolin stimulated AC activities in cardiac membranes. In addition, basal cardiac AC activities were normalized in the ACV/G αq mice (NTG=23±4.4, G αq=14±3.6, ACV/G αq=29±5.3 pmol/min/mg) as were maximal isoproterenol stimulated activities (59±8.9, 34±4.6, 52±6.7 pmol/min/mg respectively). Cardiac contractility was also improved by ACV replacement, with increased fractional shortening (51±2%, 36±6%, 46±3% respectively). In contrast, hypertrophy and expression of hypertrophy associated fetal genes were not affected. Thus the observed decrease in type V AC that accompanies the development of the cardiac phenotype in the G αq model is the dominant mechanism of dysfunctional βAR signalling and contractility. In contrast, the decrease in type V AC or βAR signalling to cAMP is not the basis of the hypertrophic response.

Protein phosphatase inhibitor-1 ablation results in depressed cardiac contractility in response to β-adrenergic stimulation and decreased phosphorylation of phospholamban

Protein phosphatase inhibitor-1 ablation results in depressed cardiac contractility in response to β-adrenergic stimulation and decreased phosphorylation of phospholamban

Effects of endotoxin on human myocardial contractility involvement of nitric oxide and peroxynitrite

OBJECTIVESThis study examined the effects of endotoxin on cardiac contractility in human myocardium.BACKGROUNDIn animal myocardium, endotoxin and cytokine treatment led to enhanced inducible nitric oxide synthase (iNOS) expression and contractile dysfunction. Effects in human myocardium are unknown.METHODSLeft ventricular myocardial preparations from failing (n = 18) and nonfailing (n = 5) human hearts were incubated for 6 and 12 h in tyrode solution or in tyrode plus lipopolysaccharides (LPS), with LPS plus NG-mono-methyl-l-arginine (l-NMMA), with LPS plus hemoglobin or with LPS plus the superoxide scavenger 4,5-dihydroxy-1,3-benzene disulfonic acid (Tiron). Force of contraction in response to isoprenaline (0.001 to 3 μmol/liter) was determined in electrically stimulated muscle preparations. The iNOS mRNA expression was examined by in situ hybridization and by polymerase chain reaction. The cyclic guanosine monophosphate (cGMP) levels were determined by radioimmunoassay.RESULTSIsoprenaline concentration dependently increased force of contraction. Six and 12 hours of LPS treatment of failing myocardium decreased maximum inotropic response to isoprenaline by 54% (p = 0.009) and by 69% (p = 0.0023), respectively. In nonfailing myocardium, 12 h of LPS treatment decreased maximum inotropic effect of isoprenaline by 66% (p < 0.001). The LPS effects were attenuated by l-NMMA, hemoglobin and also Tiron. The iNOS mRNA was expressed in all LPS-treated preparations but also in most control myocardial preparations. In situ hybridization revealed iNOS expression within cardiac myocytes. There was no increase in myocardial cGMP content in response to endotoxin.CONCLUSIONSEndotoxin exposure of human myocardium leads to a depression of cardiac contractility, which is mediated by enhanced iNOS activity and release of nitric oxide (NO). Consecutive reaction of NO with superoxide and formation of peroxynitrite may contribute to the decrease in force of contraction.

Arginine in burn injury improves cardiac performance and prevents bacterial translocation

This study examined the effects of arginine supplement of fluid resuscitation from burn injury on cardiac contractile performance and bacterial translocation after a third-degree burn comprising 43% of the total body surface area in adult rats. Before burn injury, rats were instrumented to measure blood pressure; after burn (or sham injury), paired groups of sham-burned and burned rats were given vehicle (saline), L-arginine, D-arginine, or N-methyl-L-arginine (300 mg/kg in 0.3 ml of saline 30 min, 6 h, and 23 h postburn) plus fluid resuscitation; sham-burned rats received drug only. Twenty-four hours after burn trauma, hemodynamics were measured; the animals were then killed and randomly assigned to Langendorff heart studies or to studies examining translocation of gut bacteria. Burn rats treated with vehicle, D-arginine, or N-methyl-L-arginine had well-defined cardiocirculatory responses that included hypotension, tachycardia, respiratory compensation for metabolic acidosis, hypocalcemia, cardiac contractile depression, and significant bacterial translocation. Compared with values measured in vehicle-treated burn rats, L-arginine given after burn improved blood pressure, prevented tachycardia, reduced serum lactate levels, improved cardiac performance, and significantly reduced bacteria translocation, confirming that L-arginine administration after burn injury provided significant cardiac and gastrointestinal protection. Circulating neutrophil counts fell after burn trauma and serum glucagon levels rose, but these changes were not altered by pharmacological intervention. Our finding of significantly higher coronary perfusate guanosine 3',5'-cyclic monophosphate concentration in L-arginine-treated burn rats suggests that the beneficial effects of L-arginine were mediated by nitric oxide production.

The Effects of Amrinone and Milrinone on Myocardium in the Isolated Isoflurane-Exposed Rat Heart

Background : The aims of this study were to test if amrinone or milrinone reverses cardiac depression induced by the exposure to isoflurane in the isolated heart and to determine whether amrinone or milrinone dilates the coronary artery directly. Methods : Using the isolated Sprague-Dawley rat hearts, heart rate, left ventricular pressure, dp/dt (differentiated rate of pressure development), O2 delivery(DO2), myocardial oxygen consumption(MVO2), and percent O2 extraction were measured. After the isolated hearts were exposed to isoflurane at 1.2 vol% during 10 min, amrinone(10, 50, 100 M) or milrinone(1, 5, 10 M) was separately given to six groups. Results : Amrinone and milrinone reversed, not statistically significant, the depression of cardiac contractility induced by isoflurane, while the isoflurane-induced bradycardia substantially returned to normal by amrinone 100 M. And amrinone and milrinone elevated coronary flow, DO2, MVO2, while isoflurane increased in coronary flow and DO2, except MVO2. Conclusions : These results suggest that amrinone and milrinone did not counteract the isoflurane-induced cardiac depression and indirectly increased in coronary blood flow through the elevation of cardiac work. (Korean J Anesthesiol 1998; 35: 7∼15)

Comparative evaluation of the inotropic effect of lipophilic and hydrophilic forms of 17P-estradiol and progesterone

Changes in the contractility under the effect of lipophilic and hydrophilic 17^-estradiol and progesterone were studied on an isolated atrial auricula. The hydrophilic forms of female sex steroids possessed a higher cardiotropic activity than their lipophilic analogs. Lipophilic 17^-estradiol suppressed, whereas the hydrophilic form boosted the contractile function of the isolated rat atrium. Progesterone depressed cardiac contractility, no matter which forms were used.

Effect of nitric oxide synthase inhibition on myocardial contractility in anesthetized normal and endotoxemic dogs.

Nitric oxide (NO) produced by the induced NO synthase (NOS) enzyme has been implicated in the mechanisms of the circulatory changes that occur in the later stages of sepsis. As NO produced by the constitutive form of the enzyme is known to play a role in the regulation of normal circulation, we have performed a series of experiments to study the early circulatory effects of inhibition of NOS in a hyperdynamic endotoxemic dog model. Pentobarbital-anesthetized animals were used. Cardiac output (CO) was measured by thermodilution. Myocardial contractility (MC) was estimated from the slope of the left ventricular end-systolic pressure-diameter relationship obtained from sonomicrometer- and catheter-tip manometer signals in closed chest animals. All animals received a 15 mL/kg/h infusion of Ringer's lactate. A hyperdynamic response was elicited by a 2 h infusion of a total dose of 5.3 micrograms/kg Escherichia coli O55:B5 endotoxin (ETX). CO increased initially by about 25%, and total peripheral resistance decreased by 35%. These changes subsided in 60-90 min, after which a sustained decrease in CO occurred. MC elevated transiently by 25% after the first 30 min of ETX infusion, then decreased gradually below the control level. Administration of 2 mg/kg of the NOS inhibitor N-nitro-L-arginine (NNA) between the 45th and 55th min of the ETX infusion increased MC to the level in the control group, but accelerated the decline of the initially increased CO and caused a sustained increase in total peripheral resistance to about 50% above the control level. In normal (nonendotoxin treated) dogs, NNA also caused a similar increase in MC which, however, lasted at least 3 h. Left ventricular diameter increased in the NNA-treated groups. This increase also occurred in the endotoxin-only group but with a delay of about 2.5 h. Our results demonstrate the participation of constitutive NOS-produced NO in the early hyperdynamic response of endotoxemia. Suppression of NO is associated with increased myocardial contractility. NNA treatment may be favorable for the restoration of depressed cardiac contractility during endotoxemia, but this treatment is probably detrimental for the compensatory systemic flow (CO) increase.

Monoclonal Antibody to Intercellular Adhesion Molecule-1 Reduces Cardiac Contractile Dysfunction after Burn Injury in Rabbits

Cardiac dysfunction occurs after thermal injury but the pathogenesis is unclear; leukocytes have been implicated in the pathogenesis of multiorgan dysfunction after burn injury. White blood cell activation and entry into tissue involve the use of a number of adhesion molecules, including intercellular adhesion molecule (ICAM)-1, CD54. We asked the question: will administration of the monoclonal antibody (R6.5) directed against ICAM-1 alter the cardiac dysfunction which we have previously shown to occur after thermal injury? Previously instrumented New Zealand White rabbits were anesthetized and given a full-thickness burn over 30% of the total body surface area by applying brass probes heated to 100°C to the animals’ backs for 15 sec. Animals were monitored for 24 hr and given lactated Ringer's (LR) solution (4 cc/kg/% burn, Parkland formula) with additional LR given to maintain cardiac output and urine output. Three experimental groups were studied: sham burn controls had catheters placed and were monitored for 24 hr (N= 8); burn rabbits were divided into vehicle treated (saline, 1 ml/kg,N= 6) or R6.5 treated (2 mg/kg,N= 6). Vehicle or antibody was administered 30 min postburn and every 8 hr until 24 hr postburn; at this time, rabbits were sacrificed and hearts were harvested forin vitroassessment of contractile performance (Langendorff). Compared to values measured in sham burn controls, burn injury caused cardiac contractile depression as indicated by a fall in left ventricular pressure (LVP) (77 ± 2 vs 56 ± 3 mm Hg,P= 0.01), +dP/dt (1223 ± 64 vs 842 ± 64 mm Hg/sec,P= 0.001), and −dP/dt (973 ± 63 vs 666 ± 42 mm Hg/sec,P= 0.01). Administration of R6.5 significantly improved cardiac contractile function compared to the vehicle-treated burns as indicated by higher LVP (67 ± 2 mm Hg,P> 0.05), +dP/dt (1017 ± 33 mm Hg/sec,P> 0.05), and −dP/dt (858 ± 40 mm Hg/sec,P> 0.05) than values measured in vehicle-treated burns. These results suggest that ICAM-1-mediated WBC activation and/or tissue entry are involved in the pathogenesis of cardiac dysfunction following thermal injury.