Advances in myocardiology最新文献

Inosine was administered as a continuous intravenous infusion (100 mg/kg per hr) in rats treated with isoproterenol (25 mg/kg, s.c.). After 24 hr, the isoproterenol-induced decline in myocardial ATP and total adenine nucleotides was attenuated by inosine. Infusion of ribose (100 mg/kg per hr) had a similar cardioprotective influence. The effect of inosine may have been due to the incorporation into cardiac adenine nucleotides of the degradation products of inosine, either of the ribose moiety via the de novo synthesis pathway or of hypoxanthine via the salvage pathway utilizing 5-phosphoribosyl-1-pyrophosphate. To decide this, [8-(14)C]inosine was injected intravenously 4 hr after administration of isoproterenol. Its incorporation into myocardial adenine nucleotides was enhanced. Furthermore, the effect of inosine on the de novo synthesis of adenine nucleotides in normal and isoproterenol-stimulated hearts was studied and compared to that of ribose. The normal rate was attenuated and the isoproterenol-elicited increase was reduced by inosine. In contrast, ribose stimulated adenine nucleotide biosynthesis in the control rat heart and potentiated the isoproterenol-induced enhancement. These results indicate that the effect of inosine is not due to the metabolism of ribose-1-phosphate via the pentose phosphate and the de novo synthesis pathways, but rather to the 5-phosphoribosyl-1-pyrophosphate-dependent salvage of hypoxanthine. Obviously, this pathway is of such a magnitude that the isoproterenol-evoked decline in myocardial adenine nucleotide levels is attenuated.

This study compares the effect of three anesthetics on infarct size and regional myocardial blood flow. The anesthetics--fentanyl, Na-pentobarbital, and halothane--differ in their effects on such hemodynamic parameters as blood pressure and heart rate. The mean blood pressure during ligation was 144/91 mm Hg with fentanyl, 141/104 mm Hg with Na-pentobarbital, and 113/82 mm Hg with halothane. The heart rate was 98, 146, and 135 beats/min, respectively. The most significant finding of our study following 90 min of reflow was the infarct size of 26 +/- 8% of the occluded vascular bed under the influence of fentanyl; infarct size under Na-pentobarbital and halothane was 32 +/- 5 and 47 +/- 7%, respectively. The regional flow in relation to the zones of the infarction also differed among the groups. Regional flow under Na-pentobarbital was 24 +/- 6% of normal flow at 90 min of occlusion in the infarcted tissue; regional flow under fentanyl and halothane was 9 +/- 2 and 5 +/- 1%, respectively. The flow in the nitroblue-tetrazolium-staining zone of the occluded vascular bed was 69 +/- 11% (fentanyl), 77 +/- 11% (Na-pentobarbital), and 83 +/- 25% (halothane). It is concluded that anesthetics may well influence infarct size and the outcome of a myocardial infarction following a 90-min ischemia. Hemodynamic effects induced by these anesthetics may well be responsible for this outcome and could be determinants of infarct size, possibly by influencing collateral flow.

Oxfenicine (S-4-hydroxyphenylglycine) is a cardioselective inhibitor of long-chain fatty acid oxidation. In anesthetized dogs, oxfenicine (3.3 mg/kg, i.v.) increased myocardial blood flow by 33% under normal conditions and by 71% during isoprenaline infusion, but produced no other hemodynamic changes. Similar results were obtained with two other inhibitors of fatty acid oxidation, 2-bromopalmitate and 2-tetradecylglycidate. Chronic administration of oxfenicine to dogs for 1 year produced dose-related, nonpathological increases in relative heart weight (up to 85% at 750 mg/kg per day). Smaller effects (up to 30% at 900 mg/kg per day) were observed in a similar study in rats. Cardiac hypertrophy has previously been reported in rodents treated with 2-tetradecylglycidate. Moreover, cardiomegaly is frequently observed in cases of carnitine deficiency. We therefore suggest that coronary hyperemia and cardiac hypertrophy following either inhibition of fatty acid oxidation or an increase in cardiac work load may be adaptive changes triggered by a common mechanism-namely, a fall in cytosolic phosphorylation potential. In support of this, oxfenicine decreased the phosphocreatine/creatine ratio in rat hearts perfused in the presence of oleate. These findings suggest the possibility that metabolic abnormalities may provide the key to many idiopathic cardiomyopathies of uncertain origin.

We have assessed the ability of several of the main groups of antiarrhythmic agents to modify the incidence of reperfusion-induced ventricular fibrillation in the isolated working rat heart preparation with transient coronary artery occlusion. Hearts were perfused with Krebs-Henseleit medium containing 5 microM epinephrine to provide some level of exogenous catecholamine support. Compounds selected were: the fast sodium channel inhibitors lignocaine (1 and 10 microM) and prenylamine (4 microM) (the latter also possessing slow calcium channel antagonistic actions); the beta-adrenergic blocking agents oxprenolol (1.2 microM), timolol (0.13 microM), metoprolol (1.0 microM), and acebutolol (5.6 microM); and the slow calcium channel antagonist nifedipine (0.05 and 0.5 microM). After 15 min of coronary artery occlusion, over 90% of control hearts fibrillated 30-60 sec after the onset of reperfusion. Drugs reduced this to the following: prenylamine, 0% (p less than 0.001); 1 microM lignocaine, 83%; 10 microM lignocaine, 33% (p less than 0.01); oxprenolol, 92% (NS); timolol, 92% (NS); metoprolol, 42% (p less than 0.01); acebutolol, 67% (p less than 0.05); 0.05 microM nifedipine, 83% (NS); and 0.5 microM nifedipine, 67% (NS). Thus, inhibition of the fast inward sodium channel with agents such as prenylamine and lignocaine, (when begun before coronary-artery occlusion) offers maximal protection against reperfusion-induced ventricular fibrillation, while beta-blockade with timolol and oxprenolol and slow calcium channel inhibition with nifedipine do not offer any significant protection. The beta-blocking agents metoprolol and acebutolol produce a partial reduction that may be due to a membrane-stabilizing action, rather than to beta-blockade.

Rates of lipolysis in isolated myocardial cells (myocytes) from rat heart, as measured by the release of glycerol and a reduction in endogenous triacylglycerols, can be stimulated by isoproterenol. Myocyte preparations were calcium-tolerant and were quiescent, even in the presence of isoproterenol, so the stimulation of lipolysis by isoproterenol cannot be secondary to a physiological (inotropic) response. N6-Phenylisopropyladenosine did not reduce isoproterenol-stimulated rates of lipolysis. Increasing the calcium concentration in the incubation medium from 0.75 to 3 mM did not increase the basal output of glycerol. Furthermore, incubation of calcium-tolerant myocytes in the absence of calcium had no effect on either basal or isoproterenol-stimulated rates of lipolysis. Therefore, calcium ions must not influence the lipolytic process directly, and so the calcium dependency for lipolysis observed with perfused heart preparations must reflect the effect of calcium on the contractile performance of the heart, which only secondarily produced a change in rates of lipolysis.

To obtain further knowledge of the antigen-antibody system, immunochemical characterization of the adenine nucleotide translocator was achieved by crossed immunoelectrophoresis, immunoreplica technique, radioimmunoassay, immunoabsorption studies, and nucleotide-transport measurements. Sera of 18 patients with proven congestive cardiomyopathy (CCM) were tested. On the adenine nucleotide translocator (ANT) from heart, kidney, and liver, organ-specific antigenic determinants were demonstrable, although a partial cross-reactivity existed. Conformation specificity was also confirmed by experimental studies. Of the patients studied, 17 of 18 with CCM showed a significant binding to the heart ANT, while no or a lower binding was seen on the kidney/liver ANT. In CCM, a correlation exists between the ejection fraction and the anti-ANT titer. These results give new evidence for autoimmunological events in MC and CCM and indicate a possible causal relationship between these two diseases.

BAY K 8644 [methyl 1,4-dihydro-2,6-dimethyl-3-nitro-4-(2-trifluoromethyl -phenyl)-pyridine-5-carboxylate] is a nifedipine-like 1,4-dihydropyridine (DHP). In contrast to the well-known calcium antagonistic DHPs, it has vasoconstricting and positive inotropic properties. In the pentobarbital-anesthetized dog, it increases blood pressure, peripheral resistance, and left ventricular (dP/dt)max dose-dependently from 3 to 100 micrograms/kg i.v. If the vagus is blocked, heart rate is unchanged. In the isolated isovolumic perfused guinea pig heart, BAY K 8644 has positive inotropic and coronary constricting actions from 10(-9) mole/liter. At 10 times higher concentrations, this compound also increases the heart rate up to 20%. BAY K 8644 has no effect on rabbit aortic strip at physiological K+ concentrations, but potentiates the K+ -induced contraction of the strip. In the partially depolarized aortic strip (18 mM K+), BAY K 8644 induces concentration-dependent contractions, which are competitively inhibited by the calcium-antagonistic DHP nifedipine. Chemically different calcium antagonists such as verapamil or diltiazem inhibit the BAY-K-8644-induced contractions noncompetitively. These results indicate that a specific DHP receptor exists, which binds nifedipine and BAY K 8644. In contrast to the calcium-antagonistic DHPs like nifedipine, BAY K 8644 increases the calcium influx into the cell.

Tritiated 1,4-dihydropyridines (nimodipine, nitrendipine, nifedipine, PN 200-110) and [3H]D-cis-diltiazem as well as [3H]verapamil were employed to directly identify calcium channels in membranes for excitable tissues. The channels, when probed with 1,4-dihydropyridines, exhibit the following properties: 1,4-Dihydropyridine calcium channel blockers bind in a temperature-dependent, reversible manner and with high affinity (dissociation constants 0.2-2 nM at 37 degrees C) to a finite number of sites. For chiral 1,4-dihydropyridines, the binding is stereoselective. Hill slopes of approximately 1.0 are observed. In brain, heart, and solubilized skeletal-muscle membranes, an absolute requirement for certain divalent cations exists in order to bind the ligands with high affinity. Cooperativity (negative and positive) between Me2+ and 1,4-dihydropyridine binding sites is observed. 1,4-Dihydropyridine binding sites are down-regulated in a complex manner by the optically pure enantiomers of D-600 and verapamil. These channel blockers induce, to a different extent, a low-affinity state of the 1,4-dihydropyridine binding site. It is postulated that this allosteric site, at which these blockers act, is closely coupled to the 1,4-dihydropyridine binding site and that a spectrum of compounds exists that differ in their affinity as well as their intrinsic activity to induce the down-regulation. The 1,4-dihydropyridine binding sites are up-regulated by D-cis-diltiazem and KB-944. The up-regulation is temperature-dependent and induces a high-affinity state for 1,4-dihydropyridine channel blockers, accompanied by distinct alterations of the kinetics as well as the pharmacological profile of the 1,4-dihydropyridine binding sites. Complex interactions exist between the channel blockers that induce up-regulation and those that induce down-regulation of the binding. For a given radiolabeled 1,4-dihydropyridine, a tissue-specific (but not species-specific) equilibrium binding dissociation constant is observed. Thus, all heart (human, rat, guinea pig, frog, bovine) have the same KD (0.25 nM at 37 degrees C) for, [3H]nimodipine. The same is observed for brain (KD = 0.5 nM) and for skeletal muscle (KD = 1-2 nM). Three subtypes of channels can be distinguished on the basis of the KD and the tissue-specific up-regulation by D-cis-diltiazem. Subtype-selective drugs exist; e.g., AQA 39 is an inhibitor of [3H]nimodipine binding at skeletal-muscle calcium channels, but not at brain channels. Despite their different pharmacological and kinetic profiles, calcium channels in skeletal muscle and brain have the same molecular size (Mr) when probed by radiation inactivation.(ABSTRACT TRUNCATED AT 400 WORDS)

Neutrophil infiltration of the myocardium is an important component of such diverse disease entities as myocarditis, ischemia, and ischemia-reperfusion injury. We have hypothesized that activated neutrophils are capable of disrupting myocardial function via an oxygen free-radical mechanism. Human neutrophils activated with phorbol myristate acetate disrupted calcium transport by canine cardiac sarcoplasmic reticulum, and this process was inhibited by a combination of superoxide dismutase and catalase. In addition, the activated neutrophil system was also inhibited by the combination of cyclooxygenase inhibitors (ibuprofen and indomethacin) and catalase and accelerated by MK-447. These results incriminate both hydrogen peroxide and the hydroxyl radical as mediators of neutrophil-induced myocardial dysfunction. A test of this hypothesis in vivo was performed by neutrophil-depleting dogs with anti-canine leukocyte antisera prior to coronary artery ligation. Following 6 hr of reperfusion, there was a 43% reduction in infarct size compared to non-immune-sera-injected animals. We conclude that oxygen free radicals generated by neutrophils are capable of inducing significant myocardial injury and play an important role in the pathophysiology of ischemia reperfusion injury.

In isolated coronary-ligated rabbit hearts, quantification of epicardial flow distribution pattern and of ischemic area was performed from flow indicator and endogenous NADH-fluorescence pictures, respectively, after UV-flash photography. After being digitized (256 X 256 pixels), the fluorescence photos were analyzed by an Apple desk computer using self-written software (fast machine routines called from BASIC programs). The ischemic area (= sum of pixels with enhanced NADH fluorescence) corresponds to the area with disturbed coronary perfusion (= sum of pixels with diminished indicator fluorescence). Since coronary-active drugs might affect both parameters--local myocardial perfusion and metabolism--differentially, the method presented seems to be a very useful technique for differentiated analysis of the action profile of coronary-active drugs.