Positive Inotropic Substances Research Articles

Vasoactive agents to improve brain perfusion: pathophysiology and clinical utilization.

This review highlights the aspects of pathophysiology that make it difficult to predict the effects of any attempt to improve brain perfusion and reviews the options to improve brain perfusion according to the needs of an individual patient, focusing on the choice of a suitable threshold for cerebral perfusion pressure. Typically, vasopressors or vasodilators that do not directly influence the cerebral vascular bed are used to improve cerebral perfusion. Positive inotropic substances are rarely used, as the relationship between cardiac output and cerebral blood flow is complex and difficult to measure. Combining perfusion pressure monitoring with monitoring of brain metabolism or oxygenation to adapt cerebral perfusion to the needs of an individual patient has been disappointing. Recently, attempts to individualize perfusion pressure based on measurements of cerebrovascular autoregulation have shown promising results in the management of traumatic brain injury and during cardiac surgery. Currently, only preliminary data are available linking optimized cerebral perfusion to improved outcome. Optimizing cerebral perfusion remains a difficult goal. All our attempts to manipulate brain perfusion are influenced in an unpredictable manner by underlying diseases. Autoregulation-based strategies to individualize cerebral perfusion management warrant further investigation.

Adequate fluid resuscitation in septic shock with high catecholamine doses

Appropriate fluid resuscitation is a fundamental aspect for the hemodynamic management of septic shock patients and should ideally be achieved before vasopressors and positive inotropic substances are administered. The development of hemodynamic monitoring has revealed that in some cases patients had been improperly treated with high-dose catecholamines for initially insufficient fluid resuscitation. The aim of this study was to show that in some cases it is possible to actively reduce catecholamines by a volume challenge adapted according to the individual patient needs. In this retrospective observational study 29 patients with septic shock in a surgical intensive care unit (ICU) at a university hospital (17 male, 12 female, mean age 71 ± 10 years) on high-dose catecholamines (median values norepinephrine 0.204µg/kg body weight/min, dobutamine 3.876µg/kg/min and epinephrine 0.025µg/kg/min, ranging up to 0.810µg/kg/min, 22.222µg/kg/min and 0.407µg/kg/min in 28, 20 and 17 patients, respectively) were analyzed. The extremities of the patients were initially cold with a mottled marbled appearance whereas the mean arterial pressure (MAP) was ≥ 65mmHg. The median central venous pressure (CVP) was 17mmHg (range 55-34mmHg) and the mean lactate concentration was 2.78mmol/l (range 0.93-10.67mmol/l). The standard therapy concept consisted of a forced volume challenge combined with active reduction of catecholamines to achieve an adequate fluid loading status, guided by the passive leg raising test (PLR), clinical signs and in 19 cases by hemodynamic monitoring (pulmonary artery catheter Vigilance II(™) n = 10, FloTrac(™), Vigileo(™) n = 9 andPreSep(™) n = 5; Edwards Life Sciences). The forced volume challenge was stopped after clinical improvement with rewarmed extremities, increasing diuresis volumes and lack of improvement by PLR. Catecholamine doses could be significantly reduced in all patients: norepinephrine to 0µg/kg/min, dobutamine to 1.852µg/kg/min and epinephrine to 0µg/kg/min (up to 0.133µg/kg/min, 6.289µg/kg/min and 0.091µg/kg/min, respectively, p < 0.05 Wilcoxon signed rank test). Volume challenge test: + 4,500ml Ringer solution (range 0-24,000ml) and 1,000ml hydroxyethyl starch (range 0-2,500ml) and mean fluid balance + 6,465ml (range + 2,040ml to + 27,255ml). The median weaning time from catecholamineswas 12h (range 4-43h). After treatment all patients showed rewarmed extremities and a decrease in mean lactate levels from 2.78mmol/l (range 0.93-10.67mmol/l) to 2.05mmol/l (range 0.7-5.4mmol/l). The measured hemodynamic constellations showed clear interindividual differences but no cardiac deterioration occurred. The median oxygenation index (paO2/FiO2) showed a statistically insignificant change from 264mmHg (range 75-418mmHg) to 250mmHg (range 120-467mmHg). Of the patients 20 survived and 9 died. It is possible to wean a substantial proportion of septic shock patients from high-dose catecholamines in combination with a needs-adapted forced volume challenge test. The importance of appropriate fluid loading prior to the use of high catecholamine doses should be a main subject of discussion in patients with severe septic shock and was confirmed in this study. This should be oriented to clinical and if possible, hemodynamic parameters and should not be underestimated.

Levosimendan, a New Inotropic and Vasodilator Agent

Several clinical studies suggest substantial limitations of currently available positive inotropic substances, including beta1-adrenoceptor agonists and phosphodiesterase III inhibitors in the short- and long-term treatment of heart failure. The reasons for these detrimental effects are related to the mechanism of action of these drugs, including increases in intracellular Ca2+ with subsequent increases in myocardial oxygen demand and arrhythmogenesis. Levosimendan, a myofilament Ca2+ sensitizer with inotropic effects, increases myocardial performance without substantial changes in oxygen consumption and with neutral effects on heart rhythm. In addition, levosimendan has vasodilatory effects that are achieved by stimulation of adenosine triphosphate-dependent potassium channels. This action may be of specific interest in the setting of myocardial ischemia. To date, levosimendan is approved in 31 countries worldwide, and more patients with heart failure have participated in randomized controlled trials with levosimendan than with any other intravenous inotropic agent.

New Inotropic Agent-Levosimendan

Several clinical studies suggest substantial limitations of currently available positive inotropic substances, including beta1-adrenoceptor agonists and phosphodiesterase III inhibitors. Levosimendan, a myofilament calcium sensitizer with inotropic effects, increases myocardial performance without substantial changes in oxygen consumption and with neutral effects on heart rhythm. In addition, levosimendan has vasodilatory effects that are achieved by stimulation of adenosine triphosphate-dependent potassium channels. This review article briefly discusses the pharmacology of levosimendan and evaluates current available evidence to assess the safety and efficacy of levosimendan. (Korean J Anesthesiol 2006; 51: 519~27)

Modification of the terminal residue of apelin-13 antagonizes its hypotensive action.

The apelin peptide is the endogenous ligand for the apelin G protein-coupled receptor. The distribution of the apelin peptides and receptor are widespread in the central nervous system and periphery, with reported roles in the hypothalamic-pituitary-adrenal axis, blood pressure regulation and as one of the most potent positive inotropic substances yet identified. In this report, we show that in native tissues preproapelin exists as a dimer. Dimeric preproapelin was reduced to monomers by dithiothreitol treatment, indicating disulfide linkages. To evaluate the role of the carboxyl-terminal phenylalanine in the hypotensive action of apelin-13, analogs were generated and tested for their role on blood pressure regulation. Injections of apelin-13 and apelin-12 (15 microg/kg) into spontaneously hypertensive rats lowered systolic and diastolic blood pressure to result in decreases of approximately 60% and 15% in mean arterial blood pressure, respectively. Apelin-13(13[D-Phe]) treatment did not differ from apelin-13 in either efficacy or duration of effect, whereas apelin-13(F13A) revealed a loss of function. However, concomitant administration of apelin-13(F13A) (30 microg/kg) blocked hypotensive effects of apelin-13 (15 microg/kg), which revealed that apelin-13(F13A) behaved as an apelin-specific antagonist.

Regulation of the mitochondrial ATP-synthase in health and disease

In most tissues the mitochondrial ATP-synthase plays a central role by synthesizing the bulk of ATP. According to the classical theory of respiratory control, flux through this enzyme is solely determined by substrate (ADP) concentration while the enzyme has a fixed capacity. However, in different cell types such as rat cardiomyocytes and neurons, dog heart, human fibroblasts, and skeletal and heart muscle from children, it has been shown that active regulation of the mitochondrial ATP-synthase in response to cellular energy demand exists. For example, in rat cardiomyocytes the mitochondrial ATP-synthase activity is down-regulated in response to anoxia or mitochondrial uncoupling. By this mechanism cellular ATP is conserved, as under these conditions the ATP-synthase would work in reverse and hydrolyze ATP. When cardiomyocytes are stimulated to contract, ATP-synthase activity is up-regulated in line with the increased energy demand. Preincubation of the cardiomyocytes with positive inotropic substances results in further up-regulation of the ATP-synthase. By blocking calcium transport, it has been shown that the up-regulation of the enzyme is calcium-dependent. On a molecular level, up-regulation is probably mediated by the calcium-binding inhibitor protein (CaBI) and down-regulation via the inhibitor protein IF 1. The ATP-synthase system is disturbed under several pathophysiological conditions. First, mutations can cause a primary defect in the mitochondrial ATP-synthase (respiratory chain defect). Furthermore, secondary defects of the ATP-synthase occur. In rat models abnormalities of ATP-synthase can be detected in different types of cardiomyopathy/heart hypertrophy. The changes are reversible in response to treatment of the heart diseases. Abnormalities of the ATP-synthase system can be observed in fibroblasts from patients with neuronal ceroidlipofuscinoses. Toxic metabolites accumulating in methylmalonic acidurias can inhibit ATP-synthase. When neurons are incubated with 3-OH glutarate — a substance accumulating in glutaric aciduria I—as a model for glutaric aciduria I, ATP-synthase activity is compromised. This lack of energy may lead to ‘slow onset’ excitotoxicity and finally cell death. Cells can be rescued by adding creatine to the incubation medium. In d-2-hydroxyglutaric aciduria, inhibition of the ATP-synthase has been observed.

Apelin, the novel endogenous ligand of the orphan receptor APJ, regulates cardiac contractility.

The orphan receptor APJ and its recently identified endogenous ligand, apelin, exhibit high levels of mRNA expression in the heart. However, the functional importance of apelin in the cardiovascular system is not known. In isolated perfused rat hearts, infusion of apelin (0.01 to 10 nmol/L) induced a dose-dependent positive inotropic effect (EC50: 33.1+/-1.5 pmol/L). Moreover, preload-induced increase in dP/dt(max) was significantly augmented (P<0.05) in the presence of apelin. Inhibition of phospholipase C (PLC) with U-73122 and suppression of protein kinase C (PKC) with staurosporine and GF-109203X markedly attenuated the apelin-induced inotropic effect (P<0.001). In addition, zoniporide, a selective inhibitor of Na+-H+ exchange (NHE) isoform-1, and KB-R7943, a potent inhibitor of the reverse mode Na+-Ca2+ exchange (NCX), significantly suppressed the response to apelin (P<0.001). Perforated patch-clamp recordings showed that apelin did not modulate L-type Ca2+ current or voltage-activated K+ currents in isolated adult rat ventricular myocytes. Apelin mRNA was markedly downregulated in cultured neonatal rat ventricular myocytes subjected to mechanical stretch and in vivo in two models of chronic ventricular pressure overload. The present study provides the first evidence for the physiological significance of apelin in the heart. Our results show that apelin is one of the most potent endogenous positive inotropic substances yet identified and that the inotropic response to apelin may involve activation of PLC, PKC, and sarcolemmal NHE and NCX.

Altered responsiveness to endothelin-1 of myocardium from pacing-induced heart failure model in the dog.

In congestive heart failure, in addition to a compensatory increase in neurohumoral activation, there is an increase in the endothelial-derived vasoconstrictive and positive inotropic substance, endothelin. Whether downregulation of the cardiac inotropic effects of this endothelial-derived substance occurs, as has been shown to occur with neurohumoral beta- and alpha-adrenergic agonists, remains unknown. In this study we investigated the effects of endothelin-1 [dose-response curve (10(-11) to 10(-7) M)] on the contractile characteristics of isolated papillary muscles from normal dogs and from dogs with heart failure induced by pacing overdrive, with or without removing endocardial endothelium from the papillary muscles. Endothelin-1 caused a similar absolute increase in myocardial contractile indices in all four groups, except for shortening, which increased more in muscles with heart failure without endocardial endothelium. However, in muscles with an intact endocardial endothelium, the relative increase was greater in muscles from pacing overdrive dogs (failing) as compared with normal dogs (tension increase of 110% vs. 53%, p < 0.01 and shortening increase of 127% vs. 24%, p < 0.01). Also, failing muscles with intact endocardial endothelium began responding to endothelin-1 at lower endothelin-1 concentrations (10(-10) vs. 10(-9) M) than normal muscles with intact endocardial endothelium. Endocardial endothelial removal increased the contractile effects of endothelin-1, whether this was done in normal or failing myocardium. This study thus indicates that, in contrast to other positive inotropic substances, in this model of heart failure there is an increase in sensitivity and relative response to endothelin-1. It also indicates that although endocardial endothelial removal increases the relative effects of endothelin-1 in both normal and failing myocardium, the increased responsiveness of failing myocardium is not endocardial endothelial dependent.

Comparison of hypervolemic hemodilution concepts in acute stroke

Patients suffering from acute ischemic stroke have impaired cerebral autoregulation. For this reason, the perfusion of the penumbra depends directly on BP and CO. The CO can be increased by hypervolemic hemodilution and administration of positive inotropic drugs. In the present study, we examined the effect of different therapy protocols on hemodynamics in three patient groups. In patients with no manifest cardiac insufficiency, suffering from non­ acute cerebrovascular diseases (group 1, n=6) we carried out a hypervolemic hemodilution with an initial loading dose. In a second group of patients (group 2, n=6), suffering from an acute stroke and limited cardiac capacity, we combined hypervolemic hemodilution with administration of digitalis. In a third group of patients, suffering from an acute stroke, without manifest cardiac insufficiency, we combined hypervolemic hemodilution with the administration of sympathomimetics (group 3, n=6). Group 1 showed a rapid, 15% increase in CO that lasted approximately 3 hours. Group 2 showed a slow improvement in CO, which became apparent during the course of the therapy. Group 3 showed a rapid and lasting increase in CO of more than 30% which correlated closely with the administered dopamine/dobutamine dose. Hypervolemic hemodilution alone does not result in a rapid and long­ lasting increase of CO, particularly not in patients with myocardial insufficiency. To improve the hemodynamic status of acute stroke patients, the administration of positive inotropic substances is a viable alternative.

4-(4-Guanidinobenzoyl)-2-imidazolones and related compounds: phosphodiesterase inhibitors and novel cardiotonics with combined histamine H2 receptor agonist and PDE III inhibitor activity.

A series of new positive inotropic agents was synthesized with the aim of combining the pharmacophores of the imidazolone-type phosphodiesterase (PDE) inhibitor enoximone and guanidine-type histamine H2 receptor agonists such as arpromidine. All compounds are para-substituted 4-benzoyl-5-alkyl-2-imidazolones. H2 agonism was incorporated by p-(hetero)arylalkyl substituents, in particular by an imidazolylpropyl guanidine group. In addition analogous ureas, cyanoguanidines, alkyl guanidine carboxylates, and amides were prepared. These functional groups were either directly attached to the phenyl ring or linked by an appropriate spacer. The compounds were screened for positive inotropic activity in the isolated electrically stimulated guinea pig papillary muscle and for inhibition of PDE III (cGMP-inhibited cAMP PDE, isolated from guinea pig heart). The cardiotonics obtained proved to be either PDE III inhibitors, some of them surmounting up to 3-fold the potency of enoximone, or pharmacological hybrids combining both PDE III inhibitor and histamine H2 receptor agonist activities. These hybrids were the most potent positive inotropic substances at the papillary muscle, probably due to their synergistic mechanism of action. The participation of histamine H2 receptors could be demonstrated in the papillary muscle preparation by pretreatment with the H2 antagonist famotidine (10 microM) as well as by further pharmacological experiments using isolated perfused hearts of guinea pigs and rats, isolated guinea pig right atria, adenylyl cyclase and H2 receptor binding assays. At equieffective concentrations the moderate PDE III inhibitor and histamine H2 agonist N1-(4-[(1,3-dihydro-5-methyl-2-oxo-3H-imidazol-4-yl)-carbonyl]phenyl)-N2 - [3-(1H-imidazol-4-yl)propyl]guanidine 65 and the 5-ethyl homologue 66 were about 2 and 10 times more potent than enoximone at the papillary muscle. Moreover, both compounds produced a 2.5-fold higher maximal response than the reference compound.

Endogenous Positive Inotropic Substance (EPIS) in the porcine heart lacks digitalislike cardiotoxicity: Jagdish C. Khatter and Moses Agbanyo. Cardiovascular Section, Departments of Medicine and Pharmacology, University of Manitoba, Winnipeg Canada R3E OZ3

Endogenous Positive Inotropic Substance (EPIS) in the porcine heart lacks digitalislike cardiotoxicity: Jagdish C. Khatter and Moses Agbanyo. Cardiovascular Section, Departments of Medicine and Pharmacology, University of Manitoba, Winnipeg Canada R3E OZ3

A novel positive inotropic substance enhances contractility without increasing the Ca 2+ transient in rat myocardium

We have investigated the mechanism of action of a novel positive inotropic agent, the thiadiazinone derivative 5-(1-(3,4-dimethoxybenzoyl)-1,2,3,4-tetrahydrochinolin-6-yl)-6-methyl-3,6-dihydro-2H-1,3,4-thiadiazin-2-on (EMD 53998). This subsance inhibits phosphodiesterase III and, in skinned myocardial fibers, it increases myofilament sensitivity to Ca 2+. However the effects of EMD 53998 on intact myocardial preparations are still undefined. In isolated rat hearts EMD 53998 (0.5 to 5 μ m) had a dose-dependent effect to increase left ventricular systolic pressure. In isolated left ventricular myocytes loaded with the ester derivative of the Ca 2+ probe indo-1, EMD 53998 (0.5 to 5 μ m) enhanced twitch amplitude without increasing the associated indo-1 transient. The myofilament responsiveness to Ca 2+ was assessed as the relationship between twitch and the indo-1 transient amplitudes as the latter is varied by altering the bathing [Ca 2+], or stimulation pattern. EMD 53998 reversibly shifted this relationship to the left which indicates that for indo-1 transients of the same amplitude in the absence and presence of the drug, twitch amplitude was enhanched by EMD 53998. In isolated myocytes studied in the absence of electrical stimulation, EMD 53998. (1.5 to 5 μ m) had a concentration-dependent effect to markedly and reversibly decrease cell length without increasing indo-1 fluorescence ratio. Thus, the cellular basis for the positive inotropic action of EMD 53998 in rat myocardium is related to the unique effect of this substance to enhance myofilament responsiveness to Ca 2+ and not to an increase in the indo-1 transient amplitude.

Influence of the Positive Inotropic Substance Pimobendan (UD-CG 115 BS) on Contractile Economy of Guinea Pig Papillary μscles

Influence of the Positive Inotropic Substance Pimobendan (UD-CG 115 BS) on Contractile Economy of Guinea Pig Papillary μscles

Present Use of Positive Inotropic Drugs in Heart Failure

Cardiac failure is treated with increasing success by phosphodicsterase-III (PDE-III) inhibitors such as amrinone. milrinone. and enoximone. While relatively pure positive inotropic substances (e.g., dopamine and dobutamine) are limited by tolerance development and MVO2 increase, the efficacy of PDE inhibitors is maintained by avoiding catecholamine and β-reeeptors. They have positive inotropic, positive lusitropie. and vasodilatatory properties: myoeardial oxygen consumption remains unaltered. PDE-III inhibitors act by selectively inhibiting PDE-III. leading to an increased cAMP concentration in myoeardial and smooth muscle cells. In contrast, forskolin increases intracellular cAMP by activation of adenylate cyclase. It could be shown that parenteral administration of the PDE inhibitors sulmazole. amrinone. and enoximone resulted in preload and after-load reduction due to vasodilation with concomitant decrease of peripheral and pulmonary vascular resistance: they also led to elevated cardiac output and ejection fraction as well as a significant increase in dp/dtmav. while left ventricular filling pressures were markedly lowered. Pulmonary pressure values fell significantly, whereas heart rate and myoeardial oxygen consumption showed no clinically relevant alterations. In patients with angiographi-cally documented coronary artery disease, the anti-is-chemic efficacy of enoximone could be proven both during exercise and stress pacing. The decrease of the pathologically elevated pulmonary pressures during ischemia was accompanied by reduced ST-segment depression following enoximone without changing MVO2 significantly. First tests after intracoronary application of enoximone confirmed its direct myoeardial efficacy, indicating its positive inotropic and lusitropie properties. Thus, patients in cardiac failure have useful therapeutic alternatives at their disposal when taking PDF. inhibitors. The anti-isehemic properties of these drugs need further evaluation

Present Use of Positive Inotropic Drugs in Heart Failure

Cardiac failure is treated with increasing success by phosphodiesterase-III (PDE-III) inhibitors such as amrinone, milrinone, and enoximone. While relatively pure positive inotropic substances (e.g., dopamine and dobutamine) are limited by tolerance development and MVO2 increase, the efficacy of PDE inhibitors is maintained by avoiding catecholamine and beta-receptors. They have positive inotropic, positive lusitropic, and vasodilatatory properties; myocardial oxygen consumption remains unaltered. PDE-III inhibitors act by selectively inhibiting PDE-III, leading to an increased cAMP concentration in myocardial and smooth muscle cells. In contrast, forskolin increases intracellular cAMP by activation of adenylate cyclase. It could be shown that parenteral administration of the PDE inhibitors sulmazole, amrinone, and enoximone resulted in preload and afterload reduction due to vasodilation with concomitant decrease of peripheral and pulmonary vascular resistance; they also led to elevated cardiac output and ejection fraction as well as a significant increase in dp/dtmax, while left ventricular filling pressures were markedly lowered. Pulmonary pressure values fell significantly, whereas heart rate and myocardial oxygen consumption showed no clinically relevant alterations. In patients with angiographically documented coronary artery disease, the anti-ischemic efficacy of enoximone could be proven both during exercise and stress pacing. The decrease of the pathologically elevated pulmonary pressures during ischemia was accompanied by reduced ST-segment depression following enoximone without changing MVO2 significantly. First tests after intracoronary application of enoximone confirmed its direct myocardial efficacy, indicating its positive inotropic and lusitropic properties. Thus, patients in cardiac failure have useful therapeutic alternatives at their disposal when taking PDE inhibitors. The anti-ischemic properties of these drugs need further evaluation.

ChemInform Abstract: Synthesis of Positive Inotropic Substances: Aryloxyalkylguanidines.

ChemInformVolume 19, Issue 43 Heterocyclic Compounds ChemInform Abstract: Synthesis of Positive Inotropic Substances: Aryloxyalkylguanidines. A. BUSCHAUER, A. BUSCHAUER Inst. Pharm., FU, D-1000 Berlin 33Search for more papers by this author A. BUSCHAUER, A. BUSCHAUER Inst. Pharm., FU, D-1000 Berlin 33Search for more papers by this author First published: October 25, 1988 https://doi.org/10.1002/chin.198843215Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat No abstract is available for this article. Volume19, Issue43October 25, 1988 RelatedInformation

The effectiveness of inotropic agents in isolated cardiac preparations from the human heart

This review analyses the present knowledge on differences in human and animal heart preparations in respect to positive inotropic stimulation. The pharmacological effects of new positive inotropic drugs usually are evaluated in cardiac preparations from healthy and young animals. Human myocardium, especially from patients with heart failure has, however, distinctly different properties in respect to the positive inotropic effectiveness of several agents. This fact prohibits the extrapolation of results of experiments in laboratory animals to the diseased human heart. The partial ineffectiveness of several established positive inotropic substances in papillary muscles from failing human hearts indicates a membrane defect not present in healthy animal myocardium.

Individualized Care in Patients with Chronic Congestive Heart Failure

Based on our experience with the prospective follow-up study in a group of patients (n = 21) with congestive heart failure (CHF) (NYHA III n = 10, NYHA IV n = 11) and left ventricular ejection fraction below 30%, who were referred to our ordinary care unit by their family physicians after an initial work-up, we investigated the impact of a special treatment program in 25 patients with similar CHF despite therapy (60 +/- 4 years, NYHA III n = 11, NYHA IV n = 14, LVEF less than 30%, 17 +/- 3%). The program focused on three issues: (1) individualized medical therapy of CHF, (2) antiarrhythmic treatment and close follow-up visits, and (3) continuous education of patients and physicians in order to improve treatment compliance and the early management of complications. Medical treatment was based on diuretic and vasodilator therapy in all the patients, while positive inotropic substances including digoxin were given selectively. Vasodilator treatment was started with prazosin in 22 patients and with ACE inhibitors in three patients with low serum sodium. Fifty-five percent of the patients on prazosin had to be changed over to ACE inhibitors. Amiodarone was used as first line drug to treat symptomatic ventricular tachycardia in two patients and two survivors of ventricular fibrillation.(ABSTRACT TRUNCATED AT 250 WORDS)

Reduced positive inotropic effects in diseased human ventricular myocardium

In isolated contracting human ventricular myocardium taken from patients undergoing mitral valve replacement the positive inotropic effects of calcium, isoprenaline, dobutamine, dopamine, histamine, milrinone, isobutylmethylxanthine, and theophylline were determined. Calcium (15 mmol X litre-1) produced an increase in force of contraction similar to that of a maximal effective concentration of ouabain (1 X 10(-7) mol X litre-1); significantly lower maximal effects were measured with all the other positive inotropic compounds tested. The addition of these positive inotropic substances after a stable maximum effect with ouabain (1 X 10(-7) mol X litre-1) had been reached increased the incidence of toxicity without producing any further inotropic effects. These results suggest that inotropic substances acting through cyclic adenosine monophosphate give less than the maximum inotropic response in isolated muscle from diseased human hearts, which is not additive to the maximal ouabain induced inotropy.

Assessment of myocardial function by calculation of two energetic parameters from pressure-volume relations and wall thickness in human ventricles.

For defining myocardial performance in chronic cardiac diseases and during acute pharmacological interventions we created a new index of performance based on myocardial mechanical and energetic counterparts. From angiocardiographic pressure-volume data the pressure-volume integral is analyzed and divided by left ventricular muscle mass, yielding work done by a unit of myocardium (E1). From pressure-volume data the stress-time integral integral of sigma.t is evaluated by using an ellipsoidal calculation model. In order to compare E1 with the integral of sigma.t the integral of sigma.t is transformed into energetic units on the basis of new physiologic myothermal findings (E2). Then, the sum of E1 and E2 (i.e.,the maximum of mechanical performance), the ratio of E1 to the sum of E1 and E2 can be defined (i.e., the myocardial work related to the energy consumed during a contraction). By calculating E1 and E2, we are able to analyze the myocardial efficiency of work production. These parameters are proposed for judging the myocardial performance and efficiency in congestive heart failure and the effects of positive inotropic substances and vasodilators.