Advances in myocardiology最新文献

A method has been developed that allows the direct quantitation of cardiac messenger RNA in heart-muscle biopsies. This provides a new tool to directly assess changes in cardiac gene expression in cardiac biopsies. Using this method, we have analyzed changes in cardiac gene expression during induction and regression of triiodothyronine-induced heart hypertrophy, during development of heart atrophy secondary to starvation and protein depletion, in adriamycin cardiomyopathy, and in patients with mitral-valve diseases.

Cardiac myosin light chains are phosphorylated in vivo and in vitro. The enzyme myosin light-chain kinase, has been purified and found to be very specific for cardiac myosin light chains. Experiments with skinned cardiac fibers suggest that phosphorylation of myosin light chain-2-decreases ATP consumption, presumably by lowering the cross-bridge cycle. These results are discussed in this chapter.

We applied 31P nuclear magnetic resonance to the study of acute ischemia in vivo. In open-chest rabbits, the left anterior descending coronary artery was occluded after control spectra were obtained. Phosphocreatine concentration decreased in the first minute and ATP concentration declined subsequently, and pH decreased to 5.8 within 20 min. Intracellular acidosis was greater than that previously reported for the isolated perfused rabbit heart.

Experiments were conducted on 18 dogs using an in situ blood-perfused canine heart model. Intracoronary infusion of AMP resulted in increased ATP and total adenine nucleotide levels. On reperfusion following a 15-min period of ischemia, ATP and total adenine nucleotide levels were significantly higher than control. Most important, contractile function recovered more rapidly in the AMP-treated dogs. It is therefore concluded that the delayed functional recovery noted after periods of ischemia is likely to be a direct result of delayed ATP resynthesis.

Polymorphonuclear leukocytes activated by latex (polystyrene) beads or the chemotactic peptide N-formyl Met Leu Phe stimulated the oxidation of adrenaline (0.3 microM-10 mM) to adrenochrome, detected spectrophotometrically at 480 nm or by a high-performance liquid chromatographic (HPLC) method. This oxidation was detectable within 5 min and continued for at least 4 hr. Over the concentration range 0.3-10 microM, more than 80% of the adrenaline oxidation occurred via the adrenochrome pathway rather than the amine oxidase-catechol methyltransferase pathway. Medium isolated after stimulation of the polymorphonuclear leukocytes retained the ability to oxidize adrenaline to adrenochrome. Serum from patients after myocardial infarction induced more oxidation of adrenaline to adrenochrome than control serum. Superoxide dismutase, catalase, and azide inhibited by 70-95% the oxidation of adrenaline to adrenochrome, either by cells or medium. Commercially available adrenochrome was biologically active, but some of the actions were due to contaminants of the preparation. HPLC of an extract of synovial fluid from a patient with rheumatoid arthritis, a fluid that contains polymorphonuclear leukocytes, showed a peak identical to that of the adrenochrome standard. The results provide a cellular mechanism for adrenochrome formation and preliminary evidence that adrenochrome can be produced in inflammatory conditions in which polymorphonuclear leukocyte infiltration occurs.

A cell is described that has enabled isolated Langendorff-perfused ferret hearts to be studied in a Bruker WM200 widebore superconducting nuclear magnetic resonance (NMR) spectrometer. Left ventricular pressure was monitored with a latex balloon catheter, and the hearts were paced with a stimulator triggered from the spectrometer's central computer, enabling gated studies to be performed. Suitable radiofrequency filtering for the pacing leads is described. Phosphorus (31P) NMR was used to determine internal pH and the concentration of phosphorylated metabolites under resting conditions. The perfusion rate is shown to affect the phosphocreatine/ATP ratio at low flow rates, but the removal of phosphate from the perfusate is shown not to affect metabolite levels or the internal pH. The time resolution of the method is assessed and its potential for monitoring transient effects illustrated by studies of the effects of acetylcholine and cyanide-induced anoxia. The cardiac gated 31P NMR experiment is discussed and four spectra, corresponding to mid- and end systole and mid- and end diastolic are presented. No effects of cycling of high-energy phosphates are evident in these results.

In studies of the calcium paradox, we have used an isolated rat heart preparation to investigate the relationship between myocardial creatine kinase leakage and the concentration of slow-calcium-channel blockers (nifedipine or verapamil) in the perfusion fluid during a cycle of calcium reduction and repletion. The results indicated that enzyme leakage could be further reduced to a degree greater than that seen under conditions of a full calcium paradox (complete calcium depletion). Detailed dose-response studies with verapamil and nifedipine at a calcium concentration of 1.0 mM during a 20-min period of calcium repletion following a 10-min period of calcium reduction (12 microM calcium) revealed complex dose-response characteristics for each drug. In the dose range studied (0-20 microM), nifedipine was able to reduce enzyme leakage maximally by 57 +/- 8% and verapamil by 37 +/- 4%. Optimal concentrations for verapamil and nifedipine were 4.0 and 2.0 microM, respectively. Both drugs exhibited bell-shaped dose-response curves without a loss of efficacy at higher concentrations. There was no resumption in contractile activity in the drug-treated groups. Simultaneous use of verapamil and nifedipine at their optimal concentrations failed to improve the reduction in enzyme leakage to a reduction greater than that observed with one drug alone.

The modulating role of the cholinergic system in epinephrine (EP)-induced ventricular arrhythmias (VAs) was studied in anesthetized (alpha-chloralose and pentobarbitone sodium) dogs. Unifocal VAs were produced by subepicardial infusion of EP (4 X 10(-3)M) in 2.5 X 10(-3) M CaCl2-0.9% NaCl at a rate of 10 microliter/min for a maximum period of 10 min at a time. One of the interacting drugs acetylcholine Cl (ACh), carbachol Cl (CCh), physostigmine salicylate (PHY), DL-propranolol HC1 (PROP), quindine HC1 (QD), lidocaine HC1 (LD), and atropine sulfate (AT) was given in an equimolar concentration (4 X 10(-3)M) along with EP. The effects of bilateral vagotomy (VT) were also studied. The time of onset, frequency, and duration of VAs were recorded. Reproducible cognizable VAs (less than 10%) were produced by EP in 38 of 43 experimental dogs. Focal infusion of the cholinomimetic agent ACh or CCh marketedly inhibited the arrhythmogenic activity of EP at the focal site. The effect of the anticholinesterase agent PHY was similar. These experiments showed that exogenous administration of a cholinomimetic agent or focal facilitation of endogenous cholinergic influence had an antiarrhythmic activity against EP. On the other hand, bilateral VT or focal infusion of AT markedly potentiated the arrhythmogenic potentiality of EP. Thus, it appeared that removal of endogenous influence facilitated EP-induced arrhythmias. The antiarrhythmic activities of the beta-adrenoceptor-blocking agent PROP and the membrane-stabilizing agents LD and QD against EP were confirmed using the subepicardial infusion technique. These studies show that the presence of cardiovagal tone or its facilitation inhibits, and its blockade increases, the propensity to VAs in situations in which the adrenergic system may be involved primarily or otherwise. The receptors involved appear to be muscarinic in nature.

Several independent studies have demonstrated that there is a degradation of membrane phospholipids during myocardial ischemia. At present, most of the data support the initial activation of a phospholipase A pathway of phospholipid degradation. The extent of total phospholipid degradation is in the nanomole per gram wet weight quantity, as opposed to ischemic liver, in which the extent of phospholipid depletion approaches the micromole per gram wet weight level. However, in vitro studies suggest that calcium permeability properties and other myocardial cell membrane functions are sensitive to nanomole levels of phospholipid degradation. Clearly, further work is necessary in intact cell and heart preparations to correlate the degradation of phospholipid with the development of irreversible membrane injury during ATP depletion and hypoxia.