Advances in myocardiology最新文献

The effect of noradrenaline on myocardial sodium-pump activity has been studied, using a direct measure of active ion transport via the pump; namely, the ouabain-sensitive uptake of the radioisotope and potassium analogue rubidium-86 into guinea pig ventricular tissue slices. Physiological concentrations of noradrenaline caused a dose-dependent stimulation of rubidium uptake (peak response at 2 X 10(-7) M). With higher concentrations, the uptake fell progressively. At 6 X 10(-5) M, noradrenaline uptake was lower than control. The stimulatory action is not mediated by classic adrenergic mechanisms. It was not blocked by either alpha- or beta-blockade. Indirect actions via changes in membrane permeability to sodium and potassium ions are also considered. The inhibitory effect of high concentrations of noradrenaline, however, was mediated by alpha-receptors. Stimulation of the pump by noradrenaline could stabilize cellular ion concentrations and resting membrane potential. Since the pump is electrogenic, this is one mechanism by which noradrenaline will cause shortening of action potential. This may provide an explanation for the greater Q-T shortening during exercised-induced tachycardia, compared with atrial pacing. At high concentrations, attained locally during maximal sympathetic stimulation, these advantageous effects may be lost.

Myocardial metabolism in live guinea pigs was investigated by 13C and 31P nuclear magnetic resonance (NMR) at 20.18 and 32.5 MHz, respectively. 13C NMR studies allowed monitoring of myocardial glycogen synthesis during intravenous infusion of D-[1-13C]glucose and insulin. Anoxia resulted in degradation of the labeled glycogen within 6 min and appearance of 13C label in lactic acid. Infusion of sodium [2-13C]acetate resulted in incorporation of label into the C-4, C-2, and C-3 positions of glutamate, reflecting "scrambling" of the label expected from tricarboxylic-acid-cycle activity. 31P NMR spectra of heart in live guinea pigs were obtained continuously in 20.5-sec time blocks during 3 min of anoxia, during subsequent reoxygenation, and, in separate animals, during terminal anoxia. Reversible anoxia resulted in rapid degradation of phosphocreatine (t1/2 = 54.5 +/- 2.5 sec), which recovered fully during reoxygenation. Heart inorganic phosphate increased during anoxia and returned to basal levels after oxygen was restored. During 3 min of anoxia, no significant changes in ATP levels or pH were detected.

Ouabain-sensitive Na+,K+-ATPase of isolated membranes represents a biochemical correlate of the "Na+ pump" that is present in intact tissue and is responsible for dissimilar distributions of Na+ and K+ across cellular plasma membranes. The enzyme has been purified from a variety of sources and its properties have been reported. Only a limited number of studies, however, deal with the cardiac Na+,K+-ATPase. We solubilized this enzyme from dog heart with deoxycholate and effected its further purification by NaI treatment. The method yielded an enzyme preparation of high specific activity (140 mumole/mg protein per hr). The following characteristics were noted: (1) pH optima of 7.4 and greater than 9.0 for ouabain-sensitive and -insensitive ATPases; (2) inhibition by Ca2+ and ouabain, the latter effect being allosteric in nature; (3) inhibition by sulfhydryl reagents (N-ethylmaleimide, p-chloromercuribenzoate) of the ouabain-sensitive ATPase but not of the -insensitive enzyme activity. All these properties resembled those seen in isolated plasma membranes (sarcolemma), suggesting that the purification procedure did not alter the properties of mono- and divalent interacting sites as well as a digitalis recognition domain of the Na+ pump. These results thus aid in further understanding the regulation of this vectorial pump that is critical in myocardial function.

The ability of intravenous or oral bepridil to reduce infarct size was studied in the rat submitted in situ to coronary-artery ligation. Infarct size was measured by planimetry of serial 8-micron sections at known intervals 48 hr after left-coronary-artery ligation. Succinate dehydrogenase activity (nitroblue tetrazolium stain) was used as an index of tissue viability. Bepridil was administered either intravenously (5 mg/kg) 15 min before (pretreatment) or 10 min after (post-ligation treatment) coronary-artery ligation, or orally (50 mg/kg per day) for 8 days before coronary ligation. Intravenous bepridil pretreatment reduced infarct size by more than 30%. This reduction was accompanied by a better preservation of the myocardial content of adenine nucleotides and a reduction in lactate accumulation. Intravenous post-ligation treatment and chronic oral treatment induced a reduction in infarct size similar to the one observed with intravenous preligation treatment. Thus, bepridil is equipotent in reducing infarct size whether the drug is administered intravenously before or after coronary-artery occlusion, or orally before coronary occlusion.

This chapter presents a brief review of measurements of rapid inward sodium current in single cardiac cells. It is shown that the simplified morphology of the individual cells, with a lack of restricted extracellular space, has been exploited to provide improved spatial and temporal voltage control, resulting in the first recordings of both the activation and inactivation phases of rapid inward sodium current. It is to be expected that future research will produce much interesting data on this component of membrane current, which will have direct relevance to many processes concerned with cardiac function at the cellular level.

Therapeutic application of prostaglandin I2 (PGI2) is rendered difficult by its instability. The 7-oxo-derivative synthesized by Kovács et al. [8] proved to be stable in aqueous solution. Both drugs were tested in experimental model angina in anesthetized thoracotomized dogs with critical stenosis of the left anterior descending coronary artery, in which drug-induced reduction of ischemic ST-segment elevation evoked by frequency loading was estimated [10]. Both drugs markedly reduced blood pressure (BP) even if given by intravenous infusion for 60 min in a total dose of 20 micrograms/kg for PGI2 and 250 micrograms/kg for 7-oxo-PGI2-Na. BP returned to normal soon after infusion and did not substantially change. After a latency of 90-120 min, a 40-50% reduction of ischemia-induced ST-segment elevation appeared in the epi-, endo-, and intramyocardial ECG. Intracoronary infusion of PGI2 in 1 microgram/kg and 7-oxo-PGI2-Na in 25 micrograms/kg total dose minimized systemic actions, but a delayed protective effect appeared, due probably to some nonvasoactive metabolite of these substances. Although both substances exert a potent platelet-aggregation-inhibiting action, serial ex vivo determination of ADP aggregation at different times has shown a dissociation of antiaggregatory action from the protection, this dissociation reaching its maximum when antiaggregatory action was already over.

The effects of pretreatment with metoprolol (2 mg/kg, i.v.), UK 38,485 (5 mg/kg, i.v.), and a combination of the two drugs were examined on early (0-0.5/hr) and late (0.5-4 hr) ischemic arrhythmias resulting from coronary artery ligation in the anesthetized rat. Metoprolol was administered at different times after the onset of ischemia to determine any relationship between antiarrhythmic effects and the time of administration. Studies with two other thromboxane synthetase inhibitors, dazoxiben and carboxyheptylimizadole, and a thromboxane analogue, U 46,619, were performed on the early arrhythmias to investigate a possible role of thromboxane A2 in the genesis of ischemic arrhythmias. Pretreatment and very early intervention with metoprolol caused a significant reduction in the incidence of ventricular fibrillation (VF) in the 0-0.5 hr period. The number of ventricular ectopic beats (VEBs) and the incidence of ventricular tachycardia (VT) during the 0.5-4 hr period were markedly reduced by both pretreatment and late intervention with metoprolol. VEBs and VT in the 0-0.5 hr phase were reduced by UK 38,485 and carboxyheptylimidazole and increased by U 46,619. Administration of a combination of the drugs produced a significant reduction in early VF and late VEBs.

Catecholamine-induced myocardial hypertrophy and necrosis in rats have been measured and compared following treatment with different catecholamines. Significant degrees of both hypertrophy (whether measured as biventricular weight or biventricular/body weight ratio) and necrosis (measured by enzyme histochemical techniques on a standardized series of cryostat sections through the apex of each heart) occurred following 10 days' treatment with daily isoproterenol (0.5 or 5 mg/kg s.c.) or dobutamine (5 mg/kg s.c.) (N = 6-12). These agents given to conscious restrained animals lowered blood pressure and increased heart rate for 3, 6, or 1 hr, respectively. Neither hypertrophy nor necrosis occurred after norepinephrine (1 mg/kg) or dopamine (5 mg/kg); both these agents acutely increased blood pressure for about 30 min. Hemodynamic factors may therefore contribute to catecholamine-induced necrosis, which may in turn contribute to the associated hypertrophy.