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Endothelin-1 (ET-1) is a potent vasoconstrictor peptide, which may also elicit severe ventricular arrhythmias. The aims of our study were to compare the effects of total left anterior descending coronary artery (LAD) occlusion to intracoronary (ic.) ET-1 administration and to investigate the pathomechanism of ET-1 induced arrhythmias in 3 groups of anesthetized, open-chest mongrel dogs. In group A (n=10) a total LAD occlusion was carried out for 30 min, followed by a 60 min reperfusion period. In groups B and C ET-1 was administered into LAD for 30 min at a rate of 30 pmol/min (n=6) and 60 pmol/min (n=8). Epi- and endocardial monophasic action potential (MAP) recordings were performed to detect electrophysiologic changes and ischemia Blood samples for lactate measurements were collected from the coronary sinus (CS) and from the femoral artery. Infrared imaging was applied to follow epimyocardial heat emission changes. At the end of the ET-1 infusion period coronary blood flow (CBF) was reduced significantly in groups B and C (deltaCBF30MIN B: 21+/-2%, p

The supposed direct arrhythmogenic property of endothelin-1 (ET-1) has not yet been clearly proven. Our study aimed to characterize the electrophysiological changes during left anterior descending artery (LAD) occlusion and intracoronary (i.c.) ET-1 infusion, and to differentiate between the supposed direct and ischemic arrhythmogenic actions of ET-1 in a canine model. Changes of monophasic action potential duration (MAPD90) and upstroke velocity (UV) are capable of detecting local ischemic changes. Left and right ventricular endo- (LVEND, RVEND) and epicardial (LVEP, RVEP) monophasic action potentials were recorded. MAPD90, monophasic action potential dispersion (MAPDISP) and UV were determined. In group A (n = 8) 30 min LAD occlusion was followed by a 60 min reperfusion period. In groups B and C ET-1 was administered into the LAD at rates of 30 (n = 8) and 60 pmol/min (n = 10), respectively. In group A after the LAD occlusion both MAPD90 and UV decreased significantly in the LAD region (LVEP and LVEND 18 +/- 3% and 10 +/- 1%, p0.05, and 65 +/- 4% and 52 +/- 8%, respectively, p0.05; control and 30 min values in all groups), whereas the increase in MAPDISP remained unchanged. No severe arrhythmias were noticed in this group. In group B, both MAPD90 and MAPDISP increased significantly (LVEP and LVEND 11 +/- 4% and 18 +/- 3%, p0.05; MAPDISP 200 +/- 40%, p0.05), whereas UV remained unchanged at the end of the infusion. Early afterdepolarizations (EADs) were present in three instances. In group C both MAPD90 and MAPDISP increased significantly (LVEP and LVEND 12 +/- 5% and 26 +/- 8%, respectively, p0.05; MAPDISP 215 +/- 30%, p0.05) and UV decreased slightly in the LAD region. EADs were observed in five instances. Severe arrhythmias were observed in both groups B and C. We concluded that MAP prolongation, increased MAP dispersion and development of EADs all contribute to the arrhythmogenic action of ET-1. The lack of the almost prompt decrease of UV and MAPD90 which was observed in group A in groups B and C strongly supports the probability of a direct arrhythmogenic effect of ET-1.

The development of ventricular tachyarrhythmias caused by low-dose intracoronary infusion of endothelin-1 (ET-1) has recently been observed in dogs. The aim of the present study was to investigate the pathomechanism of ET-1-induced ventricular arrhythmias in 32 anesthetized, open-chest mongrel dogs in group A (n = 14) without, in group B (n = 14), and in group C (n = 4 control) with atrioventricular node ablation. The coronary blood flow (CBF) was measured in the left anterior descending (LAD) coronary artery by an electromagnetic flowmeter. Standard ECG, atrial and ventricular electrograms, and in groups B and C endocardial and epicardial monophasic action potentials (MAPs) were recorded. ET-1 was administered into the LAD at a low dose (30-60 pmol/min). At the time of the appearance of premature beats, CBF was only slightly decreased. The effective ventricular refractory period did not change significantly. Onset of spontaneous polymorphic and monomorphic sustained ventricular tachycardia (sVT) was observed in five dogs without bradycardia and in nine dogs with bradycardia. VTs in dogs with complete AV block were longer and slower. In most of the cases, ventricular fibrillation occurred. ET-1 treatment resulted in a significant increase in MAP 90% duration (255 +/- 9 vs. 290 +/- 8 ms endocardial, 244 +/- 10 vs. 292 +/- 12 epicardial; p0.05) at 70 beats/min ventricular pacing. In eight cases (group B), third-phase early afterdepolarization could be recorded. According to our results, the mechanism of ET-1-induced arrhythmias appears to be based on prolongation of MAP duration and development of afterdepolarizations.

Endothelin-1 (ET-1) is the strongest vasoconstrictor peptide isolated so far, which has a known arrhythmogenic property, as well. Intracoronary ET-1 infusion may cause ventricular premature beats (VES), ventricular tachycardia (VT) and ventricular fibrillation (VF). The aim of our study was to compare the thermographic and electrophysiologic changes during left anterior describing coronary artery (LAD) occlusion and ic. ET-1 administration. The measurements were performed on 16 sodium-pentobarbital anesthetized, open- chest dogs. The dogs were divided into 2 groups. In group A LAD occlusion was carried out for 30 minutes, followed by a 60 min reperfusion period. In group B ET-1 was administered into LAD at 60 pmol/min dose. Arterial blood pressure, coronary blood flow (CBF), heart rate (HR) and standard ECG were monitored. IR thermography was applied to follow epimyocardial heat emission changes. To determine the electrophysiological changes an endocardial monophasic action potential (MAP) electrode was inserted into the right ventricle and an MAP electrode was placed onto the left ventricle and an MAP electrode was placed onto the left ventricular epicardium. In group A CBF returned to baseline 20 minutes after releasing the occlusion. Ic. ET-1 infusion significantly reduced CBF in group B. Epimyocardial temperature decreased in both groups. In group A ventricular extrasystoles were noticed. In group B ventricular techycardias occurred with satisfactory CBF in 4 cases. In 5 dogs VF was observed. MAP duration 90 (MAPD90) decreased significantly in group A whereas significant increase was observed in group B. The left ventricular epicardial upstroke velocities correlated excellently with the epimyocardial temperature changes. Our result suggests that the decrease of epimyocardial heat emission and upstroke velocity correlates well in both groups, indicating ischemia, whereas the lack of the other ischemic MAP signs and the change of MAPD90 in the opposite direction suggests a different arrhythmia pathomechanisms in the ET group. Cardiothermography proved to be a useful tool in monitoring epimyocardial temperature changes during coronary artery occlusion and ET-1 induced vasoconstriction.

Objectives: Recently, extremely high levels of endothelin-1 (ET-1) were detected in the pericardial fluid of patients with heart disease; however, the pathophysiological importance of this finding is not known. The present study was designed to characterize ET-1 levels in canine pericardial fluid and to investigate the effects of local high concentrations of exogenous ET-1 in vivo. Methods: In anesthetized, open-chest dogs ET-1 (Groups 1 and 2: 11 and 33 pmol·kg−1·min−1; n =6 and 6, respectively) or physiological saline (Group 3, n =5) were infused into the closed pericardial sac for 40 min. In serial pericardial fluid and aortic blood plasma samples, ET-1 levels were measured by radioimmunoassay, and analysed by high-performance liquid chromatography (HPLC). Systemic arterial blood pressure, heart rate, cardiac output (CO), standard ECG and right ventricular endocardial monophasic action potentials (MAPs) were recorded. Results: Basal pericardial fluid ET-1 levels were significantly higher than respective plasma levels (342±210 vs. 8.0±5.2 pmol·l−1, n =14, P

In a previous study we established that endothelin-1 (ET-1) can induce characteristic ventricular tachycardias (VT) with significant prolongation of QT and QT c time. In this investigation we studied the role of Ca 2+ channels in the proarrhythmic effects of ET-1. In 24 anesthetized, open-chest mongrel dogs, ET-I was administered into the left anterior descending coronary artery at a comparatively low dose (60 pmol/min) for 30 min. Twelve dogs received the Ca 2+ -channeh blocker verapamil (0.4 mg/kg) before ET-1 application. The following parameters were recorded continuously over the infusion period: systemic arterial blood pressure, coronary blood flow, surface ECG leads, epicardial atrial and ventricular electrograms, and right and left ventricular endocardial monophasic action potentials (MAP). Electrophysiologic studies were performed by programmed electrical stimulation of the heart. Blockade of myocardial Ca 2+ channels attenuated the arrhythmogenic action of ET-1. After verapamil administration to ET-1-treated dogs, sustained VT did not appear and ventricular fibrillation (VF) developed only in two dogs. In the control group serious and sustained VT and VF developed in nine animals. It is noteworthy that verapamil did not prevent ET-1-induced prolongation of QT time. The results appear to prove that myocardial Ca 2+ channels are involved in the proarrhythmic effect of ET-1.

The effect of atrial stretching on the genesis of atrial arrhythmias was studied in 26 dogs. Left atrial dilatation was produced by inflation of a balloon catheter. Electrophysiological studies were performed by programmed electrical stimulation of the atrium and ventricle. The irritability of the atrium markedly increased when it was distended and atrial arrhythmias (sustained or non-sustained atrial tachyarrhythmias) could regularly be induced by administration of an early extrastimulus or--more rarely--by atrial burst pacing. In 10 cases spontaneous atrial tachycardia appeared during atrial balloon dilatation. The atrial effective refractory period shortened and the atrial conduction time lengthened on atrial stretching, while other electrical variables (cycle length, sinus node recovery time, atrioventricular conduction time, intraventricular conduction, ventricular refractory period, QT interval) remained unchanged. Atrial balloon dilatation was not accompanied by marked haemodynamic changes, and the left ventricular pressure curve, the contractility of the left ventricle and the central venous pressure did not change significantly on atrial stretching. The experimental data suggest that the atrial dilatation plays an important part in the pathogenesis of atrial arrhythmias.

An 16 Hunden, die 7 Tage taglich 5 mg ostronacetat intramuskular erhalten hatten, wurden Kreislauf und Kreislaufregulation untersucht. Die Durchblutung von Gehirn, Herz, Nieren, Muskeln und Haut und die Minutenvolumen-Fraktionen dieser Organe wurden mit86Rubidium und131Jodantipyrin bestimmt.

Aufgrund der bei einem grosen klinischen Material ermittelten Beobachtungen wurde zwei wichtige mit Infarkt und Pacemakertherapie zusammenhangende Fragen untersucht: 1. Indikation und Durchfuhrung der Pacemakertherapie bei akutem Infarkt; 2. durch den akuten Infarkt bedingte diagnestische und therapeutische Fragen bei einer Pacemakerimplantation unterworfenen Patienten. Die Analyse der ersten Frage erfolgte anhand der Beobachtung von 210, an einem akuten Infarkt leidenden Patienten, wahrend ihrer Behandlung in der “Wachstation”. In 42 der 210 Falle meldete sich im Laufe des Infarkts ein AV-Block 2. bzw. 3. Grades. Bei 18 der 42 Patienten kam es zu einer Pacemakerimplantation. Die Mortalitat der einer Schrittmacherbehandlung unterworfenen Patienten lag wesentlich niedriger, als die der konservativ behandelten an Infarkt und AV-Block leidenden Kranken. Die moglichst fruhe Pacemakerimplantation wird besonders im Falle gewisser AV-Blocktypen (2b bzw. 3b) als erforderlich betrachtet. In 9 der 200 Falle, in denen eine Schrittmachereinpflanzung vorgenommen worden war, lies sich das Auftreten eines akuten Infarkts registrieren. Im Laufe der Beobachtung einer jeden dieser 9 Falle meldeten sich eigenartige diagnostische und therapeutische Probleme, welche in der Arbeit eine eingehende Besprechung finden.

Mit Hilfe rekonstruktiver Operationen wurde eine bessere Behandlungsmethode fur obliterative Gefaskrankheiten entwickelt. Es ist jedoch nur wenig daruber bekannt, wie sich diese Operationen auf die Durchblutung, die Sauerstoffaufnahme und den peripheren Widerstand der Extremitaten auswirken. Zweck unserer Untersuchungen war es, die Extremitatendurchblutung der pra-operativen Periode mit derjenigen Monate nach der Operation zu vergleichen. Die Kreislaufuntersuchungen wurden an 11 Patienten durchgefuhrt, die an peripheren Gefasobliterationen litten. Es handelte sich um 10 Manner in einem Durchschnittsalter von 49 Jahren und urn eine 54jahrige Frau. Bei 6 Patienten fanden wir mit Hilfe der Aortographie einen Verschlus oder eine Stenose der Beckenarterien, bei 5 Patienten entsprechende Veranderungen an der Arteria femoralis.

The effect of lymph stasis on limb blood flow was studied in 38 dogs where lymph-oedema of one of the hindlimbs was induced by ligation of the lymphatics on the thigh and of the regional lymph-node. Haemodynamic examinations were conducted in 17 animals; total blood flow and the nutritive flow to the muscles and skin (86Rb extraction) were determined in both hindlimbs. Microcirculation was studied in 16 dogs by means of the india ink-gelatin injection method, the benzidine reaction and by the polyvinylchloride injection technique. In all cases specimens were taken from muscle, skin and subcutaneous connective tissue of both hindlimbs for light microscopic analysis. The results presented indicate an increase in total blood flow without any change in the nutritive flow to the skin or muscle in the lymph-oedematous limb. Lymph stasis induced intimal swelling and plasma infiltration of the intima and media of small vessels (pre-capillaries and metarterioles) of skin, muscles and subcutaneous tissue, which led to a blocked transportation of proteins. Small vessels of the limb with lymph-oedema were spottily dilated, whereas at other areas compressed capillaries could be seen. Evidence is supplied for the appearance of arteriovenous shunt circulation in lymph-oedema of the lower limb. In a previous study we observed that, unlike venous congestion, lymph-oedema of the limbs in man was accompanied by increased blood flow and a conspicuously low arteriovenous oxygen difference in the limb. (1) This finding led us to assume that chronic lymph stasis may induce arteriovenous shunt circulation. The present experiments were designed to study relative changes of total and nutritive limb blood flow and to examine alterations of the microcirculation in experimental lymph-oedema of the limb.

In 12 anesthetized, open-chest mongrel dogs, endothelin-1 (ET-1) was infused into the left anterior descending coronary artery through an indwelling catheter at a dose of 30 pmol.min-1 for 30 min (n = 8). In four dogs the ET-1 dose was increased to 60 pmol/min for 10 min. Programmed electrical stimulation was used for electrophysiologic studies. Coronary blood flow was reduced by 32% on average without any ischemic ECG signs. QT time (186 +/- 3 ms vs. 218 +/- 6, p0.05, and 225 +/- 9, p0.05, p0.05). Ventricular irritability increased in all cases; ventricular extrasystoles, and nonsustained and sustained tachycardias occurred and, in 11 cases, ventricular fibrillation terminated the experiments. In two dogs, early afterdepolarization was recorded. Therefore, ET-1 is capable of inducing fatal ventricular arrythmias at least partly independent of its vasoconstrictor effect. QT prolongation appears to have a pathophysiologic role in this arrythmogenic effect.

The effect of permanent bradycardia on the proarrhythmic action of endothelin-l (ET) was investigated in 24 open-chest anesthetized mongrel dogs. In 12 dogs, permanent bradycardia was induced by radiofrequency ablation of the AV node and the hearts were paced at 70 beats/min. ET (60 pmol/ min) was infused into the left anterior descending coronary artery. Blood pressure, coronary blood flow (CBF), and atrial and ventricular epicardial surface ECG were recorded continuously. Polymorphous ventricular tachycardia developed in every dog with permanent bradycardia. and ventricular fibrillation terminated the experiments in 11 cases. Bradycardia prolonged the basal QT but there was no difference in the frequency corrected QTc time between the two groups. ET prolonged the QT time in a similar fashion in both groups. In the control group, six dogs developed sustained ventricular tachycardias and ventricular fibrillation occurred in nine cases. EADP was found in six cases of eight registered. Signs of myocardial ischemia did not accompany the development of arrhythmias. We conclude that permanent bradycardia augments the direct proarrhythmic effect of ET in dogs.

Recently, extremely high levels of endothelin-1 (ET-1) were detected in the pericardial fluid of patients undergoing cardiac surgery. This study was designed to assess the pathophysiologic importance of this finding by infusing ET-1 into the closed pericardial sac of anesthetized dogs. Systemic arterial blood pressure, heart rate, and standard ECG were recorded. Intrapericardial infusion of ET-1 (11 and 33 pmol/kg/min; n = 4/4) for 40 min induced ventricular arrhythmias in all instances. The lower dose of ET-1 induced a substantial number of ventricular extrasystoles, couplets, and triplets. In one instance, ventricular extrasystoles accelerated into nonsustained ventricular tachycardia (VT). In animals receiving the higher dose, nonsustained VTs occurred regularly, whereas sustained VTs were detected in two of four animals. Before the onset of arrhythmias, QT time was significantly prolonged [ET-1 (11 pmol/kg/min) 180 +/- 12 to 198 +/- 10 ms, p < 0.05; ET-1 (33 pmol/kg/min) 192 +/- 15 to 233 +/- 13 ms, p < 0.01]. Hemodynamic variables did not change significantly before the onset of ventricular arrhythmias. Our results show that administration of exogenous ET-1 into the pericardial space induces ventricular arrhythmias associated with prolongation of QT time.