G. Raberger

The Effects of an Intracoronary Infusion of Adenosine on Cardiac Performance, Blood Supply and on Myocardial Metabolism in Dogs

SummaryThe effects of 10-min intracoronary infusion of 10μg/kg/min adenosine on coronary and systemic haemodynamics, cardiac performance, myocardial CO2 and H+ balance and myocardial substrate metabolism were investigated in7 anaesthetized dogs. The following results were obtained. 1.During the adenosine infusion coronary blood flow rose 3-to 4-fold above the preinfusion value whereas the coronary AVD-O2 and coronary resistance fell. Cardiac oxygen consumption fell significantly during the first 5 min of infusion but rose thereafter to values exceeding the starting value. The aerobic efficiency of the heart was significantly increased during the first 7 min of the adenosine infusion.2.The myocardial release of total CO2 was significantly diminished within the second minute and increased at the end of the adenosine infusion. Myocardial H+ release showed a tendency to increase during the first 7 min of infusion becoming significant if a correction was applied for the concomitant decrease in myocardial CO2 production.3.Myocardial balance and OER values for FFA indicated a FFA release whereas glucose and pyruvate uptake were significantly increased during the whole infusion period. The myocardial lactate uptake and OER were significantly decreased between the 5th and 10th min of the infusion.4.The temporal course of the decrease in myocardial lactate uptake and of the increase in myocardial flow was nearly identical. Myocardial glucose uptake showed a similar course but with a 2-min lag period. 5 min after the commencement of the adenosine infusion 34 μmoles/100 g more of glucose and 63 μmoles/100 g less of lactate (mean values) were taken up by the heart.5.The results were interpreted on the basis of a glycolytic and lipolytic action of adenosine on the myocardium brought about by a stimulation of myocardial 3,5-AMP production. A connexion between the observed metabolic effects and the effects of adenosine on coronary resistance and flow is discussed and the myocardial metabolic acidosis as mediator in positive feedback control over myocardial metabolic processes and cardiac blood supply is stressed.

The dependence of the effects of i.cor. Administered adenosine and of coronary conductance on the arterial pH,pCO2 and buffer capacity in dogs

SummaryCoronary conductance and the coronary dilatory action of adenosine, injected into the left coronary artery, were investigated at different arterial pH andpCO2 in intact anaesthetized dogs. Four groups of experiments were carried out: Experiments with slow i.v. infusion 1. of 0.1 N HCl, 2. of 5% NaHCO3, 3. of 1 M THAM and 4. of 0.1 N HCl following a preceding infusion of THAM. The following results were obtained:1.The vasodilatory effect of an intracoronarily injected dose of 1–2μg/kg adenosine showed a highly significant negative correlation with the arterial pH and a significant positive correlation with the arterialpCO2 in those groups, where the changes in arterial pH andpCO2 were accompanied by changes in the extracellular buffer capacity (infusions of HCl, NaHCO3 and THAM).2.Coronary conductance showed a significant negative correlation to the arterial pH in those experiments where changes in arterial pH were accompanied by reciprocal changes in arterialpCO2 (infusions with HCl, THAM and HCl after THAM). Even on exclusion of the influence of concomitant changes in heart rate on coronary conductance by a partial correlation analysis the correlation between coronary conductance and arterial pH remained highly significant in the experiments with HCl and THAM infusions.3.The results obtained with adenosine were discussed with respect to the theory of a “propagated metabolic acidosis” as an underlying mechanism of the coronary dilatory action of adenosine. An importance of the coronary smooth muscle intracellular pH as a determining factor of coronary vascular tonus was suggested.

Enhancement of the coronary dilator effect of intravenous and intracoronary administered adenosine by hexobendine in dogs

Abstract The effects of i.v. and i.cor. administered adenosine on coronary vascular resistance were investigated before and following intraduodenal adminisration of 1 or 2 mg/kg hexobendine in anaesthetized dogs. The following results were obtained: 1. 1) The intraduodenal application of hexobendine (2 mg/kg) led to a significant potentiation of the coronary dilator effects of i.v. administered adenosine (relative potency = 18) for a period of more than 3 hr. The coronary dilator effects of i.cor. administered adenosine (manifest at one hundredth of the i.v. effective dosage) were less-markedly enhanced (relative potency = 2.6) by pretreatment with hexobendine. 2. 2)Potentiation of the coronary dilator effect of i.v. administered adenosine reached its maximum 40–50 min following hexobendine pretreatment, whereas the effects of i.cor. administered adenosine reached maximum potentiation only 150–180 min following the intraduodenal application of hexobendine, at a time when the potentiation of i.v. injected adenosine had already declined. From this significant difference in the temporal course of the potentiation of the effects of adenosine administered by different routes, it may be concluded that specific myocardial binding of hexobendine occurs, leading to a direct effect of hexobendine on the myocardial site of adenosine action .

Die Wirkung von Aminorex (Menocil®) auf die Hämodynamik des kleinen und großen Kreislaufs bei i.v. Darreichung am Hund

SummaryThe effects of a single i.v. injection or infusion of Aminorex (2-amino-5-phenyl-2-oxazoline-fumarate) on blood pressure, blood flow, and haemodynamic resistance of the pulmonary and femoral arteries were investigated in anaesthetized dogs and compared with those of Norepinephrine. The following results were obtained:1.Aminorex (dose-range between 10 and 160 μg/kg i.v.) caused a transient increase in the mean blood pressure of the pulmonary artery and in the mean pulmonary perfusion pressure (Part. pulm. - Pleft atrium). At the same time the pulmonary blood flow fell by 10–20%. A dose-dependent increase in the vascular resistance of the pulmonary vessels was observed in all experiments. The effects lasted for 20 to 60 min, according to the dose. Isoproterenol (1,0 μg/kg i.v.) led to a fall in the pulmonary vascular resistance and abolished the resistance increase following the Aminorex-administration.2.An i.v. infusion of Aminorex (dose-range between 5 and 50 μg/kg/min) led to an increase in pulmonary blood pressure and vascular resistance. At the same time a slight decrease in heart rate and pulmonary blood flow was obtained. These pulmonary haemodynamic changes reached their maximum 15 min after the onset of the infusion and remained constant during the whole period of an infusion lasting 40 min. After discontinuing the infusion the pressure and resistance values returned only partially to the preinfusion values.3.An infusion of 10 μg/kg/min Aminorex led to an increase in the blood pressure of the systemic circulation and in the total peripheral vascular resistance. Both changes were less marked when compared with the simultaneously occurring effects on the pulmonary haemodynamics. At the same time the blood flow in the femoral artery was diminished to a greater degree than in the pulmonary artery. As a result of the observed flow- and pressure changes in the pulmonary and femoral arteries the influence of an Aminorex-infusion on the haemodynamic resistance of both vessels was identical with regard to the time course and the intensity of the observed effects.4.Pretreatment with Phentolamine abolished the effects of an infusion of 10 μg/kg/min Aminorex on pulmonary blood pressure and vascular resistance, whereas pretreatment with Propranolol enhanced these effects.5.Following an i.v. infusion of 0.5 μg/kg/mm Norepinephrine pulmonary blood pressure and vascular resistance rose only transiently, whereas the pulmonary blood flow decreased at the same time, due to an initial fall in heart rate. These initial changes did not last in spite of a continued Norepinephrine infusion.6.The effects of Norepinephrine on the systemic blood pressure were more pronounced than those on the pulmonary blood pressure. As a consequence, the increase in the work done by the left ventricle was greater than the increase in the work done by the right ventricle. In contrast, the increase in blood pressure and vascular resistance caused by Aminorex was more pronounced in the pulmonary circulation and therefore the right ventricular work increased more than the left ventricular work.

The effects of an intravenous infusion of norepinephrine on pulmonary and systematic haemodynamics with and without propranolol pretreatment in dogs

Abstract The effects of an infusion of 0.75 μg/kg/min norepinephrine on blood pressure, blood flow and vascular resistance in the pulmonary and femoral circulations and on heart rate were investigated with and without pretreatment with 2 mg/kg propranolol (Inderal®) i.v. in anaesthetized (chloralose/N2O) open chest dogs. The following results were obtained: 1. 1) Infusion of norepinephrine caused a maximum relative increase in mean peripheral blood pressure of 46%, whereas the mean pressure in the pulmonary artery rose only by 16%. There was almost no change in pulmonary pressure gradient (Part.pulm.-Pleft atrium). At the same time, the mean femoral blood flow decreased after a transient initial increase to a minimum value, 37% below the pre-infusion level. The pulmonary blood flow fell by 22%. Consequently, a relative increase of 138% was observed in femoral resistance, while the pulmonary vascular resistance rose insignificantly only by 28%. 2. 2) These differences in the haemodynamic effects of a norepinephrine infusion on the two vascular systems were not abolished by pretreatment with propranolol. Therefore, the established differences do not seem to be caused by a specific β-adrenergic autoinhibition of the norepinephrine effects on the pulmonary vessels. 3. 3) A significant decline in the haemodynamic changes took place in the femoral circulation during norepinephrine infusion. The norepinephrine effects on the pulmonary circulation exhibited this phenomenon of acute tolerance only to a small and insignificant extent. 4. 4) After pretreatment with propranolol, the infusion of norepinephrine led to an increase in pulmonary and femoral vascular resistance approximately equal to that found in the control animals but remained maximal until the end of the infusion. (No acute tolerance with propranolol pretreatment). In the discussion, the difference in the intensity of the norepinephrine effects on the pulmonary and femoral vascular systems is explained by the special elasticity of the pulmonary vessels, the role of the β-receptor in the development of acute tolerance is pointed out, and a comparison of the effects of norepinephrine with those of aminorex on pulmonary and femoral haemodynamics is made.

Blut- und Gewebsspiegelkurven sowie renale Ausscheidung von α-Acetyldigoxin bei i.v. Darreichung am Hund

SummaryBlood and tissue levels of α-acetyldigoxine were investigated in mongrel dogs at different intervals following the intravenous administration of 0.4 mg/kg of the glycoside, using a chromatographic separation and a fluorometric determination method. The following results were obtained:1.During the phase of distribution (up to 5 min post. inj.) a blood elimination rate with a half-life of 105 sec was observed.2.In organs with a high blood flow rate the following maxima of tissue glycoside levels were reached 5–10 min after the administration of α-acetyldigoxine: kidney (2.98), adrenal (1.31), heart (1.02), liver (0.76) and skeletal muscle (0,59 μg/g). In adipose tissue, maximal tissue levels were reached significantly later (approximately 30 min after the inj.).3.Following the phase of distribution an exponential decline of the glycoside tissue levels was observed in all organs with marked differences in rate and half-life between the different organs. Especially the difference between half-live values of heart (75 min) and adipose tissue (167 min) indicated a redistribution from organs with a high blood flow to organs with a high lipid content.4.Within the first two hours α-acetyldigoxine was excreted mainly by the kidneys. The average recovery for this period was 5% of the administered dose. In all animals the i.v. administration of 0.4 mg/kg α-acetyldigoxine leads to increasing toxic alterations of the ECG even during the period of decreasing cardiac glycoside levels. Most animals died 1–2 hours post inj. from ventricular fibrillation.Zusammenfassungα-Acetyldigoxin wurde an Hunden in einer Dosis von 0,4 mg/kg i.v. verabreicht und die Blut- und Gewebsspiegel zu verschiedenen Zeitpunkten nach der Injektion mittels chromatographischer Auftrennung und nachfolgender fluorometrischer Messung bestimmt. Es wurden die folgenden Ergebnisse erhalten.1.In der Verteilungsphase (bis 5 min post inj.) erfolgte die Elimination aus dem Blut mit einer Halbwertszeit von 105 sec.2.In den gut durchbluteten Organen wurden 5–10 min nach der Injektion folgende Mittelwerte für die Maximal-Konzentrationen von α-Acetyldigoxin erreicht: Niere (2,98), Nebenniere (1,31), Herz (1,02), Leber (0,76) und Skeletmuskulatur (0,59 μg/g). Im Fettgewebe wurden die Konzentrationsmaxima erst nach 30 min erreicht.3.In allen untersuchten Organen erfolgte nach Erreichen der Maxima ein exponentieller Abfall der α-Acetyldigoxin-Spiegel, wobei zum Teil stark unterschiedliche Halbwertszeiten bestimmt werden konnten. Extremwerte: Herz (75 min), Fettgewebe (167 min). Aus diesen Befunden wurde auf eine Rückverteilung aus den Organen mit hoher Durchblutung in solche mit hohem Lipoidgehalt geschlossen.4.Innerhalb der ersten beiden Stunden nach der i.v. Zufuhr wurde α-Acetyldigoxin im wesentlichen durch die Niere ausgeschieden, wobei bis zu 5% der verabreichten Dosis wiedergefunden werden konnten.5.Die Verabreichung von 0,4 mg/kg α-Acetyldigoxin führte bei allen Tieren zu toxischen EKG-Veränderungen, die auch in der Phase des exponentiellen Abfalls der Glykosidkonzentration im Herzen ständig an Schwere und Häufigkeit zunahmen, wobei die meisten Tiere 1–2 Std post inj. durch Kammerflimmern endeten.

Die Wirkung von Hexobendin auf Stoffwechsel und Durchblutung des Gehirns. Beitrag zur Theorie der Wirkungsweise cerebral-vasodilatatorischer Substanzen

An Hunden (Chloralose/N20) wnrden nach Anbringen einer Schraubkaniile in den Sinus eonfluens die eerebral-arteriovenSsen Konzentrationsdifferenzen fiir 03, pCO~, H+, Glucose, Laetat und Pyruvat vor nnd zu verschiedenen Zeitpunkten nach i.v. Verabreiehung yon 0,4mg/kg Hexobendin laufend bestimm%. Parallel dazu wurden elektromagnetische Messungen des cerebral-venSsen Aasflusses (V. maxillaris int.) durchgefiihrt. Unter Hexobendin kam es zu gegensinnigen Ver&nderungen der AVD-O 2 (Abfall) und des venSsen Ausflusses (Ans%ieg), die yon einer signifikanten Zunahme der auf den Sauerstoffverbraueh bezogenen Glucoseaufnahme (Sauerstoff-Extrak~ionsr~te) bei gleichzeitigem Riiekgang einer vorher naehgewiesenen cerebralen Laetatund Pyruvatfreisetzung begleitet waren. Die vor Hexobendin nachweisbare cerebrale H +und C02-Abgabe ~ntrde nach Verabreichung der Substanz vorfibergehend verst&rkt. Aus den BeIhnden wird eine metabolische Acidose mit Rfick~irkungen anf den cerebralen Gef&Bwiderstand als Mechanismus der vasodilatatorischen Wirkung yon ttexobendin diskutiert.

Blut- und Gewebsspiegelkurven von ?-Acetyldigoxin bei i.v. Darreichung am Hund

~-Acetyldigoxin wurde nach i.v. Darreichung yon 0,4 mg/kg am I tund bezfiglich seiner Verteilung und Elimination aus B]ut und Organen untersucht. Die Bestimmung erfolgte nach T6tung der Tiere aus den Blurund Harnproben bzw. den Organen mittels einer s£ulenchromatographischen Auftrennung und nachfolgenden spektrofluorometrJschen Messung. Aus den erhaltenen Werten wurden die Regressionsgeraden sowie Italbwertszeiten ffir Blutund Organelimination errechnet. Aus den Kurven wurde auf zwei Phasen tier Verteilung geschlossen, eine durchblutungsabh/ingige und eine zweite, w~hrend der die Verteilung gem~13 der LipoidlSsliehkeit vor sich geht. Weiterhin kormte nachgewiesen werden, dag das Herz keine Vorrangstellung in der Speieherung oder Aufnahme der IIerzglykoside besitzt, tIinsichtlich der Korrelation yon Glykosid-tIerzkonzentration und Glykosid-lterzwirkung zeigte sich, dab auch w~hrend der Phase des Abfalles der Konzentration die EKGVer/inderungen ztm~hmen und die meisten Tiere zwischen 1 und 2 Std nach der Injektion s~arben. Im H~rn wurden innerhalb yon 2 Std 5o/o der verabreichten Dosis ausgeschieden, im Gallenblaseninhalt waren es zum selben Zeitpunkt nur 0,45 °/o. c~-Acetyldigoxin kann aufgrund dieser Untersuchungen als Glykosid mit rascher Elimination aus dem Blur und rascher Verteilung nnd Riickverteilung in den Organen angesehen werden.