Biomedical subjects

G Raberger

Publications and source records attributed to G Raberger.

At least 37 records · Page 2Linked to original sources

PubMed1991

Effects of beta-adrenoceptor antagonism upon delayed reperfusion arrhythmias in conscious dogs.

Whereas isolated heart preparations or anesthetized animals have been used to assess the actions of beta-adrenoceptor antagonists upon reperfusion-induced arrhythmias, this study evaluated the possible antiarrhythmic effects of beta-adrenoceptor antagonism in conscious animals. Conscious, chronically instrumented dogs were subjected to a temporary occlusion of the left anterior descending coronary artery for 4 h. After the first hour of reperfusion, flestolol (N-(1,1-dimethyl-2- ureidoethyl)-2-hydroxy-3-(O-fluorobenzoyloxy)-propylamine sulfate), an ultra short-acting beta-adrenoceptor antagonist, was administered i.v. at infusion rates of 1 and 2.6 micrograms/kg per min. A control group received the equivalent volume of saline during this period. Delayed reperfusion-induced arrhythmias were evaluated by using a computerized analysis system. Treatment with flestolol did not affect the total number of beats, the number of normal and ectopic beats, and the arrhythmic ratio, i.e. the ratio of ectopic beats to the total number of beats. Hence, beta-adrenoceptor antagonism does not appear to suppress delayed ectopic activity during coronary reperfusion in conscious dogs.

Adrenergic beta-Antagonists↗

PubMed1991

Alpha 1-adrenoceptor blockade and/or 5-HT1A agonism during treadmill exercise in dogs.

1. The hypotensive effects of alpha 1-adrenergic blockade and/or stimulation of central nervous 5-HT1A receptors were studied using drugs with different affinity for central nervous 5-HT1A and peripheral alpha 1-adrenoceptors. Urapidil, 5-methylurapidil, flesinoxan and 8-OH-DPAT were compared under states of different activation of the autonomic nervous system, i.e. at rest and during graded treadmill exercise. 2. The rank order of hypotensive potency as derived from the most extensive decrease in resting diastolic arterial blood pressure was urapidil greater than 5-methylurapidil greater than flesinoxan much greater than 8-OH-DPAT. 3. The reflex increase in heart rate due to the decrease in arterial blood pressure at rest was suppressed after 0.1 mumol kg-1 flesinoxan. 4. The reflex increase in heart rate due to the decrease in arterial blood pressure at rest was less accentuated after high doses of urapidil and 5-methylurapidil. 5. During exercise both 5HT1A receptor agonists, flesinoxan and 8-OH-DPAT, decreased sympathetic tone. 6. The combined effects of alpha 1-adrenoceptor blockade and 5-HT1A receptor stimulation (urapidil and 5-methylurapidil) result in distinct decreases in blood pressure and slight suppression of reflex tachycardia at rest after high doses. Stimulation of 5-HT1A receptors alone (flesinoxan) suppresses reflex tachycardia by modulation of baroreceptor reflex and at high dose also diminishes exercise-induced increase in sympathetic tone.

8-Hydroxy-2-(di-n-propylamino)tetralin↗

PubMed1991

Ventricular arrhythmias after reperfusion: is there a correlation with infarct size?

The aim of this investigation was to examine whether any correlation exists between enzymatically estimated infarct size and arrhythmias arising in response to coronary reperfusion. Four hour occlusion of the left anterior coronary artery followed by reperfusion was carried out in conscious dogs. Serum creatine phosphokinase (CPK) analysis and planimetric determination of infarct size were performed. The Holter monitoring technique was used to analyze the arrhythmias. A good correlation was observed between the number of premature ventricular complexes (PVC) occurring during 4-h coronary artery occlusion and peak serum CPK values (CPKmax; r = 0.74). While PVC in the early 2-h reperfusion phase and on days 1 and 2 of the late reperfusion phase did not show a correlation with CPKmax nor with occlusion arrhythmias, arrhythmic activity on day 3 of the late reperfusion phase correlated well with CPKmax (r = 0.71) and occlusion arrhythmias (r = 0.75). Whereas it cannot be ruled out that arrhythmias on days 1 and 2 are related to coronary reperfusion as well as to the established infarction, we speculated that arrhythmias on day 3 are delayed arrhythmias in response to the occlusion procedure and not a consequence of reperfusion. Providing that arrhythmias occurring in the early reperfusion phase are almost exclusively induced by the arrhythmogenic phenomenon of reperfusion, we conclude that in contrast to occlusion arrhythmias, reperfusion arrhythmias are not markers of infarct size. Thus, a higher number of arrhythmias after reperfusion is not necessarily associated with a larger infarct size.

Animals↗

PubMed1990

[Cardiovascular pharmacology. An example of the need of clinically relevant pharmacological research].

Like all other scientific disciplines, preclinical pharmacological research is subject to permanent changes. New measuring devices and the possibility of continuous on line data acquisition have markedly influenced basic research in this field. Another aim of modern cardiovascular pharmacology is the testing of promising drugs in clinically relevant animal models of disease, particularly under conditions, referring to the everyday situation in patients, e.g. physical activity. Investigations carried out in this way allow an exact assessment of the clinical efficacy of new drugs, and are, thus, clearly indispensable, also from the ethical point of view, before primary evaluation of the drug in man.

Angina Pectoris↗

PubMed1990

Haemodynamic and metabolic effects of xamoterol in exercising dogs.

The effects of xamoterol on the haemodynamic adaptation to graded treadmill exercise were evaluated during five subsequent cycles in chronically instrumented dogs. At rest xamoterol, 0.2 mg/kg i.v., preferentially showed a positive inotropic effect, whereas 1 mg/kg i.v. also exhibited a marked chronotropic effect. The cardiac output and left ventricular power increased dose dependently. The mean left atrial pressure and total peripheral resistance decreased concomitantly. Xamoterol did not produce a noteworthy decrease in heart rate or positive dp/dtmax during exercise, even at a dosage of 1 mg/kg. A beta-adrenoceptor blocking effect could only be seen from the diminution of the exercise-induced changes in heart rate, dp/dtmax, cardiac output, left ventricular power and total peripheral resistance. Determination of the blood glucose, lactate and pyruvate levels before the start of each exercise cycle revealed that the drug induced a decrease in blood glucose and an increase in blood pyruvate. Thus, xamoterol exerted a dose-dependent sympathomimetic effect in dogs at rest. However, there was little evidence for a beta-adrenoceptor blocking action even at higher work loads, although preliminary experiments in conscious dogs showed that xamoterol shifted the isoprenaline dose-response curve to the right by a factor of 1.31 (0.2 mg/kg) and 3.05 (1 mg/kg).

Animals↗

PubMed1990

Efficacy of nitroglycerin in stress-induced regional myocardial dysfunction is dependent on the chosen model: investigations in anesthetized and conscious dogs.

The antianginal efficacy of nitroglycerin (1 microgram/kg per min) was investigated in two different experimental models, one using chloralose-anesthetized open-chest dogs, the other using conscious, chronically instrumented dogs. Heart rate, arterial pressure, left ventricular dp/dtmax, and left ventricular end-diastolic pressure were registered. Left ventricular regional contractile function in the area supplied by the left circumflex coronary artery (LCX) and the left anterior descending artery (LAD) were assessed using sonomicrometry. In both models, the coronary flow reserve was limited by a hydraulic occluder around the LCX. Cardiac stimulation was achieved by a bolus injection of isoproterenol (ISO 0.5 microgram/kg) in the anesthetized animals and by graded treadmill exercise in the conscious animals. In both cases, transient contractile dysfunction occurred in the area supplied by the stenosed vessel. This contractile dysfunction was completely abolished by nitroglycerin in the conscious animals, while nitroglycerin failed to show any antianginal effect in the anesthetized dogs. Although hemodynamic differences in open and closed chest should be considered, remarkable differences in mechanisms of blood-pressure regulation according to the mode of stimulation were observed: in contrast to the situation during treadmill exercise, the ISO-induced decrease in arterial blood pressure does not correspond to the clinical picture of an anginal attack. These results show that it is most important to mimic the complex pathophysiological reactions of angina pectoris in man as closely as possible in the experimental model.

Anesthesia, General↗

PubMed1990

Cardiovascular effects of flesinoxan in anaesthetized and conscious dogs.

Stimulation of 5-HT1A receptors is known to decrease the arterial blood pressure in anaesthetized rats, cats and dogs. We investigated the hypotensive activity of flesinoxan (0.1 + 0.2 + 0.7 mumol/kg), a 5-HT1A-receptor agonist, in dogs anaesthetized with either morphine and pentobarbital or enflurane and also in the conscious state. Flesinoxan led to a decrease in arterial blood pressure in anaesthetized, but not in conscious dogs. In the conscious state the marked increase in heart rate, which can be taken as an indicator of sympathetic tone, may have masked the consequences of vasodilatation. These different haemodynamic responses to flesinoxan may be dependent on side effects of the drug in the conscious dogs, in particular hyperventilation and salivation combined with anxiety, and on the magnitude of the decrease in baroreceptor reflex activity during anaesthesia with morphine and pentobarbital on the one hand and enflurane on the other hand.

Anesthesia↗

PubMed1990

Programmed electrical stimulation after myocardial infarction and reperfusion in conscious dogs.

The hemodynamic and electrophysiologic variables and the inducibility of arrhythmias were studied before coronary artery occlusion (CAO, 4h) and on days 4, 14, and 28 of the late reperfusion phase in conscious, chronically instrumented dogs. Despite a lack of significant changes in the hemodynamic and the electrophysiologic variables, the response to programmed electrical stimulation (PES) before and after CAO with subsequent reperfusion varied substantially. Before intervention arrhythmias such as sustained ventricular tachycardia (SVT) or ventricular fibrillation (VFib) could not be induced by PES via ultrasonic crystals located subendocardially (LAD and LCX region) or via common stimulation electrodes (right ventricle) in any of six instrumented animals. All six animals were inducible after CAO and reperfusion. Five animals showed SVT and one animal showed VFib in response to stimulation on days 4 and 14 of the late reperfusion phase after CAO. On day 28 four animals showed SVT, and two showed VFib. Antiarrhythmic drug testing carried out in the late reperfusion phase with lidocaine (1 mg/kg bolus followed by continuous infusion) revealed 50% efficacy at a dosage of 40 micrograms/kg/min, 100% at 80 micrograms/kg/min, and 67% at 120 mu/kg/min. The persistent inducibility of arrhythmias for the entire experimental period of 24 days may be attributable to the following features of our model: 1. Electrical stimulation carried out from three different locations. 2. The use of up to three extrastimuli in the PES studies. 3. The use of conscious dogs during CAO, reperfusion, and PES. This novel experimental approach thus promises to be of clinical relevance for the investigation of new antiarrhythmic drugs.

Animals↗

PubMed1990

Verification of a canine model of transient exercise induced myocardial dysfunction: antianginal effects of flestolol, an ultra short acting beta adrenoceptor antagonist.

STUDY OBJECTIVE - The aim of the study was to verify the reproducibility of a canine model of treadmill exercise induced regional myocardial dysfunction designed to mimic exertional angina pectoris in man. DESIGN - Dogs trained to run on a treadmill were chronically instrumented with a microtip manometer in the left ventricle, a hydraulic occluder around the circumflex branch of the left coronary artery, two pairs of crystals for sonomicrometry, and arterial and venous catheters. Experiments were started 10 d after surgery, when the animals were submitted to seven treadmill exercise cycles, each of 3 min, with a 7 min recovery period. Ischaemia was adjusted so as not to impair regional function at rest but to produce progressive dysfunction with increasing work load. Flestolol (1 microgram.kg-1.min-1) was infused intravenously during the third and fourth exercise cycle. SUBJECTS - Six mongrel dogs, 13.5-29.5 kg, were used. MEASUREMENTS and RESULTS - Flestolol caused a marked reduction in the exercise induced increase in left ventricular positive dP/dtmax, and minor reductions in heart rate and systolic blood pressure, resulting in a decrease in myocardial oxygen demand and an improvement in regional function in the circumflex area of the left coronary artery. The functional improvement was transient and disappeared entirely after termination of flestolol infusion. CONCLUSIONS - The results show that flestolol is beneficial in conditions of limited coronary reserve and exercise induced myocardial dysfunction. The fact that the extent of regional myocardial dysfunction was comparable before and after flestolol infusion confirms the stability and usefulness of this experimental model in the evaluation of antianginal drugs.

Adrenergic beta-Antagonists↗

PubMed1990

Effects of flestolol, an ultra-short acting beta-adrenoceptor antagonist, on hemodynamic changes produced by treadmill exercise or isoprenaline stimulation in conscious dogs.

The beta-blocking activity of flestolol was established during increasing isoprenaline infusions and during graded physical exercise in conscious, chronically instrumented dogs. After a control cycle, flestolol was infused at three doses (1, 2.67, and 10 micrograms/kg/min). Flestolol has an extremely short half-life, demonstrated by an 83% loss of effect within 25 min. Thus, flestolol allows easy titration of the effect, which might be a valuable property for its use in the treatment of critically ill patients. Due to the difference between pure beta-adrenergic stimulation and the much more complex regulation of circulation during exercise, the hemodynamic response to flestolol elicited marked differences between both set ups. Flestolol shifted the dose-response curves of isoprenaline-induced changes in heart rate, positive left ventricular dp/dtmax, and diastolic arterial pressure dose dependently to the right, while its main effect during exercise was a decrease in positive left ventricular dP/dtmax. Thus, testing of beta-adrenoceptor blockers using isoprenaline-induced tachycardia leads to an overestimation of potency and therefore is not appropriate to predict the clinical efficacy of these drugs to prevent stress- or exercise-induced increases in heart rate and hence myocardial oxygen-demand.

Adrenergic beta-Antagonists↗

PubMed1990

Cardiac and hemodynamic effects of diltiazem during exercise-induced myocardial dysfunction in dogs.

The effects of diltiazem were tested in chronically instrumented dogs in a model of exercise-induced myocardial dysfunction. Since various bradycardiac agents have beneficial effects on myocardial function during ischemia, it was of interest to find out how a decrease in afterload, possibly combined with a decrease in myocardial oxygen demand, influences dysfunction. Therefore, diltiazem (1 mg/kg i.v.) was tested during critical stenosis of the circumflex branch of the left coronary artery, which led to exercise-induced myocardial dysfunction. At rest, diltiazem causes a reflex increase in heart rate. During exercise, a decrease in heart rate and hence in myocardial oxygen demand was neutralized by a decrease in arterial blood pressure and hence a lowered myocardial perfusion pressure. Therefore, systolic shortening in the ischemic area improved neither at rest nor during exercise after diltiazem.

Angina Pectoris↗

PubMed1990

Antiarrhythmic efficacy of labetalol as assessed by programmed electrical stimulation.

1. The purpose of the present study was to investigate the haemodynamic, electrophysiological and antiarrhythmic effects of labetalol in the late reperfusion phase after myocardial infarction in conscious dogs. 2. Labetalol was administered in cumulative doses (0.5, 1 and 3 mg kg-1 90 min-1, i.v.). Compared to control the systolic blood pressure was significantly decreased 20 min after 0.5, 1 and 3 mg kg-1 and up to 30 min after 3 mg kg-1 labetalol. The diastolic blood pressure was significantly decreased 20 and 30 min after 0.5 and 3 mg kg-1 but was not significantly altered after 1 mg kg-1 labetalol. 3. Labetalol significantly increased the PQ, QRS, QT and QTc intervals, the 2:1 AV-conduction point, the ventricular effective refractory periods and the intraventricular conduction time from the apex of the right ventricle to the infarcted LAD-area. With the exception of the alterations in the PQ interval and 2:1 AV-conduction point the effects described above were dose-dependent. 4. Labetalol was active against arrhythmias induced by programmed electrical stimulation. This effect was already present after the lowest dose (0.5 mg kg-1). 5. The good antiarrhythmic activity of labetalol in this study can be explained by the adrenoceptor blocking properties and both the class I and III activity of this drug. Labetalol may be of potential benefit in controlling arrhythmias arising following myocardial infarction.

Animals↗

PubMed1990

Esmolol: effects on isoprenaline- and exercise-induced cardiovascular stimulation in conscious dogs.

Esmolol, a recently developed ultra-short acting beta-adrenoceptor blocking agent, was evaluated in 12 conscious chronically instrumented dogs with intact autonomic reflexes. The significance of its beta 1-adrenoceptor selectivity was examined at various cardiovascular activation levels established by either incremental isoprenaline infusion or graded treadmill exercise. The observed parameters were heart rate, systolic and diastolic arterial blood pressure, left ventricular dp/dtmax, and left ventricular end-diastolic pressure. Intravenous infusion of esmolol (25 and 250 micrograms.kg-1.min-1) led to a dose-dependent reduction of the isoprenaline-induced increase in positive dp/dtmax. The concomitant increase in heart rate was suppressed to a lesser extent. Characteristically of a beta 1-selective agent, esmolol had only a slight effect on the isoprenaline-induced reduction in diastolic blood pressure. The impact of esmolol on exercise-induced hemodynamic activation was much smaller. Exercise-induced increase in positive dp/dtmax was more sensitive to beta-adrenoceptor blockade than the concomitant increase in heart rate. Diastolic blood pressure was not influenced significantly. beta-Adrenoceptor blockade was virtually reversed within 20 min of discontinuation of esmolol infusion.

Adrenergic beta-Antagonists↗

PubMed1990

Investigations on pharmacological and immunological properties of imuthiol.

An observation was made that imuthiol exerts inhibitory effect on hemolysins forming cells (PFC) and on NK cells activity. It also reduces the number of T lymphocytes (in vitro), increases the activity of interleukin-1 and of the lymph node permeability factor. Well recognized is also its protective effect on thymocytes against hydrocortisone. Imuthiol was found to enhance rosette formation and to stimulate stem cells and partly suppressor cells. It reduces the level of cAMP. Its effect on the circulatory system is negligible.

Adjuvants, Immunologic↗

PubMed1990

Effects of acylcarnitine transferase blockade on metabolism and function in the normally and underperfused canine myocardium.

The acylcarnitine transferase blocking agent, sodium 2(5-(4-chlorophenyl)-pentyl)-oxirane-2-carboxylate (Clomoxir, INN), effectively inhibits free fatty acid oxidation, thereby decreasing myocardial oxygen consumption in the normally perfused myocardium without influencing cardiodynamic parameters. As a consequence, however, arterial free fatty acid levels increase significantly. In an acute dog model, we investigated the hypothesis that the sodium 2(5-(4-chlorophenyl)-pentyl)-oxirane-2-carboxylate-induced decrease in myocardial oxygen consumption may also improve the energetic situation in the underperfused myocardium. Regional myocardial function was assessed by means of subendocardially inserted ultrasonic crystals, and changes in metabolism were measured regionally by means of a catheter inserted into a local myocardial vein in the underperfused area. The flow in the circumflex coronary artery was reduced on average by 53.5% followed 30 min later by an infusion of sodium 2(5-(4-chlorophenyl)-pentyl)-oxirane-2-carboxylate (dosage: 20 mg/kg over 20 min). Arterial free fatty acid levels continuously increased, whereas arterial glucose levels decreased. In accordance with the situation in the normally perfused myocardium, free fatty acid uptake and oxygen uptake were also reduced in the underperfused area. However, sodium 2(5-(4-chlorophenyl)-pentyl)-oxirane-2-carboxylate induced a further, transient increase in end-diastolic segment length and a sustained decrease in systolic shortening in the underperfused area, indicating a further deterioration in regional myocardial function. Control experiments with infusion of 9 g/l sodium chloride showed no change in the degree of regional myocardial dysfunction throughout the observation period.(ABSTRACT TRUNCATED AT 250 WORDS)

Acyltransferases↗

PubMed1989

Cardiac and hemodynamic effects of the selective bradycardic agent KC 8857 during exercise-induced myocardial ischemia.

The effects of an in vitro bradycardic agent without negative inotropism, KC 8857 (3,7-di-(cyclopropylmethyl)-9,9-tetramethylene-3,7-diazabicyclo-[3.3.1]- nonane dihydrochloride), were tested in chronically instrumented dogs in a model of exercise-induced myocardial ischemia. KC 8857 was i.v. infused during critical stenosis of the circumflex branch of the left coronary artery which led to exercise-induced myocardial dysfunction. KC 8857 caused a decrease in heart rate, left ventricular dp/dtmax and calculated myocardial oxygen demand at rest and during exercise. Since positive dp/dtmax values at a given heart rate were not altered by KC 8857 it may be assumed that myocardial function was restored mainly by the decrease in heart rate.

Animals↗

PubMed1989

Holter monitoring in conscious dogs. Assessment of arrhythmias occurring during ischemia and in the early reperfusion phase.

Myocardial ischemic episodes of 5 min, 15 min, and 4 hr duration, with interposed reperfusion periods, were induced in the same conscious, chronically instrumented dogs. A drop in systolic blood pressure and an increase in heart rate and in the arrhythmic ratio (AR% = number of ectopic beats x 100/total number of beats, as assessed by Holter monitoring) was registered in response to the induction of myocardial ischemia. Reperfusion-induced salvage after coronary occlusion of 5 and 15 min duration was documented by an immediate return of systolic blood pressure, heart rate, and AR to the preocclusion control level. However, after coronary occlusion lasting for 4 hr, reperfusion induced a further drop in blood pressure and an increase in heart rate and in AR. We conclude that in conscious dogs, reperfusion-induced arrhythmias do not occur after short-lasting myocardial ischemic episodes. Reperfusion after long-lasting ischemia induces marked ventricular ectopic activity, yielding an arrhythmic ratio of more than 80%. Although these reperfusion-induced arrhythmias impair the hemodynamic state, they are well tolerated in the conscious dog and can be assessed by the Holter monitoring technique. This new experimental approach promises to be of clinical relevance for investigations on the therapeutic efficacy of new antiarrhythmic drugs.

Animals↗

PubMed1989

Holter monitoring in conscious dogs. Assessment of arrhythmias occurring in the late reperfusion phase after coronary occlusion.

Arrhythmias occurring in the late reperfusion phase, i.e., up to 3 days after episodes of 5 min, 15 min, and 4 hr of coronary occlusion (CAO), were investigated in six conscious, chronically instrumented dogs using the Holter monitoring technique. The arrhythmic ratio (AR% = number of premature ventricular complexes x 100/total number of beats) of a 24-hr preocclusion control record was 0.004% and did not differ from the values assessed for day 1 (0.004%) and 2 (0.001%) of the late reperfusion phase after 5 min CAO. After 15 min, CAO increased, but insignificantly elevated AR values were registered on days 1 (2.5%), 2 (0.26%), and 3 (0.1%) of the late reperfusion phase. On day 1 of the late reperfusion phase after 4 hr CAO, the AR increased markedly to 75%. On day 2 of this phase, the AR was lower (20%) but still significantly elevated. On day 3, the AR was 3.5%, a value still markedly, although not significantly, above the preocclusion control level. We conclude that in conscious dogs, arrhythmias in the late reperfusion phase do not occur after 5 min CAO. However, after 15 min CAO and, especially, after 4 hr CAO, an increase in arrhythmic activity occurs in the late reperfusion phase and gradually declines towards the preocclusion control level over a period of 3 days. Thus, it could be demonstrated that the long-term assessment of reperfusion arrhythmias by ECG monitoring using the Holter technique is feasible in conscious dogs. This method represents a promising approach to clinically relevant experimental investigations on the therapeutic efficacy of a new antiarrhythmic drugs.

Animals↗