Amiodarone concentration in human myocardium after rapid intravenous administration.

Intravenous amiodarone has been found useful in the emergent management of life-threatening arrhythmias. Experimental studies have shown that its electrophysiologic effects are proportional to its myocardial concentration. However, early after its intravenous administration, the extent of the concentration of amiodarone in the human myocardium, the site of its action, is not well known. This study was performed to measure the myocardial concentration of amiodarone shortly after rapid intravenous injection. Amiodarone, 150 mg, was injected over 15 seconds intravenously into 9 patients, 52 +/- 9 years of age, weighing between 65 and 98 kg (mean = 81 +/- 15.6). All patients suffered from idiopathic dilated cardiomyopathy, were in NYHA functional class II, and the mean left ventricular ejection fraction was 21 +/- 6%. Right ventricular endomyocardial biopsy, required for the establishment of the diagnosis, was performed 2-5 minutes after drug administration for measurements of its myocardial concentration. Plasma concentrations of amiodarone were also measured at 2, 5, 10, and 60 minutes, and measurements of right heart hemodynamics were made 2 and 10 minutes after the injection. At 2.5 +/- 1.2 minutes after amiodarone administration, the mean myocardial concentration was 95.7 +/- 67.4 micrograms/g (range, 16-175), and the myocardial/plasma amiodarone ratio was 5.05 +/- 5.01. Heart rate increased from 82 +/- 17 to 90 +/- 13 beats/min (P < 0.05), and systolic blood pressure decreased from 132 +/- 19 to 118 +/- 17 mmHg (P < 0.03). The extent of myocardial fibrosis was 5.13 +/- 6.55% (range, 0.3-17.5%). Intravenous amiodarone (150 mg) accumulates rapidly in the human myocardium. This pharmacokinetic characteristic probably explains its acute efficacy in the treatment of life-threatening arrhythmias.

Distribution of amiodarone in heart tissues following intrapericardial administration.

The distribution of amiodarone (A) in heart tissues of open chest anesthetized animals was studied at 20 and 60 min following the insertion of an isotonic solution of the drug into the pericardial sac (PS) in doses from 0.25 to 3 mg per kg body weight (BW) for pigs and after 60 min in doses of 3 to 6 mg for dogs. Most of the A absorbed by the myocardium was found in the subepicardium part of the left ventricular (LV) wall. For both species the percentage of drug absorbed by the myocardium was largely and inversely related to the dose given, while uptake by the atria was positively related to the dose and was higher than that in the subepicardial LV wall. Sixty minutes after i.v. administration of A (3.0 mg per kg BW) the drug was evenly distributed across the LV wall (16 microg per g wet tissue), which was significantly lower (p < 0.02) than that of subepicardal LV wall (30 microg) after intrapericardial (IP) administration. This study shows that satisfactory drug concentrations in predicted and specific distribution in the heart tissue were derived shortly after intrapericardial administration without measurable circulation in the blood.

The sarcolemmal Ca2+-ATPase of the ischemic-reperfused myocardium: protective effect of hypocalcemia on calmodulin-stimulated activity.

This study was designed to examine the role of calcium in the ischemia-induced changes of calmodulin-stimulated Ca2+-ATPase activity of heart sarcolemma of dogs subjected to coronary artery ligation (90 min) and reperfusion (30 min). This was attained by the application of systemic hemodialysis with low Ca2+ dialysate in six dogs (group A) and the comparison of the results with those obtained from animals subjected to normal Ca2+ hemodialysis (control group B, n=7). A very significant (p<0.001) decrease was found in the calmodulin-stimulated Ca2+-ATPase activity measured in the ischemic and non-ischemic parts of group B. This was associated with a decrease in the maximal velocity (v(max)) of the reaction of stimulation and an increase in the apparent Km for calmodulin. The kinetics of the calmodulin-stimulated Ca2+-ATPase also assessed in the presence of trifluoroperazine, a specific inhibitor for calmodulin binding, showed that the affinity for calmodulin was higher in the ischemic part of group A than of B, while v(max) was not substantially different. The above data may suggest that the inhibition of the calmodulin-stimulated Ca2+-ATPase produced by ischemia-reperfusion and its preservation under low Ca2+, are exerted at the calmodulin-binding site of the enzyme.

Rapid diminution of calcium in the myocardium by transfer to pericardial solutions. Myocardial dialysis.

A new method is described for the controlled and specific depletion of calcium from the vascularly perfused heart of experimental animals by means of dialysis, using a pericardial solution. A 30-40 ml isotonic phosphate buffer pH 7.3 with a low Ca2+ and high Mg2+ concentration (0.2 and 2.7 mM respectively) was inserted into the pericardial cavity of anaesthetized dogs and kept there for 10 or 60 min. The calcium content of the subendocardial and subepicardial halves of the left ventricular wall was similarly decreased to about 70% (P < 0.01) within 10 min and to 62% (P < 0.001) at 60 min, compared to that of hearts dialysed for 60 min in a standard solution of Ca2+ 1.2 mM and Mg2+ 1 mM. Calcium content of the myocardium dialysed with low Ca2+ and a standard Mg2+ solution decreased to only 75% (P < 0.01) at 60 min. Similar changes of calcium were measured in other parts of the heart. An increase in Ca2+ concentration in the pericardial solution was observed at the same time as a decrease in calcium in the myocardium. The increase in Ca2+ reached about 0.7 mM at 60 min, but decreased slightly, and finally, fell to 85% of pre-dialysis values at 60 min. It is concluded that this method of myocardial dialysis is effective in reducing myocardial calcium and is influenced by the duration of dialysis and the Mg2+ content of dialysate.

Distribution of lidocaine and digoxin in heart tissues and aorta following intrapericardial administration.

The distribution of lidocaine and digoxin in myocardial and aorta tissues of open chest anesthetized dogs was studied, following the administration of 30 ml phosphate buffer solution of the drugs in the pericardial cavity where it was kept for increasing time intervals. Transfer of lidocaine (15 or 30 mg) from the solution to myocardium was almost complete within 60 min, while only 50% of digoxin (2 or 50 micrograms) was removed, and this occurred during the first 30 min. Accordingly, the absorption rate of lidocaine by heart tissues increased with time up to 60 min while that of digoxin decreased with time. Absorption of digoxin by the atria and absorption of both drugs by intrapericardial aorta were higher than that of other heart tissues, between 20 and 60 min. At 30 and 60 min, lidocaine was evenly distributed across the LV wall while digoxin 50 micrograms was mainly concentrated subepicardially. On the contrary, i.v. administration of digoxin resulted in even distribution in the LV wall without preferential concentration in the atria. The uptake of both drugs by aorta was several times lower compared to heart tissues after i.v. administration. Drug concentrations in LV wall almost at therapeutic level, were derived from solution of low concentration of the drug in the pericardial cavity. It is concluded that intrapericardial administration of the drugs may be used when increased concentration of them is desired in specific areas of the heart and the aorta.

Effect of low calcium on high-energy phosphates and sarcolemmal Na+/K(+)-ATPase in the infarcted-reperfused heart.

This study was undertaken to compare the effect of low to normal serum calcium on biochemical parameters in the myocardium of dogs subjected to 90 min of coronary artery ligation followed by 30 min reperfusion. The accumulation of calcium, the decrease of adenosine triphosphate (ATP) and creatine phosphate (CP) and the inhibition of sarcolemmal ouabain-sensitive Na+/K(+)-ATPase which are prominent findings in the ischemic-reperfused myocardium, were studied under normal and low serum Ca produced by normal and modified hemodialysis (HD). The results showed a lower accumulation of Ca (P less than 0.002) in the ligated-reperfused myocardium of dogs subjected to low-calcium HD. In the same group of animals ATP was protected to some extent while CP was completely preserved. This may indicate that during reperfusion with low Ca, restored ATP is further utilized for CP regeneration. The activity of Na+/K(+)-ATPase was within normal values in the ligated-reperfused myocardium of the low-calcium group. The significantly (P less than 0.001) negative correlation between tissue calcium concentration and Na+/K(+)-ATPase activity under various conditions examined, provided additional evidence that low calcium is a protective factor of the enzyme activity during ischemia and reperfusion.

Effect of hypocalcemia on isoproterenol induced cardiotoxicity in dogs.

The effect of serum calcium on the myocardial damages produced by isoproterenol was studied in the dog. Hemodialysis for 80 min in the absence of calcium was used to alter serum calcium concentration in seven experimental animals. The same number of animals were dialysed in the presence of calcium and were used as controls. After hemodialysis all animals were infused with isoproterenol 2.0 micrograms/kg/min for 4 hours. The myocardial damage was assessed by comparing serial measurements of the serum cardiac enzyme activities CK and CK-MB and the electrocardiographic findings of the two groups, before, during and after isoproterenol infusion. Serum calcium decreased significantly after dialysis only in the experimental group (1.15 vs 2.19 mmol X L-1). Total CK activities of the experimental group during and after isoproterenol infusion were 2 to 3 times lower than in the controls (190-360 vs 410-1370 IU X L-1). Changes of the CK-MB isoenzyme activities were more profound, these were detectable and measured only in 4 of the experimental animals and in much lower activities than in the controls (25-61 vs 45-445 IU X L-1). A positive correlation was found (r = 0.673, p less than 0.05) between the highest value of CK-MB of both groups and the serum calcium concentration after hemodialysis. In accordance to the differences of the biochemical estimates the effect of serum calcium on the cardiotoxic effect of isoproterenol has been further emphasized by the electrocardiographic findings. Thus arrhythmias, negative T-waves and significant ST segment depression were observed only in one experimental animal. In contrast these electrocardiographic disturbances were common and marked findings in all but one of the control animals. In both groups these electrocardiographic findings were reversed one to three hours after the termination of the isoproterenol infusion. Myocardial calcium at the end of the experiment was lower in the experimentals compared to the controls (0.23 vs 0.30 mmol X kg-1 wet weight). On the contrary magnesium concentration increased respectively. It is concluded that low serum calcium has a protective effect against the cardiotoxic action of isoproterenol. This protective action may be relevant to the decreased calcium and increased magnesium of the heart of the animals hemodialysed in the absence of calcium.

Isolation and partial characterization of the neutral glycosphingolipids and gangliosides of the human heart.

The glycosphingolipids (GSL) of the human heart muscle have been isolated from total lipids by column and thin layer chromatography and their sugars and fatty acids analyzed by gas liquid chromatography. Hearts from traffic victims were obtained at autopsy between 12 and 16 hr after death and dissected into parts (left and right ventricular walls, intraventricular septum and papillary muscle). The neutral GSL content for those parts of the hearts of two males aged 22 and one female aged 14 ranged from about 90 to 160 nmoles/g wet weight. Trihexosyl ceramide and globoside were the most abundant neutral GSL. Total ganglioside content was about 50 nmoles/g wet weight, and the most abundant gangliosides were partially characterized as GM3 and GM1; other mono-, di- and trisialogangliosides were also present. Differences in the content and composition of neutral GSL and gangliosides between the heart and other human tissues are discussed. It is concluded that the patterns of these two GSL fractions of the heart are more complex than those of the extraneural human tissues.