Olle Almgren

QTU-prolongation and torsades de pointes induced by putative class III antiarrhythmic agents in the rabbit: etiology and interventions.

When low doses of clofilium were administered to conscious rabbits, ventricular tachyarrhythmia (VT) with features typical of torsades de pointes developed. This arrhythmia was further studied and characterized in cholralose-anesthetized rabbits. In 20 of 20 rabbits, VT developed after a mean cumulative dose of 0.53 ± 0.04 μmol/kg clofilium, provided an infusion of the α1-agonist methoxamine (15 (μg/kg/min) was given concomitantly. The arrhythmia was preceded by a marked prolongation of the QTU interval and the monophasic action potential duration, as well as signs of early afterdepolarizations (EADs). In seven of 10 rabbits receiving only clofilium (cumulative dose, 20.8 μmol/kg), no VT occurred (p < 0.001 compared to the incidence in animals given both methoxamine and clofilium). In animals given both methoxamine and clofilium, pretreatment with prazosin (1 mg/kg i.v., n = 4) attenuated the arrhythmia, whereas diltiazem (0.5 mg/kg i.v., n = 4) or propranolol (0.5 mg/kg i.v., n = 8) was ineffective. Acute intervention with prazosin, isoproterenol, pinacidil, or magnesium sulfate promptly regularized the rhythm in animals with VT. Prazosin and pinacidil were equally effective in β-blocked rabbits. When other agents known to retard the repolarization currents (sematilide, UK-68,798, LY97119, amperozide, and cesium chloride) were examined, a strong correlation (r = 0.99, p < 0.001) between the potency of the drug to prolong the QTU interval and the proarrhythmic potential was obtained. This experimental model may represent an appropriate alternative for studying the acquired (“pause-dependent”) long QT syndrome.

Local release of myocardial norepinephrine during acute ischemia: an experimental study in the isolated perfused rat heart.

The appearance of an early ischemia-induced local release of myocardial norepinephrine (NE) was examined in the isolated Langendorff-perfused rat heart prelabeled with [3H]NE. Either glucose or lactate was used as the perfusion substrate. Ischemia for a 60-min period was produced by global flow reduction (by 90%) or left coronary artery ligation followed by a 15-min reperfusion period. During the first 20 min of ischemia both the concentration of [3H]NE and the fraction of total 3H representing nonmetabolized [3H]NE were increased in the coronary venous effluent. This early increase in [3H]NE concentration was most pronounced in hearts with global ischemia perfused with lactate as substrate (from 19 ± 2 to 524 ± 76 fmol/ml/g after 20 min of ischemia). The quantity of [3H]NE released was then further increased during the 60-min period of ischemia. Reperfusion of the ischemic myocardium was associated with a marked outflow of [3H]NE and [3H]NE metabolites, primarily representing a washout from the ischemic tissue. Under the present experimental conditions the ischemia-induced release of NE was attenuated by glucose, probably owing to an ongoing glycolytic ATP formation. This effect was most pronounced during global low-flow ischemia. It is concluded that ischemia is associated with a local release of myocardial NE. In the nonworking Langendorff heart preparation, clear evidence of such a local release was already obtained after 10–20 min of ischemia.

Release of noradrenaline in myocardial ischemia ― importance of local inactivation by neuronal and extraneuronal mechanisms

Summary: The mechanisms responsible for the local in-activation of noradrenaline (NA) released during myocardial ischemia were examined in the isolated perfused rat heart preloaded with 3H-NA. Two different types of ischemia were used: (a) 90% global flow reduction (global ischemia), and (b) ligation of the left coronary artery (regional ischemia). The coronary effluent was collected at different intervals during ischemia and reperfusion, and 3H-NA was separated from its tritiated metabolites using HPLC. During ischemia, a gradual increase in the efflux of 3H-NA was observed, which was accompanied by a shift from predominantly neuronal metabolism towards increased efflux of extraneuronally formed metabolites. During the first minute of reperfusion, the metabolic pattern of 3H-NA was not substantially changed as compared with that observed immediately before reperfusion, indicating a wash-out of 3H-NA and its tritiated metabolites accumulated in the tissue during the ischemic period. Addition of corticosterone to the perfusion medium (to inhibit extraneuronal uptake of 3H-NA) was associated with an increased efflux of 3H-NA during the ischemic period. In contrast, addition of the neuronal uptake blocker desipramine caused a decreased efflux of 3H-NA during ischemia. In conclusion, these experiments demonstrate an ischemia-induced release of myocardial NA, in all probability due to the recently proposed carrier-mediated efflux mechanism. The release is parallelled by an increasing extraneuronal inactivation of released transmitter.

Ischemia-induced noradrenaline release in the isolated rat heart: Influence of perfusion substrate and duration of ischemia

To examine some of the characteristics of the local noradrenaline (NA) release in myocardial ischemia a study was made on Langendorff-perfused rat hearts, prelabelled with 3H-NA. The left coronary artery was ligated for 15, 30, 60 or 120 min, followed by 10 min of reperfusion. The coronary effluent was collected and analyzed for radioactivity to indicate release of 3H-NA. In some of the experiments the fraction of 3H-NA was determined. As substrate in the perfusion medium either glucose (11.1 mM) or sodium lactate (5.0 mM) was used. During the ischemic period there was a slight decrease in the outflow of radioactivity. However, reperfusion was associated with a rapid and marked outflow of radioactivity, including an increased fraction of 3H-NA, in the effluent. Compared to glucose as perfusion substrate, lactate caused a significantly higher (P less than 0.01) outflow of tritiated substances after 60 and 120 min of regional ischemia. With lactate there was an almost linear relationship between reperfusion efflux of 3H and duration of ischemia. With glucose, the reperfusion outflow increased less rapidly after a duration of ischemia longer than 15 min. It is concluded that the degree of local NA release in myocardial ischemia depends on both the duration of the ischemic period and the substrate used. Glucose attenuates the reperfusion outflow of NA, especially after longer periods of ischemia. The effect may be due to decreased myocardial cell damage with this substrate and/or a direct protection of the adrenergic nerve endings.

Local noradrenaline release in acute myocardial ischemia: influence of catecholamine synthesis inhibition and beta-adrenoceptor blockade on ischemic injury.

Summary Left coronary artery ligations or sham operations were performed on pentobarbitone-anesthetized rats. The rats were sacrificed at various times after artery occlusion or sham operation and the creatine kinase (CK), potassium (K+), and noradrenaline (NA) content was determined in the left and right ventricular myocardium and in the interventricular septum. One group of rats was pretreated with the NA synthesis inhibitor α-methyl-p-tyrosine methyl ester (α-MT), another group with d,l-propranolol, and a third group with saline. The NA level of the ischemic left ventricle fell rapidly after the onset of ischemia. This early NA reduction was attenuated after α-MT treatment, probably due to reduced transmitter release. Both CK and K+ decreased in a time-dependent manner in the ischemic area of the heart. The early reduction of CK tended to be attenuated after α-MT as well as after propranolol. The results support the theory of a detrimental effect of locally released NA. However, in this model the injury produced by the extensive and nearly total ischemia seems so severe that the additional effect of myocardial adrenoceptor activation may well be only marginal.

Ischemia-induced local release of myocardial noradrenaline.

The isolated perfused rat heart, prelabelled with 3H-noradrenaline (NA), was used to examine the ischemia-induced release of myocardial NA, and to investigate to what extent reperfusion of an ischemic myocardium per se causes a release of NA. In a model of global myocardial ischemia with 90% flow reduction and the use of lactate as perfusion substrate, release of 3H-NA into the perfusate was already observed during the first 10–20 min of ischemia. The quantities of 3H-NA released increased further with increasing duration of ischemia. In another model with regional ischemia produced by left coronary artery ligation, a similar, though less marked, release of 3H-NA into the perfusate was observed during ischemia. Reperfusion after 60 min of ischemia was associated with a marked outflow of 3H-NA and 3H-NA metabolites, which was not reduced if reperfusion was performed with a Ca2+-free buffer. Further more, in the globally ischemic heart model, the relative amounts of 3H-NA and the various 3H-NA metabolites in the effluent remained constant during the last minute of ischemia and the first minute of reperfusion. We concluded that ischemia is associated with early local release of myocardial NA. NA can partly be trapped in the ischemic tissue and washed out during reperfusion.

Antiarrhythmic effect of reducing myocardial noradrenaline stores with alpha-methyl-meta-tyrosine.

In the adrenergic neurons the amino acid α-methyl-metatyrosine (α-MmT) is converted to metaraminol via the noradrenaline (NA) synthetic pathway. Metaraminol thereby displaces NA from its neuronal stores, and as a consequence NA levels can be drastically reduced, although normal sympathetic tone is essentially maintained by release of newly synthetized NA. In rats treated with α-MmT methylester (400 + 200 mg/kg) myocardial NA was reduced to <10% of control. Under barbiturate anesthesia, the left coronary artery was ligated, and the incidence of ventricular fibrillation and mortality during a 30-min period was recorded. Before ligation, mean arterial blood pressure was unchanged and heart rate slightly increased by α-MmT pretreatment. The energy state of the myocardium was also unchanged by the α-MmT pretreatment, as seen in a separate study where hearts from identically treated rats were taken for analysis of glycogen and adenine nucleotides. Thus, α-MmT pretreatment appeared not to have reduced the sympathetic tone of the heart. In spite of this, α-MmT pretreatment reduced the ventricular fibrillation from 65 to 33% (p < 0.01; χ2 test) and mortality from 37 to 15% (p < 0.05). The results indicate an important role of myocardial NA stores in the development of early ischemic arrhythmias.

Effects of intracoronary nifedipine on blood flow and segment shortening in normal and ischemic myocardium: potentiation by ischemia of the negative inotropic effect.

The effects of intritcoronary nifedipine on myocardial blood How (flow probe or microspheres) and regional function (ultrasonic crystals in subendoeardium) were examined both in the normal myocardium and in myocardium made ischemic by a partial coronary occlusion in the open-chest anesthetized dog. In a first group of experiments (n - 7). without ischemia, nifedipine infused into the left anterior descending coronary artery (LAD) during a 1-min period (doses 0.75–8 nmol/kg body weight) decreased coronary vascular resistance with a maximal effect at 4 nmol/kg. Systolic segment shortening was decreased from 10.7 to 7.4% (p < 0.05) by 6 nmol/kg. whereas lower doses had no effect. In a second experimental group (n - 7). a partial LAD occlusion was applied to decrease suhendocardial segment shortening by about 50%. Nifedipine (2 nmol/kg) injected into the partially occluded LAD induced a marked segmental bulging during early systole and systolic segment shortening was eliminated (from 4.2 to −3.1%. p < 0.02) in the LAD-dependent myocardium. Concomitant with the decreased regional function, nifedipine caused a trans-mural redistribution of myocardial blood How in the ischemic area, the endocardial/epicardial blood How ratio increasing from 0.44 to 0.61 (p < 0.02). It is concluded that ischemia potentiates the direct depressant effect of nifedipine on myocardial regional function.

Coronary Collateral Blood Flow in Acute Myocardial Ischemia is not Increased by Dihydropyridine-Induced Coronary Vasodilatation

The effect of two dihydropyridine derivatives, nifedipine and felodipine, on myocardial blood flow distribution 1 h after ligation of the left anterior descending coronary artery (LAD) was studied in open-chest dogs by means of radioactive microspheres. The myocardium normally perfused from the LAD was first labeled with 125I-labeled microspheres injected directly into the LAD before ligation. Microspheres used for blood flow measurements were given in the left atrium. An intravenous infusion rate of 0.3 nmol/kg/min felodipine slightly depressed mean aortic blood pressure (∼5 mm Hg) and decreased coronary vascular resistance in normal myocardium. Nifedipine, at three times the dose of felodipine, had a comparable hypotensive effect, but the decrease in coronary vascular resistance was not statistically significant. The two dihydropyridines were also compared in a dose range that was four times higher. The mean arterial blood pressure reduction (∼30% for both drugs) was counterbalanced by inflation of an intraaortic balloon to avoid a drastic decrease in afterload and coronary perfusion pressure. Under these circumstances, felodipine and nifedipine decreased coronary vascular resistance and increased blood flow to nonischemic myocardium comparably. However, in severely ischemic, truly collateral-dependent myocardium without admixture of interdigitating healthy myocardium, the blood flow was unaffected after administration of both felodipine and nifedipine. Although felodipine was three times more potent than nifedipine with regard to vasodilatation in the normal myocardium, the difference in vascular selectivity between the two agents did not influence the effect on the “true” collateral blood flow in acute myocardial ischemia.

Effects of Felodipine, a New Dihydropyridine Vasodilator, on Regional Myocardial Blood Flow During Acute Coronary Occlusion in the Pig

We studied the effects of felodipine [4-(2.3-dichlorophenyl)- 1, 4 - dihydropyridine - 2, 6-dimethyl 3, 5-dicarboxylic 3-ethylester and 5-methylester] on the coronary vascular bed of pig hearts with an ischemic region in the left ventricle following ligation of the left anterior descending coronary artery. At an infusion rate of 0.12 nmol × kg−1 × min−1, felodipine caused a slight reduction in mean arterial blood pressure and a decrease in coronary vascular resistance in both normal myocardium and partly ischemic myocardium of the border zone. In another series of experiments, felodipine was infused at a higher rate (0.38 nmol × kg−1 × min−1). The resultant decrease in mean arterial blood pressure, which was about 30%, was counterbalanced by inflation of an aortic balloon to keep the afterload and the coronary perfusion pressure constant. In this situation, felodipine caused a pronounced increase in blood flow to all parts of the heart except the central ischemic zone, where blood flow was extremely low. We conclude that felodipine has a coronary vasodilator action which is at least of the same magnitude as its peripheral vasodilator action, and that it markedly increases coronary blood flow in the border zone of an ischemic area.