The effect of experimentally induced myocardial ischemia on the norepinephrine metabolism of the dog heart.

Myocardial ischemia is known to provoke an excess in circulating norepinephrine and thus be related to an increased irritability of the heart. In the present experiments, we studied the norepinephrine and potassium content, oxygen tension, and pH values of the effluent of coronary sinus after thoracotomy and catheter placement into the coronary sinus. Once a steady state was reached, the measurements were repeated in the fifth, tenth, 20th, and 60th minutes of experimental myocardial ischemia provoked by coronary ligation of the left anterior descending coronary artery. The parameters obtained were compared to the corresponding values measured in the peripheral vessels. The results indicate an increased release and probably an increased turnover of norepinephrine in the ischemic myocardium. The role of metabolism acidosis in the changes in norepinephrine metabolism was suggested. It is assumed that intracellular acidosis is involved in the enhanced accumulation and release of norepinephrine in the damaged myocardium and that an increase of norepinephrine concentration in the myocardium may be considered a risk factor in supporting heart function.

Studies on slow cardiac action potentials occurring in potassium-rich media as a simulation of the early phase of myocardial infarction. Influence of potassium-conductance blockers and antiarrhythmic drugs.

In the acute phase of myocardial infarction, a marked intracellular potassium loss and the lack of intact coronary circulation are known to result in extracellular hyperpotassemia partially depolarizing the damaged cells. To simulate these conditions, isolated guinea pig papillary muscles were superfused with K+-rich Tyrode solution, the minimal norepinephrine concentration required to trigger slow action potentials (SR) was measured, and the characteristics of SR were studied with glass microelectrodes. The threshold norepinephrine concentration was found to be about 1.04 x 10(-6)M. This threshold concentration was decreased by substances inhibiting the outward potassium currents (4-aminopyridine, tetraethylammonium, cesium); the SR duration and the maximal rate of depolarization were increased by them. Lidocaine and procainamide have no influence on these parameters. Phenytoin and the Mg2+ ion were found to have a marked inhibitor effect by increasing the threshold norepinephrine concentration and decreasing the maximal rate of depolarization of SR.

The effect of potassium canrenoate (Aldactone) on the norepinephrine metabolism and potassium ionic currents of the heart.

Under experimental conditions, potassium canrenoate causes a significant increase in [3H]norepinephrine (NE) uptake by the heart, although the NE content remains unchanged. The increased NE uptake and unchanged NE content indicate an augmented NE turnover caused by the drug. In saluretic-pretreated animals, the intracellular hypopotassemia can be restored by Aldactone. This effect can be explained by the inhibition of the outward potassium current. When we simulated the pathophysiological conditions of the acute phase of myocardial infarction by using a K+-rich superfusate to partially depolarize the myocardial cells, slow action potentials were elicited by NE in isolated papillary muscles. Our microelectrode experiments revealed that Aldactone, by its blocking effect on the potassium conductance, increases the duration of the slow action potentials and decreases the threshold NE concentration required to elicit the slow responses. However, in clinical conditions with a higher level of circulating catecholamine and/or hyperpotassemia, the administration of the drug has a considerable risk of provoking arrhythmias.

Effect of tetraethylammonium, 4-aminopyridine, cesium and magnesium on slow responses in the guinea pig papillary muscle.

Having inactivated the sodium conductance by K-rich media, propagated slow responses were triggered by local electrical stimulation after addition of catecholamines. We determined the smallest noradrenaline concentration eliciting slow responses (noradrenaline threshold) and it was found to be 1.04 X 10(-6) mol . litre-1 +/- 0.25. The rate of rise and the amplitude of cardiac slow responses increase with the external concentration in calcium, however their development is also influenced by altering potassium conductances. Substances inhibiting gK: tetraetylammonium, 4-aminopyridine and cesium increased the maximal rate of rise and the duration of slow responses and except for the latter compound, decreased the noradrenaline threshold. On the other hand Mg ions exerted an inhibitory effect on slow responses since they markedly decreased the maximal rate of depolarisation and increased the noradrenaline threshold in spite of a very small increase in the duration of slow responses. The effect of Mg ions can be explained by an inhibition of the slow inward current.

The role of potassium-canrenoate in the 3H-noradrenaline uptake and metabolism of the rat heart.

The influence of potassium-canrenoate (Aldactone) on the noradrenaline (NA) uptake and metabolism of the heart was studied in normal and hypopotassemic rats. The administration to normal rats resulted in a marked increase of 3H-NA uptake both in the atrial and ventricular tissues, but the NA content was unchanged. An increased NA uptake of myocardium in the presence of an unchanged content suggested an increased rate of NA turnover under the influence of the drug. In saluretic pretreated animals the substance normalized both the previously decreased NA uptake and the low intracellular potassium level of the heart tissue. The augmentation of catecholamine metabolism due to the drug may be involved in an enhanced activity of adenyl cyclase and form the basis of the positive inotropic effect of the compound.

The role of potassium-canrenoate on 3H-noradrenaline uptake and metabolism of the rat heart.

The influence of potassium-canrenoate (structurally related to spironolactones) on noradrenaline (NA) uptake and metabolism of the heart was studied in normal and hypopotassaemic rats. In normal rats spironolactone administration resulted in a marked increase of 3H-NA uptake in both the atrial and the ventricular tissues, but the NA content was unchanged. An increased myocardial NA uptake in the presence of an unchanged content suggested an increased rate of NA turnover under the influence of spironolactone. In saluretic pretreated animals, spironolactone normalized both the previously decreased NA uptake and the low intracellular potassium level of the heart tissue. The augmentation of catecholamine metabolism due to spironolactone may be involved in enhanced activity of adenyl cyclase and forms the basis of the compounds positive inotropic effect.