Insights into Muscle Contraction Derived from the Effects of Small-Molecular Actomyosin-Modulating Compounds.

Bottom-up mechanokinetic models predict ensemble function of actin and myosin based on parameter values derived from studies using isolated proteins. To be generally useful, e.g., to analyze disease effects, such models must also be able to predict ensemble function when actomyosin interaction kinetics are modified differently from normal. Here, we test this capability for a model recently shown to predict several physiological phenomena along with the effects of the small molecular compound blebbistatin. We demonstrate that this model also qualitatively predicts effects of other well-characterized drugs as well as varied concentrations of MgATP. However, the effects of one compound, amrinone, are not well accounted for quantitatively. We therefore systematically varied key model parameters to address this issue, leading to the increased amplitude of the second sub-stroke of the power stroke from 1 nm to 2.2 nm, an unchanged first sub-stroke (5.3−5.5 nm), and an effective cross-bridge attachment rate that more than doubled. In addition to better accounting for the effects of amrinone, the modified model also accounts well for normal physiological ensemble function. Moreover, a Monte Carlo simulation-based version of the model was used to evaluate force−velocity data from small myosin ensembles. We discuss our findings in relation to key aspects of actin−myosin operation mechanisms causing a non-hyperbolic shape of the force−velocity relationship at high loads. We also discuss remaining limitations of the model, including uncertainty of whether the cross-bridge elasticity is linear or not, the capability to account for contractile properties of very small actomyosin ensembles (<20 myosin heads), and the mechanism for requirements of a higher cross-bridge attachment rate during shortening compared to during isometric contraction.

Activation of cAMP-PKA signaling in vivo inhibits smooth muscle cell proliferation induced by vascular injury.

Injury of the arterial wall induces the formation of the neointima. This structure is generated by the growth of mitogenically activated smooth muscle cells of the arterial wall. The molecular mechanism underlying the formation of the neointima involves deregulated cell growth, primarily triggered by the injury of the arterial wall. The activated gene products transmitting the injury-induced mitogenic stimuli have been identified and inhibited by several means: transdominant negative expression vectors, antisense oligodeoxynucleotides, adenovirus-mediated gene transfer, antibodies and inactivating drugs. Results of our study show that local administration of 3',5'-cyclic AMP and phosphodiesterase-inhibitor drugs (aminophylline and amrinone) to rats markedly inhibits neointima formation after balloon injury in vivo and in smooth muscle cells in vitro. The growth inhibitory effect of aminophylline was completely reversed by the inhibition of cAMP-dependent protein kinase A (PKA). These findings indicate an alternative approach to the treatment of diseases associated with injury-induced cell growth of the arterial wall, as stimulation of cAMP signaling is pharmacologically feasible in the clinical setting.

Effects of inhibition of phosphodiesterase 3B in pancreatic islets on insulin secretion: a potential link with some stimulatory pathways.

OBJECTIVE: Elevated intracellular cAMP concentrations potentiate insulin secretion from pancreatic ß cells. Phosphodiesterase 3B (PDE3B) is highly expressed in these cells and plays a role in the regulation of insulin secretion. MATERIALS AND METHODS: In this study, effects of amrinone, an inhibitor of PDE3B on insulin release from isolated pancreatic islets, were determined. RESULTS: Exposure of islets to amrinone for 15, 30 and 90 min markedly increased secretion induced by 6.7 mM glucose. Amrinone enhanced also secretion stimulated by 6.7 mM glucose and DB-cAMP, an activator of PKA. It was also demonstrated that amrinone potentiated insulin secretion induced by 6.7 mM glucose in the combination with PMA (activator of PKC) or acetylcholine. However, the insulin-secretory response to glucose and glibenclamide was unchanged by amrinone. CONCLUSIONS: These results indicate that amrinone is capable of increasing insulin secretion; however, its action is restricted.

Drug effect unveils inter-head cooperativity and strain-dependent ADP release in fast skeletal actomyosin.

Amrinone is a bipyridine compound with characteristic effects on the force-velocity relationship of fast skeletal muscle, including a reduction in the maximum shortening velocity and increased maximum isometric force. Here we performed experiments to elucidate the molecular mechanisms for these effects, with the additional aim to gain insight into the molecular mechanisms underlying the force-velocity relationship. In vitro motility assays established that amrinone reduces the sliding velocity of heavy meromyosin-propelled actin filaments by 30% at different ionic strengths of the assay solution. Stopped-flow studies of myofibrils, heavy meromyosin and myosin subfragment 1, showed that the effects on sliding speed were not because of a reduced rate of ATP-induced actomyosin dissociation because the rate of this process was increased by amrinone. Moreover, optical tweezers studies could not detect any amrinone-induced changes in the working stroke length. In contrast, the ADP affinity of acto-heavy meromyosin was increased about 2-fold by 1 mm amrinone. Similar effects were not observed for acto-subfragment 1. Together with the other findings, this suggests that the amrinone-induced reduction in sliding velocity is attributed to inhibition of a strain-dependent ADP release step. Modeling results show that such an effect may account for the amrinone-induced changes of the force-velocity relationship. The data emphasize the importance of the rate of a strain-dependent ADP release step in influencing the maximum sliding velocity in fast skeletal muscle. The data also lead us to discuss the possible importance of cooperative interactions between the two myosin heads in muscle contraction.

Effects of amrinone in an experimental model of hepatic ischemia-reperfusion injury.

BACKGROUND: During some surgical interventions, temporary occlusion of the hepatic blood supply may cause ischemia-reperfusion (IR) injury. Recent studies suggest that type 3 phosphodiesterase inhibitors may have a beneficial effect on liver IR injury. The aim of this study was to investigate whether amrinone, a type 3 phosphodiesterase inhibitor, could have a protective effect on liver having experimental liver IR injury. MATERIALS AND METHODS: Sixty Wistar albino rats were randomly divided into three groups. The IR and amrinone groups were subjected to 1 h total hepatic ischemia, followed by 2 h of reperfusion. The sham group underwent midline laparotomy only. Amrinone 10 microg/kg/min was infused to the amrinone group during the 3 h of the IR period. Histopathological examination, biochemical liver function, and liver adenosine triphosphate concentration after reperfusion and survival rate on the seventh day after the IR insult were recorded. RESULTS: Serum aspartate aminotransferase, alanine aminotransferase, lactic dehydrogenase levels, and histological damage scores in the amrinone and IR groups were significantly higher compared with the sham group (P < 0.01). However, all of these values were significantly lower in the amrinone group than in the IR group (P < 0.05). Liver adenosine triphosphate levels and the rat survival rate in the amrinone and IR groups were significantly lower than those in the sham group (P < 0.01). However, these values were significantly higher in the amrinone group compared to those in the IR group (P < 0.01). CONCLUSIONS: These results suggest that amrinone plays a significant role in the protection of liver against IR injury and that this treatment may be a novel pharmacological agent for safe and efficient liver surgery.

The role of phosphodiesterase 3 in endotoxin-induced acute kidney injury.

BACKGROUND: Acute kidney injury frequently accompanies sepsis. Endotoxin is known to reduce tissue levels of cAMP and low levels of cAMP have been associated with renal injury. We, therefore, hypothesized that endotoxin induced renal injury by activating phosphodiesterase 3 (PDE3) which metabolizes cAMP and that amrinone an inhibitor of PDE3 would prevent the renal injury. METHODS: Animals were divided into three groups (n = 7/group): 1) Control (0.9% NaCl infusion without LPS); 2) LPS (0.9% NaCl infusion with LPS); 3) Amrinone+LPS (Amrinone infusion with LPS). Either lipopolysaccharide (LPS) or vehicle was injected via the jugular vein and the rats followed for 3 hours. We explored the expression of PDE3 isoenzymes and the concentrations of cAMP in the tissue. RESULTS: The PDE3B gene but not PDE3A was upregulated in the kidney of LPS group. Immunohistochemistry also showed that PDE3B was expressed in the distal tubule in the controls and LPS caused PDE3B expression in the proximal as well. However, PDE3A was not expressed in the kidney either in the control or LPS treated groups. Tissue level of cAMP was decreased after LPS and was associated with an increase in blood urea nitrogen, creatinine, ultrastructural proximal tubular changes, and expression of inducible nitric oxide synthase (iNOS) in the endotoxemic kidney. In septic animals the phosphodiesterase 3 inhibitor, amrinone, preserved the tissue cAMP level, renal structural changes, and attenuated the increased blood urea nitrogen, creatinine, and iNOS expression in the kidney. CONCLUSION: These findings suggest a significant role for PDE3B as an important mediator of LPS-induced acute kidney injury.

Design, synthesis and pharmacological evaluation of 6-hydroxy-4-methylquinolin-2(1H)-one derivatives as inotropic agents.

Selective PDE3 inhibitors improve cardiac contractility and may be used in congestive heart failure. However, their proarrhythmic potential is the most important side effect. In this research we designed, synthesized and evaluated the potential cardiotonic activity of thirteen PDE3 inhibitors (4-[(4-methyl-2-oxo-1,2-dihydro-6-quinolinyl)oxy]butanamide analogs) using the spontaneously beating atria model. The design strategy was based on the structure of cilostamide, a selective PDE3 inhibitor. In each experiment, atrium of reserpine-treated rat was isolated and the contractile and chronotropic effects of a synthetic compounds were assessed. All experiments were carried out in comparison with IBMX, amrinone and cilostamide as standard compounds. The results showed that, among the new compounds, the best pharmacological profile was obtained with the compound 6-[4-(4-methylpiperazine-1-yl)-4-oxobutoxy]-4-methylquinolin-2(1H)-one, 4j, which displayed selectivity for increasing the force of contraction (165 +/- 4% change over the control) rather than the frequency rate (115 +/- 7% change over the control) at 100 microM and potent inhibitory activity of PDE3 with IC(50) = 0.20 microM.

Effect of nitric oxide/cyclic guanosine mono-phosphate pathway on gallbladder relaxant response in bile duct-ligated guinea pigs.

BACKGROUND/AIMS: Common bile duct ligation (CBDL) in the guinea pig is a well-defined model of acalculous cholecystitis. Nitric oxide (NO) mediates smooth muscle relaxation by stimulating the activity of soluble guanylate cyclase. The aim of this study was to determine whether the NO/cyclic guanosine monophosphate pathway plays a role in gallbladder relaxant response after CBDL. METHODS: Relaxant response of gallbladder muscle strips from CBDL and sham-operated guinea pigs was studied in vitro. Animals were treated with saline, aminoguanidine or an aminoguanidine + L-arginine combination in vivo. Concentration-response curves of papaverine, diethylamine/NO, YC-1, sildenafil and amrinone were obtained and relaxations in each group were calculated as the percent of the contractions induced by carbachol (10(-6) M). RESULTS: There was a significant decrease in the gallbladder muscle relaxant responses to these substances in CBDL and aminoguanidine groups compared with sham surgical controls. The decreased relaxant response was reversed by aminoguanidine + L-arginine but not by aminoguanidine alone. CONCLUSION: Decreased relaxant responses might be due to the reduced guanylate cyclase enzyme activity, but further studies are required.

Comparison of the initial hospitalization costs between the patients treated with dobutamine and the patients treated with amrinone for acute decompensated heart failure in a Japanese institute.

OBJECTIVES: Phosphodiesterase (PDE) III inhibitor therapy is effective for treatment of acute decompensated heart failure (ADHF). Nevertheless, this drug is expensive than conventional inotropic agent dobutamine. We compared total medication costs of the patients treated with PDE III inhibitor amrinone therapy to that of the patients treated with conventional dobutamine therapy during initial hospitalization. METHODS: We analyzed 160 consecutive patients with ADHF admitted to our hospital. Shock, dehydration, severe infection, multiple organ failure, and mild heart failure (New York Heart Association class IIs) were not eligible for the study. Ninety-seven patients were divided into two groups: 1) DOB group treated with dobutamine therapy; and 2) AMR group treated with amrinone therapy. Total medication costs and cost for hospital room charge were calculated based on their usage during the initial hospitalization for each patient. Group comparison was done between the DOB and AMR groups. RESULTS: Length of stay was longer in the DOB group than in the AMR group. Mean calculated cost of intravenous drugs was higher in the DOB group (173,186 +/- 239,147 yen) than in the AMR group (63,145 +/- 47,223 yen, P < 0.05). Total medication costs were higher in the DOB group than in the AMR group. Cost for hospital room charge was higher in the DOB group than in the AMR group. CONCLUSIONS: In the treatment of ADHF, appropriate therapy even with expensive drugs makes total medication costs less expensive comparing with conventional therapy with cheaper drugs during initial hospitalization.

Inotropic and chronotropic effects of 6-hydroxy-4-methylquinolin-2(1H)-one derivatives in isolated rat atria.

BACKGROUND: Selective phosphodiesterase (PDE3) inhibitors improve cardiac contractility and may use in congestive heart failure. However, their proarrhythmic potential is the most important side effect. METHODS: In this research, we evaluated the potential cardiotonic activity of six new synthesized selective PDE3 inhibitors (6-hydroxy-4-methylquinolin-2(1H)-one derivatives) using the spontaneously beating atria model. In each experiment, atrium of reserpine-treated rat was isolated and the contractile and chronotropic effects of a synthesized compound were assessed. The 3-isobutyl-1-methylxanthine, a non-selective PDE inhibitor, was used for comparison. RESULTS: The results showed that, among new compounds, the best pharmacological profile was obtained with the compound 6-[4-(4-methylpiperazine-1-yl)-4-oxobutoxy]-4-methylquinolin-2(1H)-one, C6, which displayed selectivity for increasing the force of contraction (168 +/- 5% change over the control) rather than the frequency rate (138 +/- 5% change over the control) at 300 microM. However, C6 at concentrations of 10 and 100 microM produced left and upward shift in the positive inotropic concentration-response curve of isoprenaline. The -log EC50 of isoprenaline was 8.843 +/- 0.171 in the absence, 9.448 +/- 0.138 and 9.456 +/- 0.107 in the presence of 10, 100 microM of C6, respectively (P<0.001, n = 6). Also, amrinone, a selective PDE3 inhibitor, shifted the isoprenaline concentration-response curve to the left and upward. The concentration of 10 and 100 microM amrinone decreased -log EC50 of isoprenaline to 9.527 +/- 0.287 and 9.423 +/- 0.243, respectively (P<0.001, n = 6). Moreover, the positive chronotropic effect of isoprenaline was not affected by amrinone or C6. CONCLUSION: This study provides functional evidence for the positive inotropic effect of C6. Considering the augmentation of isoprenaline positive inotropic concentration-response with C6 and amrinone, we conclude that C6 produces its effect via potentiation of cAMP-dependent signaling system and possibly by inhibition of PDE3 activity.

Treatment of virus-induced myocardial injury with a novel immunomodulating agent, vesnarinone. Suppression of natural killer cell activity and tumor necrosis factor-alpha production.

Controversy still exists concerning the therapy for viral myocarditis which manifests a wide variety of clinical symptoms. Vesnarinone, a quinolinone derivative that was developed as a positive inotropic agent with complex actions, including phosphodiesterase inhibition and cation channel modification, has recently been confirmed to improve the prognosis of patients with chronic heart failure. However, the precise mechanism of this beneficial effect is not yet clearly understood. In this study, using a murine model of acute viral myocarditis resulting from encephalomyocarditis virus infection, survival and myocardial damage were markedly improved by treatment with vesnarinone. In contrast, survival was not improved by treatment with amrinone, a phosphodiesterase inhibitor. Although vesnarinone did not inhibit viral replication or protect myocytes from viral direct cell injury, it did inhibit the increase in natural killer cell activity after viral infection. On the other hand, amrinone failed to inhibit natural killer cell activity. Both vesnarinone and amrinone suppressed the production of tumor necrosis factor-alpha. Therefore, we postulate that vesnarinone exerted its beneficial effects through an inhibition of natural killer cell activity, and that it serves as an immunomodulator providing new therapeutic possibilities for the treatment of viral myocarditis and/or immunological disorders.

Effects of amrinone, a cardiotonic drug, on calcium movements in dog erythrocytes.

Dog erythrocytes (RBC) have a system for passive Ca and Na movements that resembles the Ca-Na exchanger first described in cardiac muscle. Amrinone, a new cardiotonic drug active in humans with congestive heart failure, is shown to stimulate net Ca uptake by dog RBC. Amrinone's action is on Ca influx rather than efflux. The influence of Amrinone on Ca uptake is enhanced when the cells are placed in low Na media; raising external Na or lowering intracellular Na both abolish the effect of the drug. The data suggest that amrinone potentiates passive Ca entry into the cells by a Na-dependent pathway. If Ca moves through myocardial sarcolemma as it does through dog RBC membranes, then the inotropic action of amrinone can be explained on the basis that the drug increases intracellular Ca levels.

[Protection of amrinone against lung injury induced by ischemia/reperfusion in rats].

OBJECTIVE: To investigate the protective effect of amrinone against experimental lung ischemia /reperfusion (I/R) injury. METHODS: Twenty-four Sprague-Dawley rats were randomly divided into 3 groups (n=8 each): sham- operated group, I/R group, and amrinone-treated I/R group (AMR group). The left lung of rats was subjected to ischemia for 90 minutes, followed by reperfusion for 2 hrs, to induce an I/R lung injury model. The rats of the AMR group received amrinone (10 mg/kg) intravenously 30 minutes before ischemia and 5 minutes before reperfusion. After 2 hrs of reperfusion, carotid artery blood was collected for blood-gas analysis and detection of serum levels of IL-1beta, IL-8 and TNF-alpha. The left lung was removed for detection of the lung wet/dry ratio, the erythrocuprein (SOD) activity and the malonaldehyde (MDA) content as well as the pathological changes. RESULTS: After 2 hrs of reperfusion, there were no significant differences in artery partial pressure of oxygen (PO2) and partial pressure of carbon dioxide (PCO2) among the three groups. The lung wet/dry ratio (5.3 +/- 0.5 vs 4.8 +/- 0.1) and the MDA content (0.66 +/- 0.16 nmol/mg prot vs 0.47 +/- 0.06 nmol/mg prot) in the I/R group were significantly higher than those of the sham-operated group (P <0.05). The administration of amrinone markedly reduced the lung wet/dry ratio (4.8 +/- 0.2) and the MDA content (0.51 +/- 0.09 nmol/mg prot) and increased the SOD activity (54.7 +/- 6.8 vs 39.3 +/- 3.0 U/mg prot) when comparing the I/R group (P < 0.05). The serum levels of IL-1beta, IL-8 and TNF-alpha in the I/R group were 22.08 +/- 3.85, 21.92 +/- 5.56 and 30.50 +/- 3.77 pg/mL respectively, which were significantly higher than those of the sham-operated group. The AMR group showed lower serum levels of IL-1beta, IL-8 and TNF-alpha (16.66 +/- 3.02,14.73 +/- 2.75 and 22.48 +/- 3.82 pg/mL, respectively) compared with the I/R group (P < 0.01). The pathologic examination displayed that the lung tissue structure was normal and there was no hyperemia in the sham-operated and the AMR groups. The lung tissue structure of the I/R group was nearly normal but there were hyperemia and more inflammatory cells than the sham-operated and the AMR groups. CONCLUSIONS: Amrinone has protections against lung I/R injury, possibly through its anti-oxidation effects and an inhibition of inflammation factors releasing.

A comparison of three phosphodiesterase type III inhibitors on mechanical and metabolic function in guinea pig isolated hearts.

Little is known about of the comparative cardiac lusitropic and coronary vasoactive effects of type III phosphodiesterase inhibitors independent of their systemic circulatory effects. We hypothesized that phosphodiesterase inhibitors have dissimilar concentration-dependent effects on cardiac function and metabolism and that their coronary vasodilatory effects are solely dependent on flow autoregulation secondary to positive inotropic effects. Our aim was to compare the dose-response electrophysiologic, mechanical, vasodilatory, and metabolic properties of three clinically available phosphodiesterase inhibitors in isolated Langendorff perfused guinea pig hearts. We found that, over a range from 10(-7) to 10(-4) M, amrinone, enoximone, and milrinone each produced maximal concentration-dependent positive chronotropic (12%, 18%, 26%), inotropic (16%, 26%, 26%), and lusitropic (14%, 21%, 19%) effects. At clinical concentrations, all phosphodiesterase inhibitors increased heart rate, but only milrinone significantly enhanced contractility and relaxation (11%). Each phosphodiesterase inhibitor similarly increased contractility at its highest concentration; this was accompanied by an increase in oxygen consumption, which was matched by comparable increases in coronary flow and oxygen delivery. Coronary flow reserve was preserved at the highest concentration of each drug, indicating that an increased metabolic rate was responsible for the increase in coronary flow by each drug at each concentration. Over the concentrations examined, we conclude that each of the phosphodiesterase inhibitors does not directly promote coronary vasodilation and that milrinone has the most prominent effects on contractility and relaxation at clinically relevant concentrations.

Treatment of poisoning caused by beta-adrenergic and calcium-channel blockers.

PURPOSE: The toxic effects and treatment of beta-adrenergic blocker and calcium-channel blocker (CCB) overdose are reviewed. SUMMARY: Overdoses with cardiovascular drugs are associated with significant morbidity and mortality. Beta-blockers and CCBs represent the most important classes of cardiovascular drugs. In overdose, beta-blockers and CCBs have similar presentation and treatment overlaps and are often refractory to standard resuscitation measures. The common feature of beta-blocker toxicity is excessive blockade of the beta-receptors resulting in bradycardia and hypotension. Poisoning by CCBs is characterized by cardiovascular toxicity with hypotension and conduction disturbances, including sinus bradycardia and varying degrees of atrioventricular block. Therapies include beta-agonists, glucagon, and phosphodiesterase inhibitors. However, in beta-blocker poisoning where symptomatic bradycardia and hypotension are present, high-dose glucagon is considered the first-line antidote. Traditionally, antidotes for CCB overdose have included calcium, glucagon, adrenergic drugs, and amrinone. For cases of CCB poisoning where cardiotoxicity is evident, first-line therapy is a combination of calcium and epinephrine; high-dose insulin with supplemental dextrose and potassium therapy (HDIDK) is reserved for refractory cases. Health-system pharmacists should be aware that when these drugs are used as antidotes, higher than normal dosing is needed. CONCLUSION: Poisoning by beta-blockers or CCBs usually produces hypotension and bradycardia, which may be refractory to standard resuscitation measures. For cases of beta-blocker poisoning where symptomatic bradycardia and hypotension are present, high-dose glucagon is considered the first-line antidote. For cases of CCB poisoning where cardiotoxicity is evident, a combination of calcium and epinephrine should be used initially, reserving HDIDK for refractory cases.

Inotropic and vasoactive drug treatment of interleukin 2 induced hypotension in sheep.

The side effects associated with recombinant interleukin 2 administration, including systemic hypotension and a vascular leak syndrome, may limit therapy before reaching maximum doses of this innovative and promising treatment for cancer. In an attempt to reverse this hypotension without decreasing cardiac output and systemic oxygen delivery (DO2), we studied several inotropic agents, dobutamine, dopamine, amrinone, CaCl2, and a pure alpha-adrenergic vasoconstrictor, methoxamine. These were administered singly or in combination to sheep with chronically implanted arterial and pulmonary artery catheters following 24 h of 3 x 10(5) units/kg recombinant interleukin 2. Compared to baseline values, 24 h of recombinant interleukin 2 infusion caused a significant increase in cardiac output from 4.4 +/- 0.9 (SD) to 5.0 +/- 0.6 liters/min, a significant fall in systemic vascular resistance (SVR) from 21 +/- 7 to 15 +/- 5 units, a decrease in mean systemic blood pressure (SBP) from 88 +/- 9 to 78 +/- 6 mm Hg, and a decrease in left ventricular stroke work from 51.5 +/- 8 to 49 +/- 6 gram meters (P less than 0.05) without any change in DO2. Dopamine, dobutamine, and CaCl2 returned SBP to baseline values by increasing cardiac output without increasing SVR. Methoxamine increased SBP by increasing SVR, but cardiac output decreased significantly. A combination of 12 micrograms/kg/min of dopamine and 2 to 3 mg of methoxamine infused over 15 min resulted in an increase in SBP, cardiac output, and SVR to baseline values while maintaining DO2 and oxygen consumption (VO2). We suggest that this latter combination would be appropriate for clinical use since it returns physiological parameters to normal.

[Current approaches to intraoperative diagnosis and treatment of low cardiac output during cardiosurgical operations].

The paper deals with the development of a diagnostic and therapeutic algorithm of intraoperative heart failure during cardiosurgical operations on the basis of evaluation of systolic and diastolic functions of the left and right ventricles. The study included 101 patients with low cardiac output in the postperfusion period. All the patients suffered from coronary heart disease and they underwent myocardial revascularizing operations under extracorporeal circulation. In all the patients, in addition to traditional hemodynamic parameters (heart rate, blood pressure, central venous pressure), the functional status of the left and right ventricles was evaluated by transesophageal Doppler echocardiography (TED echoCG) and the thermodilution technique using a Swan-Ganz catheter having a prompt thermistor. Evaluating the diastolic and diastolic functions of the right and left ventricles makes it possible to identify 2 types of left and right ventricular failure: 1) that due to systolic dysfunction and 2) that due to concomitance of systolic and diastolic dysfunctions. Dobutrex (5-7.5 microg/kg/min) should be used in right ventricular systolic dysfunction. Amrinone (5-10 microg/kg/min) should be given to patients with concomitance of systolic and diastolic dysfunction; in this situation, a combination of dobutrex and nitroglycerin (100-150 ng/kg/min) may be used. The drugs of choice in impaired left ventricular systolic function are epinephrine (30-100 ng/kg/min), dopamine (5-10 microg/kg/min), or dobutrex (5-7.5 microg/kg/min). Their combination with sodium nitroprusside can enhance the efficiency of therapy. In patients with left ventricular failure caused by systolic and diastolic dysfunction, epinephrine, dopamine, or dobutrex may be combined with amrinone (5-10 microg/kg/min) or nitroglycerin (100-150 ng/kg/min).

Differential effects of amrinone and milrinone upon myocardial inflammatory signaling.

BACKGROUND: Mounting evidence links systemic and local inflammatory cytokine production to myocardial dysfunction and injury occurring during ischemia-reperfusion, cardiopulmonary bypass, and heart failure. Phosphodiesterase inhibitors (PDEIs), used frequently in these states, can modulate inflammatory signaling. The mechanisms for these effects are unclear. We therefore examined the effects of 2 commonly used PDEIs, amrinone and milrinone, on cardiac cell inflammatory responses. METHODS AND RESULTS: Primary rat cardiomyocyte cultures were treated with endotoxin (LPS) or tumor necrosis factor-alpha (TNF-alpha), alone or in the presence of clinically relevant concentrations of amrinone or milrinone. Regulation of nuclear factor-kappa B (NFkappaB), nitric oxide synthase and cyclooxygenase isoforms, and cytokine production were assessed by electrophoretic mobility shift assays, Western immunoblotting, and enzyme-linked immunoassays, respectively. Both LPS and TNF-alpha induced significant NFkappaB activation, cyclooxygenase-2 (COX-2) expression, and inducible NO synthase (iNOS) and cytokine production; with the exception of COX-2 expression, all were significantly reduced by amrinone, beginning at concentrations of 10 to 50 micro mol/L. In contrast, milrinone increased nuclear NFkappaB translocation, iNOS and COX-2 expression, and cardiomyocyte production of interleukin-1beta. Cell-permeable cAMP increased inflammatory gene expression, whereas cell-permeable cGMP had no effect, indicating that the effects of amrinone were not due to phosphodiesterase inhibition. Similar results were seen in macrophages and coronary vascular endothelial cells. CONCLUSIONS: Both amrinone and milrinone have significant effects on cardiac inflammatory signaling. Overall, amrinone reduces activation of the key transcription factor NFkappaB and limits the production of pro-inflammatory cytokines, whereas milrinone does not.