Effects of morphine on catecholamine release and arrhythmias evoked by myocardial ischaemia in rats.

The effects of morphine (10 mg kg-1 i.p.) on haemodynamics, arrhythmias and plasma and myocardial catecholamines (CA) were studied after coronary artery occlusion in anaesthetized rats. Myocardial intraneuronal CA were assessed histofluorimetrically and CA concentrations measured by high performance liquid chromatography. Morphine increased blood pressure, presumably due to higher plasma noradrenaline (NA) concentrations found in morphine-treated rats. Morphine increased the area of catecholamine-containing fluorescing neurones in the myocardium (as a percentage of total field area) 60 min after sham-operation (0.87 +/- 0.07%) or occlusion (0.57 +/- 0.05%) compared to untreated animals (0.67 +/- 0.06 and 0.38 +/- 0.03% respectively). Tissue NA content was not significantly affected by coronary occlusion and/or morphine within the first 60 min. Morphine had no effect on ischaemia-induced arrhythmias. Whether the higher intraneuronal NA content following morphine resulted from reduced central sympathetic outflow to the heart, presynaptic inhibition of NA release, or increased uptake due to higher plasma concentrations is unclear. Ischaemia-induced local NA release appears independent of these mechanisms, as it was unaffected by morphine.

The effect of aminosteroid, ORG 6001, on hypothermia induced ventricular fibrillation in the cat.

1 The effect of the antidysrhythmic aminosteroid, ORG 6001, on hypothermia-induced ventricular fibrillation was investigated in cats anaesthetized with pentobarbitone. 2 ORG 6001 (total dose, 10 mg/kg, by intravenous injection) reduced both the incidence of fibrillation and the temperature at which it occurred. The number of animals that survived to 16 degrees C was increased. 3 This protective effect of ORG 6001 could not be explained by changes in respiratory acidosis, plasma concentrations of sodium and potassium, or by changes in the action potential of excised hypothermic ventricular muscle. The hypothermia-induced elevation of blood lactate was less in cats treated with the aminosteroid. 4 Over a limited temperature range, ORG 6001 prolonged the P wave and QRS duration and shortened the QTc interval. ST segment elevation was slightly reduced in the drug-treated group. J deflections were observed but were not correlated with the development of fibrillation. 5 The onset of fibrillation was not considered to be due to temperature differences between the myocardium and arterial blood or between localized areas of the left ventricular wall.

The effects of verapamil, prenylamine, flunarizine and cinnarizine on coronary artery occlusion-induced arrhythmias in anaesthetized rats.

In male rats, anaesthetized with pentobarbitone, ligation of the main left coronary artery causes an early phase of ventricular arrhythmias which last about 30 min. In approximately 60% of control animals, ventricular fibrillation occurs but since spontaneous reversion to sinus rhythm may occur, mortality is of the order of 30%. When administered intravenously 15 min prior to ligation, verapamil (0.01 and 0.05 mg kg-1), prenylamine (0.5 mg kg-1), flunarizine (0.1, 0.25, 0.5 and 1.0 mg kg-1) and cinnarizine (0.25, 0.5 and 1.0 mg kg-1) protected against these arrhythmias. Higher doses of verapamil (0.1 and 0.5 mg kg-1), prenylamine (5 mg kg-1) and flunarizine (2.5 mg kg-1) did not afford a similar protection and mortality was increased to or above control values. Death was due in prenylamine-treated rats to atrioventricular block leading to asystole whereas in those administered verapamil or flunarizine it was a consequence of persistent ventricular fibrillation. Prior to ligation, a sustained fall in mean arterial blood pressure was observed only following the administration of the highest doses of prenylamine, flunarizine and cinnarizine. Heart rate was reduced by administration of only the highest dose of prenylamine. These studies show that although the four calcium antagonists studied, i.e. verapamil, prenylamine, flunarizine and cinnarizine do suppress ischaemia-induced arrhythmias, this protective effect may be limited to a narrow concentration range.

Aspects of the cardiovascular pharmacology of exaprolol.

This study confirms that exaprolol is a potent beta-adrenoceptor antagonist, having a pA2 value of 9.8 for the inhibition of the inotropic and chronotropic responses of guinea-pig isolated atrial preparations to isoprenaline. In the anaesthetized cat, exaprolol blocks both the myocardial stimulatory and vasodilating effects of isoprenaline, suggesting that it is a non-selective antagonist at beta-adrenoceptors. Exaprolol also has direct electrophysiological effects on cardiac (Purkinje) tissue, reducing the rate of rise of phase 0 of the action potential. This direct action together with its marked blockade of beta-adrenoceptors may explain the drug's ability to markedly suppress the ischaemic ventricular arrhythmias that follow coronary artery occlusion in anaesthetized rats.

Vicious cycle of catecholamines and K+ in cardiac ischemia.

The distribution of catecholamine (CA)-containing neurones and tissue noradrenaline (NA) concentration was investigated in pig hearts with and without myocardial ischemia. All hearts were shock-frozen using a Wollenberger clamp, and tissue samples were obtained from the mid- and apical left ventricular wall (nonischemic and ischemic areas, respectively, in hearts with coronary artery occlusion). The distribution of CA-containing neurones was assessed morphometrically from histofluorescence sections, and the NA content measured using high pressure liquid chromatography (HPLC). In hearts without myocardial ischemia, both the density of CA-containing neurones (0.96 +/- 0.07 compared with 1.09 +/- 0.07% of total field area) and the NA content (738 +/- 63 compared with 884 +/- 84 ng/g wet weight, p less than 0.025) were less in apical samples compared with those obtained at the midventricular level. These differences were more pronounced in samples from hearts obtained following 5 min (fluorescence, 0.96 +/- 0.19 compared with 1.38 +/- 0.18%, p less than 0.01; NA content, 543 +/- 109 compared with 816 +/- 82 ng/g wet weight, p less than 0.01) or 15 min (fluorescence, 0.77 +/- 0.07 compared with 1.12 +/- 0.09%; NA content, 521 +/- 43 compared with 753 +/- 79 ng/g wet weight, p less than 0.01) of coronary artery occlusion, indicating a release of CA in the ischemic myocardium.

Characterization of oral sustained release preparations of iloprost in a pig model by plasma level monitoring.

Iloprost (5-[(E)-1S,5S,6R,7R)-7-hydroxy-6-[(E)-3S,4RS)-3-hydroxy-4- methyl-octen-6-inyl]-bicyclo[3.3.0]-oct-3-ylidene)-pentanoic acid) is a chemically stable PGI2-mimetic with high pharmacological potency. Therapeutic efficacy in various disease stages (e.g. peripheral arterial occlusive disease, M. Raynaud and thromboangiitis obliterans) was shown after repeated once-a-day infusion treatment over several weeks. In order to facilitate drug therapy an oral dosage form is desirable. As a first step, a suitable animal model was needed to screen several formulation variants prior to characterization of promising candidates in man. After intravenous infusion treatment, the pig exhibited - similar to man - strictly dose-dependent steady state plasma levels and a total iloprost clearance of approximately 26 ml/min/kg (man approximately 20 ml/min/kg). Partial similarity of physiology and anatomy of the GI-tract and the possibility to administer intact capsule dosage forms led to a series of screen experiments with several sustained release preparations (pellets and matrix tablets) of iloprost exhibiting different in-vitro drug release profiles. A good correlation of in-vitro dissolution and in vivo plasma level data was obtained for all preparations containing the pellet neutral polymer. For the other formulations slight differences between duration of liberation and plasma level or time of maximum dissolution rate and tmax of plasma levels was observed. In the case of ionized polymers or matrix tablets, in vitro dissolution profiles were slightly different from in vivo data. This might be due to different dissolution behaviour in the gastro-intestinal tract. The pig seems to be a model that is suitable for verifying drug liberation profile in-vivo. Based upon plasma levels obtained in animals, selection of a formulation for characterization in man can be made.

Fluid-containing bullae in the lung.

Eight patients had air-fluid levels in the lung as a result of fluid accumulation in preexisting bullae. In four cases the cause was peribullous pneumonitis; in the other four cases the cause could not be determined. All patients had a favorable clinical course while intrabullous fluid was present. The initial interpretation of air-fluid levels was correct in only two instances. Differentiation of fluid-containing bullae from other causes of air-fluid levels is important so that unnecessary diagnostic and therapeutic maneuvers can be avoided.

Coronary artery ligation in anesthetized rats as a method for the production of experimental dysrhythmias and for the determination of infarct size.

Coronary artery ligation in anesthetized rats was assessed as a method for the production of experimental dysrhythmias and for the determination of infarct size. Following occlusion of the left main coronary artery, very marked ventricular dysrhythmias occurred in two distinct phases, an early and a late phase, at 0-30 minutes and at 1 1/2--4 hours after ligation respectively. Infarct size was measured at 4 hours after ligation using nitroblue tetrazolium to stain for the depletion of two cytoplasmic enzymes, lactate dehydrogenase and NADPH diaphorase. In this model, lignocaine (10 mg/kg plus an infusion of 5 mg/kg/hr) and ORG 6001 (10 mg/kg plus an infusion of 2.5 mg/kg/hr) had marked antidysrhythmic activity but neither drug influenced infarct size. The model, because of its simplicity, reproducibility, and low cost, should be useful for the screening of potential antidysrhythmic agents and may also be used to determine infarct size following coronary artery ligation.

Effect of propranolol on early postischemia arrhythmias and noradrenaline and potassium release of ischemic myocardium in anesthetized pigs.

In anesthetized open-chest pigs, DL- or D-propranolol (1 mg/kg i.v.) was administered 15 min prior to ligation of the left anterior descending coronary artery (LAD) about halfway from its origin. Sequential myocardial tissue samples were obtained before and after LAD occlusion. The samples were analyzed histofluorimetrically to determine the density of catecholamine containing neurons (quantified morphometrically), and radioenzymatically for total tissue noradrenaline content. The extracellular K+ concentration was measured using K+-sensitive polyvinyl chloride (PVC)-membrane electrodes on the surface of the ischemic myocardium. Under control conditions, ventricular arrhythmias (VA) occurred in a typical 1a and 1b phase. Pretreatment with propranolol diminished the number of VA generated in the 1b phase but not those in the 1a phase; however, these differences were statistically not significant. Neither pretreatment with DL- nor D-propranolol influenced the time course or probability of development of ventricular fibrillation (VF). Coronary artery occlusion led to a significant reduction in noradrenaline concentration of the ischemic myocardium in control animals (from an initial concentration of 526 +/- 65 ng/g w/w to 368 +/- 75 ng/g w/w) within the first 5 min of ischemia, whereas noradrenaline concentration remained nearly unchanged in drug-treated animals (from 838 +/- 86 to 811 +/- 61 ng/g w/w in the DL group and from 701 +/- 36 to 709 +/- 31 ng/g w/w in animals that received D-propranolol.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of lidocaine on catecholamine release in the ischemic rat heart.

The effects of lidocaine (5 or 10 mg/kg bolus + 2.5 mg/kg/h) on arrhythmias and changes in myocardial and plasma catecholamines (CAs) after left coronary artery occlusion were investigated in anesthetized rats. Myocardial intraneuronal CAs were assessed histofluorimetrically and CA concentrations were measured using high-pressure liquid chromatography (HPLC). Both doses of lidocaine caused reductions in heart rate and blood pressure. The higher dose significantly reduced the number of ischemia-induced ventricular extrasystoles from 425 +/- 123 to 25 +/- 12 in the first 60 min of ischemia and abolished ventricular tachycardia and fibrillation. In the myocardium of untreated animals, the area of fluorescing adrenergic neurons (as percentage of total field area) was 0.42 +/- 0.02% after 60 min of ischemia as compared with 1.38 +/- 0.17% in sham-operated animals. Lidocaine pretreatment resulted in a dose-dependent inhibition of this ischemia-induced CA release from adrenergic neurons (0.96 +/- 0.06 and 1.30 +/- 0.05% for the lower and higher dose, respectively). Tissue and plasma CA concentrations were not significantly affected by lidocaine pretreatment and by coronary occlusion. It is concluded that lidocaine inhibits CA release from sympathetic nerve endings in the ischemic myocardium by its endoanesthetic and membrane-stabilizing properties. The reduction in CA release may also contribute to its antiarrhythmic effects.

The effects of prolonged oral administration of a new antidysrhythmic drug (Org 6001) on coronary artery ligation dysrhythmias in conscious and anesthetized rats.

We determined the antidysrhythmic activity of acute or prolonged administration of Org 6001 on dysrhythmias following coronary artery ligation in conscious and anesthetized rats. Intravenous doses of 5 and 10 mg/kg of Org 6001 markedly protected against postligation dysrhythmias in anesthetized rats, whereas a single oral dose of 10 mg/kg given 1 hr prior to ligation did not. Prolonged oral administration of Org 6001, 10 mg/kg twice daily for 10 days, the last dose given 1 hr before ligation, reduced the incidence of ventricular fibrillation and increased survival in both conscious and anesthetized animals. This effective antidysrhythmic dose regimen resulted in drug concentrations of 335 +/- 68 ng/ml in plasma and 2,940 +/- 408 ng Org 6001/g in the whole heart. At 24 hr after the last dose no protection against the dysrhythmias remained, and drug levels in both plasma and heart tissue were low. A good correlation was observed between the levels of Org 6001 in the heart and the reduction in the rate of rise of phase zero of cardiac action potentials obtained from drug-pretreated animals. It is concluded that prolonged administration of Org 6001 is effective against postligation dysrhythmias and that this effect may be associated with the drug's Class I activity.

Acute myocardial ischaemia in the anaesthetised pig: local catecholamine release and its relation to ventricular fibrillation.

In anaesthetised open-chest pigs, sequential myocardial samples were obtained before and after occlusion of the distal half of the LAD. These samples were analysed histofluorimetrically to determine the density of catecholamine containing neurones in each sample (quantified morphometrically), and radioenzymatically for total tissue noradrenaline content. Following coronary artery occlusion, 75% of the animals (24 out of 32) died in ventricular fibrillation in the first 30 min, the other 25% (8/32) survived the first 60 min of myocardial ischaemia. Coronary artery occlusion led to a significant reduction in the density of fluorescing fibres in the ischaemic myocardium of animals which fibrillated (from 1.25 +/- 0.2% to 0.67 +/- 0.10% at 15 min) whereas in the survivors there was no significant change in fluorescing area during the course of the experiment. Animals which fibrillated had a significant reduction in tissue noradrenaline concentration of the ischaemic myocardium (from an initial concentration of 612 +/- 72 to 402 +/- 64 ng/g ww) within the first 5 min of ischaemia. It is concluded that in this model of myocardial ischaemia, the development of ventricular fibrillation in the early phase seems to be related to the release of noradrenaline from the sympathetic neurones after the onset of myocardial ischaemia.

Haemodynamic and antiarrhythmic protective effects of intracoronary perfusion during percutaneous transluminal coronary angioplasty.

In 17 anaesthetized open-chest pigs, experiments were performed to determine if a myocardial protective effect can be obtained by intracoronary perfusion through the dilatation catheter during balloon inflation for percutaneous transluminal coronary angioplasty. Placement of the catheter such that the balloon lay in the middle third of the left anterior descending coronary artery caused a significant deterioration in haemodynamic status prior to balloon inflation, and on 5 occasions led to the development of ventricular fibrillation (VF). Balloon inflation without perfusion for periods of up to 5 min produced further haemodynamic deterioration, and culminated in VF in 4/14 cases. Simultaneous perfusion during balloon inflation (proximal perfusion pressure 900-1200 mmHg), with flow rates of 14.5 ml min-1 for arterial whole blood and 21 +/- 7 ml min-1 for blood diluted with 0.90% NaCl (haematocrit approx. 25%), not only prevented the haemodynamic deterioration but resulted in an improvement compared with values obtained with the catheter in position prior to balloon inflation. In no case did VF occur during 5 min of balloon inflation plus perfusion. The use of diluted blood as the perfusate was not associated with intracatheter thrombus formation, which was sometimes seen as a complication of whole blood perfusion.