Prevention of coronary platelet aggregation with a phosphodiesterase inhibitor RX-RA 69.

The formation and prevention of coronary platelet thrombi (CPT) was studied in a modified Folts model in 23 anaesthetized dogs. The left circumflex coronary artery was acutely damaged and narrowed until resting flow started to fall. Spontaneous sharp decrease of flow indicated the acute formation of CPT. Intravenous infusion of 30 ng/kg/min of PGI2 prevented the formation of CTP. The effect lasted 3-7 min after termination of the infusion. RX-RA 69 a potent inhibitor of platelet phosphodiesterase (IC50 of 1 X 10(-9) mol/1) inhibited the formation of CPT for 9 and 18 min when 60 and 120 micrograms/kg were administered i.v. The results demonstrate that platelet aggregation induced by acute damage of the vascular wall can be inhibited by a potent PDE inhibitor.

[The "spill-over" method for flow measurements]. / Die Spillover-Flussmessung.

"Spill-over" measurement is a simple method for estimating arterial blood flow during selective angiography. It depends on a direct comparison between a known contrast flow rate and the unknown blood flow in the aortic branch that is being examined. The criterion crucial to the measurement is the back-flow of contrast into the aorta. By means of model and animal experiments, it has been established why back-flow occurs and which factors favour or retard back-flow and thereby falsify the results. The results of "spill-over" measurements were compared with electro-magnetic measurements. A modification of the "spill-over" method is described, which makes it suitable for routine use in visceral angiography.

[Haemodynamic effects of intraarterial contrast injections (author's transl)]. / Hämodynamische Effekte der intraarteriellen Kontrastmittelinjektion.

Intra-arterial contrast injections have well known systemic and pulmonary vascular effects; in addition there are local haemodynamic changes which begin immediately after the injection and last for several seconds. Three phases can be recognised: Phase 1 Increased flow, pressure and turbulence due to transmission of kinetic energy from the contrast medium to the vessel contents. Phase 2 Reduced flow due to the high viscosity of the contrast medium. Phase 3 Increased flow, probably a pharmacological results produced by contrast (osmolarity). The effects of contrast injection can be altered by changes to the catheter or to the properties of the contrast medium. This has practical consequences for injection techniques and for flow measurements. While assessing the clinical usefulness of the "spill over" flow measurements described by Olin and Redman in 1966, we concluded that the haemodynamic effects of the contrast lead to significant falsification of the measurements, and this also has some significance for the performance of angiography. We have therefore studied this phenomenon, its causes and the factors which influence it, on a model and in animal experiments. In order to quantify changes in flow caused by the injection during animal experiments, a study was carried out on the effects of contrast media on electromagnetic measurements.

An exchangable intra-atrial balloon device.

An exchangeable atrial balloon device is described. It consists of an outer guide and a latex Foley urinary retention catheter. The guide is sutured into the atrial appendage and brought out through the chest wall. The advantages of the device are discussed.

[Standardized experimental coronary stenosis. Reduction of diameter and cross-sectional area following eccentric narrowing]. / Standardisierte Coronarstenosierung im Tierexperiment. Reduktion von Durchmesser und Querschnittsfläche bei exzentrischer Einengung. Methodische Mitteilung.

The hemodynamic relevance of a coronary stenosis depends essentially upon the reduction of the cros-sectional area of the coronary lumen. However, the extent of experimental coronary narrowing is measured generally by determining the coronary diameter. In a series of experiments, the relationship between diameter and cross-sectional area (d/a) was determined using a micrometer constrictor and four different silastic tubings the size of which reflected actual coronary diameters as measured in coronary casts of German shepherd dogs. The d/a relationship was linear over a range of diameter reductions from 50 to 90%. A "physiologic" wall of thickness of 0.3-0.4 mm had no major influence on the d/a relationship. However, identical reductions of diameters and cross-sectional areas could only be achieved with the tubing fitting exactly into the curvature of the coronary constrictor.

[Effects of coronary stenosis and mean aortic pressure on coronary blood flow, poststenotic coronary pressure, and reactive hyperemia]. / Einfluss von Koronarstenose und Aortendruck auf Koronarfluss, Koronardruck und reaktive Hyperämie

Six dogs were subjected to an acute stenosis of the left anterior descending coronary artery. The mean aortic pressure was fixed with a windkessel and an occluder on four different levels. A significant decrease of coronary blood flow and poststenotic coronary pressure was closely related to the level of mean aortic pressure. With lower aortic pressure the decrease occurred earlier than with higher aortic pressure. A 50% stenosis did not significantly influence coronary flow and poststenotic coronary pressure. A 90% stenosis resulted in decrease below 10% of control. In a range of aortic pressure between 60 and 140 mm Hg reactive hyperemia was significantly diminished at a 60% stenosis. Reactive hyperemia was completely abolished when coronary stenosis was 90%.

[Intramyocardial pressure at various depths, during aortic constriction and myocardial ischemia in the dog (author's transl)]. / Der intramyokardiale Druck des Hundes in verschiedenen Tiefen, bei Druckbelastung und bei Ischämie des Herzmuskels

Systolic intramyocardial pressure (IMP) is measured with a modification of the "closed perfusion technic" in 3 different layers of the myocardium in 8 anesthetized mongrel dogs. In the subendocardium IMP exceed left ventricular pressure (LVP) by about 30% whereas it is 30% lower than LVP in the subepicardium. Under resting conditions the level of isobaric balance of IMP and LVP is at a distance of 57% from the epicardium. During thoracic aortic constriction the ratio of IMP/LVP increases in the subepicardium but decreases in the subendocardium. Occlusion of the left circumflex coronary artery for 30 seconds results in a decrease of IMP and IMP/LVP in the ischemic region. In 25% of all cases, however, an increase of these parameters is found.

[Femoral head blood flow in dogs subjected to intra-articular pressure increase and to pressure release]. / Hüftkopfdurchblutung beim Hund unter intraarticulärer Druckerhöhung und Entlastung.

In six beagles femoral head blood flow is measured with radioactive microspheres. When intra-articular pressure of the hip joint is increased by 50 mm Hg, blood flow is diminished to 48%. Reducing intra-articular pressure to the initial level increases femoral head blood flow to 78%. The results support the demand for immediate pressure relief of hemarthrosis.

[Injection methods for the demonstration of the coronary arterial vasculature (author's transl)]. / Verschiedene morphologische Darstellungen des Koronargefäss-systems des Hundes

Four different methods for the demonstration of the coronary arterial vasculature are examined. Among the techniques studied corrosion casts (epoxid- and acrylic resin) permit the best qualitative and quantitative evaluation of superficial and deep arteries and arterioles. Down to the smallest infusible vessels of 15-25 mum there is practically no shrinkage. X-ray arteriography with an aqueous solution of barium sulphate is less suitable because X-rays allow no satisfactory stereoscopic view. The demonstration of arterioles and collaterals is limited to vessels larger than 50 mum because of the low resolution of the X-ray tube. Silicone rubber does not only fill the arteries, but also the capillary bed and the venous system. Therefore deeper parts of the vasculature can only be studied after slicing the heart. The substantial shrinkage of the material makes quantitative measurements difficult.

Contralateral renal function following unilateral renal artery constriction.

The acute (0.5-3.0 h) response of the contralateral kidney to unilateral renal artery constriction was studied in 7 pentobarbital-anesthetized dogs. Within 30 min after unilateral renal artery constriction to a pressure of about 60 mm Hg, contralateral vascular resistance, sodium excretion and filtration fraction increased significantly while glomerular filtration rate, blood flow and plasma flow did not change. Renin secretion decreased dramatically within 30 min, demonstrating a negative venous minus arterial plasma renin activity in some dogs. Unilateral renal artery constriction did not change the rate of angiotensin II extraction across the contralateral kidney or the urinary renin activity (measured in 4 dogs). These results indicate that the acute response of the contralateral kidney to unilateral renal artery constriction is somewhat different from that seen in the chronic state.

Postischemic liver damage in rats: amino acid analysis and morphometric studies.

Normothermic, temporary, total ischemia of the liver was produced for 60-225 min under transient portal decompression with a by-pass between the mesenteric and the femoral vein. Total amino acids in the liver tended to increase after an ischemic period of more than 120 min without reperfusion as compared with control with increasing trends in most of the individual amino acids. In a group undergoing 120 min of ischemia and 60 min of reperfusion, total amino acids and individual amino acids tended to decrease. Total plasma amino acids significantly increased after ischemia of more than 120 min. Without reperfusion, elevations of almost all amino acids except for branched chain amino acids were found, whereas after reperfusion most of the individual amino acids also increased including branched chain amino acids. Molar ratios of branched chain amino acids to tyrosine and phenylalanine decreased only after more than 120 min ischemia without reperfusion. Volume ratios of organelle disintegration on electron micrographs such as mitochondrial degradation and autophagic vacuoles were moderately increased after 90 min ischemia with a further steep rise after more than 120 min ischemia. The survival rates of the animals after 60, 90 and 120 min ischemia were 35% (6/17), 27% (3/11) and 25% (3/12), respectively. The following conclusions were obtained: 1) Pre-necrosis of the hepatocytes with simultaneous protein degradation started after ischemia for about 2 hr. The survival rates of the animals after 60 and 90 min ischemia were very low despite of mild necrosis of the liver. 2) Most of the amino acids in the liver were washed out into the plasma to cause an abnormal plasma amino acid pattern in the acute state. However, the molar ratio of branched chain amino acids to aromatic group was not reduced, in contrast to the ischemic group without reperfusion.

Morphologic investigation of coronary arteries subjected to hypertension by experimental supravalvular aortic stenosis in dogs.

A sustained and gradual development of hypertension in coronary arteries of 16 foxhounds was induced by afterload stress with supravalvular aortic stenosis. Dogs were perfusion fixed after 4 months and 1 year of stenosis for morphologic analysis of coronary arteries with scanning electron microscopy, transmission electron microscopy, and light microscopy. Mean prestenotic pressures and SD standard deviations in millimeters of mercury for perfusion-fixed foxhounds after 4 months were systolic 141 +/- 14, mean arterial 101 +/- 8, and diastolic 81 +/- 7, and after 1 year systolic 182 +/- 31, mean arterial 128 +/- 22, and diastolic 101 +/- 16. Scanning electron microscopy results of coronary arteries subjected to 4 months of hypertension show little change from normal coronary arteries. Only isolated cases of desquamating endothelial cells were seen directly proximal to ostia of coronary arteries. Transmission electron microscopy showed no ultrastructural changes in this banding group. In four of six foxhounds subjected to 1 year of hypertension, scanning electron microscopy observations of coronary arteries revealed one to five areas of endothelial denudation, typically oriented parallel to the longitudinal axis of the artery, a few cell diameters wide and 100 to 300 microns in length. These lesions were often seen to form narrow channels between two or more branching points, either in a continuous or in series fashion. Platelets, lymphocytes, granulocytes, and monocytes adhered to the subendothelial surface. Occasional denudations were oriented transversely to the longitudinal axis. Denudations were restricted to arteries greater than 1.2 mm in diameter. In the vicinity of denudation lesions, lymphocytes and monocytes adhered to endothelium showing alterations in cell size and shape. Transmission electron and light microscopy of this banding group showed breaks and duplication of the internal elastic lamina and smooth muscle proliferation in the intima. Focal areas of intimal inflammatory reactions, sometimes superimposed upon intimal proliferative changes, were noted in those areas exhibiting luminal cell adherence to endothelium. The results indicate that the morphologic equivalent of hypertension varies depending on the manner in which it is experimentally produced. The findings of intimal proliferation and late endothelial denudation give support to the response-to-injury hypothesis for the pathogenesis of atherosclerosis and suggest a mechanism for the role of hypertension as a risk factor.(ABSTRACT TRUNCATED AT 400 WORDS)

Influence of cinepazide, a vasoactive substance, on canine coronary circulation after acute constriction of the left anterior descending coronary artery.

The left anterior descending coronary artery was variably constricted mechanically in nine dogs. Blood flow in the left anterior descending (LAD) and circumflex coronary arteries (CCA), aortic pressure and peripheral, i.e. post-stenotic coronary pressure were measured. Myocardial perfusion was determined from the clearance of radioactive xenon injected at a depth of 7 mm into the underperfused area supplied by the LAD artery. The vasoactive drug 1-(pyrrolidinyl-1-carbonyl)-methyl-4-(3,4,5-tri-methoxycinnamoyl)piperazine-maleate (cinepazide) was given at doses of 5-10 mg/kg by i.v. route. 1. Blood flow in the LAD was decreased stepwise to 50% of its initial value. There was practically no more coronary reserve. After drug injection, diastolic aortic pressure, that normally falls, was kept constant by clamping. Heart rate, perfusion pressure, post-stenotic pressure, and blood flow and resistance in the LAD showed practically no change. In the CCA, blood flow increased significantly (p less than 0.005) and flow resistance decreased (p less than 0.001). 133Xe clearance showed an increased myocardial perfusion (p less than 0.02) in the territory supplied by the LAD artery. 2. The lumen of the LAD was narrowed by 53%, i.e., coronary reserve was decreased. This constriction was followed by no haemodynamic reaction. After injection of cinepazide, mean and diastolic aortic pressure (p less than 0.02) and post-stenotic coronary pressure (p less than 0.005) decreased. Blood flow increased by 41% in the CCA and by 31% in the LAD. Coronary resistance in these vessels decreased (p less than 0.001 and 0.005, respectively). Here, too, the 133Xe clearance curve showed an increase in myocardial perfusion in the territory supplied by the LAD artery (+78%).

[Subendocardial jeopardy of the hypertrophied myocardium]. / Zur Innenschichtgefährdung des hypertrophierten Myokards.

In moderate hypertrophy (+35%) of the canine left ventricle (LV), resting myocardial blood flow (MBF, tracer microspheres) was not significantly altered when compared with controls. The endo/epi flow ratio of the LV was, however, significantly smaller (0.82-0.9) than in controls (1.02-1.17). After coronary dilatation with dipyridamole, coronary flow reserve was smaller in hypertrophied hearts. This became particularly obvious when acute coronary constriction (70%) was induced. There was, however, no indication that after coronary constriction in early hypertrophy the subendocardium was more jeopardized than in controls.

[Coagulation inhibition caused by selective thrombin blockade with hirudin]. / Gerinnungshemmung durch selektive Thrombinblockade mit Hirudin.

Hirudin causes a rapid inhibition of blood coagulation as shown by in vitro and in vivo experiments in the dog. The substance appears to be a rather specific antithrombin. Its inhibitory action is linearly dose related and therefore easy to control and reproduce. Side effects can be expected to be abolished after further purification of the substance.

[Experimental protracted shock. II. Blood coagulation and histological changes]. / Experimenteller protrahierter Schock. II. Blutgerinnung und histologische Veränderungen.

Twenty mongrel dogs are subjected to a standardized traumatic hemorrhagic shock. After reinfusion of the dogs' own blood the animals are continuously observed for the 72 hr. Deterioration of general hemodynamics and activation of intravascular coagulation is more pronounced in the nonsurviving animals. Correspondingly, histologic alterations particularly of the liver and intestine are more marked in the nonsurvivors. Increase of partial thromboplastin time and long-lasting increase of the prothrombin time (Quick) appear to be early signs of a fatal prognosis.

[Animal experiments on the hemodynamics of prehepatic portal hypertension before and following various methods of portacaval anastomosis]. / Tierexperimentelle Untersuchungen zur Hämodynamik der prähepatisch bedingten portalen Hypertension vor und nach verschiedenen portosystemischen Anastomosen.

In 24 dogs (29 +/- 5,7 kg) general and intestinal hemodynamics were measured during acute prehepatic portal hypertension before and after mesentericocaval, splenorenal, and splenocaval (SCA) shunt. From the hemodynamic point of view the SCA is superior because of its complete venous decompression of the region of the spleen and cardia and a greater blood flow to the liver. Furthermore shunt flow, and consequently volume load imposed on the general circulation, is significantly smaller in SCA.

[Regional myocardial blood flow and ventricle function following hypothermic ischemia and cardioplegia]. / Regionale Myokarddurchblutung und Ventrikelfunktion nach hypothermer Ischämie und Kardioplegie.

Regional myocardial blood flow (MBF) and left ventricular (LV) function were measured in 18 dogs after 60 min hypothermic (14-16 degrees C) arrest with (group I) and without cardioplegia (group II). Regardless whether postischemic LV function was severely (group II) or only moderately (group I) impaired, the amount of MBF and its transmural distribution was not significantly altered after 30 min reperfusion. In contrast to topical hypothermia, additional cardioplegia maintained metabolic regulation of coronary flow.

[Comparative studies on pulsatile and continuous flow during extracorporeal circulation. Effects on liver function and endocrine pancreas secretion]. / Vergleichende Studie über pulsatilen und kontinuierlichen Fluss während des extracorporalen Kreislaufs. Auswirkungen auf die Leberfunktion und endokrine Pankreassekretion.

The effects of pulsatile and nonpulsatile flow pattern on pancreas and liver blood flow were studied in nine dogs on cardiopulmonary bypass (CPB). Furthermore, plasma levels of glucose, insulin, glucagon, growth hormone, and cholinesterase were compared in 20 patients subjected to open heart surgery with either pulsatile or nonpulsatile perfusion. Impairment of liver and pancreas function was significantly greater at the end of CPB and 48 h afterwards with nonpulsatile flow as compared with the pulsatile flow pattern. A decrease of intestinal blood flow that was demonstrated in dogs subjected to nonpulsatile perfusion could at least in part be responsible for the difference in postoperative organ function observed in patients after CPB.

[Extravascular albumin and water content of the lungs in traumatic-hemorrhagic shock]. / Extravasaler Albumin- und Wassergehalt der Lunge im traumatisch-hämorrhagischen Schock.

Fifteen mongrel dogs are subjected to a standardized traumatic hemorrhagic shock. Plasma albumin, measured by J-125-albumin distribution, decreases to 58% of its original level after trauma and hemorrhage. Lung albumin content increases to 53% of the blood level. Lung water content is studied in vivo using the double indicator technique, post mortem by gravimetric methods. None of these methods shows an augmentation of lung water. The massive albumin loss occurs, particularly in the lungs, due to capillary leakage. The constant pulmonary water content can possibly be explained by early artificial respiration and by the fact that in contrast to clinical situations no infusion therapy was performed.