Closed-chest Animals Research Articles

Relative effects of propranolol and timolol on ventricular fibrillation threshold and hemodynamics in the dog

The relationship between the antifibrillatory and hemodynamic effects of propranolol and timolol was tested in 32 dogs divided into three groups. In closed-chest animals (group 1), the maximal increase of the ventricular fibrillation threshold (VFT) from the control state was 67.3 ± 22.6% ( n = 5, p < 0.01) for propranolol and 95.8 ± 18.8% ( n = 9, p < 0.005) for timolol. These effects were paralleled by a decrease in the cardiac index of 34.7 ± 10.2% ( p < 0.05) and 32.5 ± 9.4% ( p < 0.02) for propranolol and timolol, respectively. The mean systemic arterial pressure (SAP) also decreased by 25.0 ± 8.8% ( p < 0.05) and 19.2 ± 5.1% ( p < 0.01). In open-chest animals (group 2), timolol increased the VFT by 86.6 ± 27% (n = 5, p < 0.05) and decreased the cardiac index by 57.3 ± 6.3% ( p < 0.005) and the mean SAP by 28.5 ± 2.9% ( p < 0.02). In open-chest animals with stabilized peripheral hemodynamics (group 3), VFT increased by 354 ± 130% ( p < 0.05) and 437 ± 144% ( p < 0.05) after the maximal administered doses of propranolol ( n = 6) and timolol ( n = 7), respectively. These results suggest that the electrophysiologic and hemodynamic effects of beta blockade are parallel and interdependent, with the hemodynamic deterioration markedly blunting the beneficial electrophysiologic effects.

Measurement of effective pulmonary capillary pressure using the pressure profile after pulmonary artery occlusion.

Pulmonary artery catheters are frequently used to measure pulmonary vascular pressures, particularly the pulmonary wedge pressure (Pw), which reflects pulmonary venous and ideally left atrial pressures. However, the pulmonary capillary pressure (Pc) is the major force in the formation of pulmonary edema. Unfortunately, Pw has been interpreted as being identical to Pc. In this study we used 7-Fr pulmonary artery catheters to measure effective Pc in closed-chest animals and patients. The decreasing pressure profile after pulmonary artery occlusion was separated into fast and slow components, with the inflection point between them representing Pc. Pc was also estimated by mathematically analyzing the curves in terms of a precapillary resistance, a large pulmonary capillary capacitor, and a postcapillary resistance. In dogs, Pc was determined after pulmonary vascular resistance had been increased by infusing serotonin and histamine. While Pw remained unchanged, serotonin increased pulmonary artery pressure (Ppa) 52% and Pc 16%, whereas histamine increased Ppa only 25%, but increased Pc by 35%. This is consistent with studies showing that serotonin primarily elevates precapillary resistance, and histamine increases postcapillary resistance. In thoracic surgery patients, Pc was not consistently related to Pw. This measurement was simple, reproducible, and provided a more precise capillary filtration pressure than Pw. It should be clinically useful in monitoring patients with pulmonary hypertension and adult respiratory distress syndrome, especially those with pulmonary artery catheters.

Adaptive Linear Predictor Tracks Implanted Radiopaque Markers

Radiopaque markers implanted in the heart's wall permit one to observe absolute motion of the heart in closed-chest animals and humans using X-rays. The resulting data, however, are very tedious to analyze because human operators must digitize the observed marker motion from cineradiographic films (or stored video images). This paper describes an algorithm that tracks the trajectories of markers implanted in the endocardium. The algorithm uses a least-mean-squares adaptive linear predictor. By solving the marker tracking problem, one moves closer to a fully automated endocardial marker data acquisition system. The algorithm is also used to detect errors in data acquired using manual digitizing procedures. Tests run with data from nine dogs showed that the algorithm could successfully track and identify 95-100 percent of the markers in 40 out of the 60 film segments and 90-100 percent of the markers in 52 out of 60. The root-mean-square distance between the identified marker trajectories and the manually determined trajectories, a measure of accuracy, was about one-half the marker size when averaged over all of the film segments tested.

The relationship between ventricular arrhythmias and ischemia-induced conduction delay in closed-chest animals within 24 hours of myocardial infarction

To investigate the myocardial conduction characteristics of premature impulses during the first 24 hours following coronary ligation and its relationship to late infarction ventricular arrhythmias, transmural electrodes were positioned in the normal and ischemic myocardium in nine dogs. Cardiac conduction in ischemic myocardium was delayed 15 minutes post coronary occlusion both in the epicardium and endocardium, both in the anterograde (base to apex) and retrograde (apex to base) direction, and was maintained at the same level throughout the experiment. Conduction across the border of ischemic myocardium from ischemic to the normal segment was also delayed, especially in the endocardium. Spontaneous ventricular arrhythmias recorded on Holter tapes showed significant increase in the number of premature ventricular complexes and ventricular tachyarrhythmias 9 hours after infarction. Thus our findings suggest that spontaneous arrhythmias occurring in the late phase of acute myocardial infarction (AMI) are independent of the ischemia-induced conduction delay and an alternate mechanism such as abnormal automaticity may be responsible for late ventricular arrhythmias.

31P-Topical Nuclear Magnetic Resonance (31P-TMR) Studies of Cardiotoxic Effects of 5-Fluorouracil (5-FU) and 5’-Deoxy-5-Fluorouridine (5’-DFUR)

Using the 31P-topical nuclear magnetic resonance method (TMR), an attempt was made to determine the myocardial high-energy phosphate compounds (HEP) contents under in situ conditions in closed-chest animals, and the effects of opening the thorax on the myocardial energy metabolism were studied comparing the cardiotoxic effects of 5-fluorouracil (5-FU) in closed-chest and open-chest animals. It was found that the depletion of myocardial HEP produced by 5-FU was much more marked in open-chest animals than in closed-chest ones, indicating the necessity of conducting the experiments in closed-chest animals for the proper evaluation of the cardiotoxicity of certain types of compounds. Therefore, the cardiotoxicity of a prodrug of 5-FU was assessed in closed-chest animals, and it was found to be less cardiotoxic than 5-FU.

31P-topical nuclear magnetic resonance (31P-TMR) studies of cardiotoxic effects of 5-fluorouracil (5-FU) and 5'-deoxy-5-fluorouridine (5'-DFUR).

Using the 31P-topical nuclear magnetic resonance method (TMR), an attempt was made to determine the myocardial high-energy phosphate compounds (HEP) contents under in situ conditions in closed-chest animals, and the effects of opening the thorax on the myocardial energy metabolism were studied comparing the cardiotoxic effects of 5-fluorouracil (5-FU) in closed-chest and open-chest animals. It was found that the depletion of myocardial HEP produced by 5-FU was much more marked in open-chest animals than in closed-chest ones, indicating the necessity of conducting the experiments in closed-chest animals for the proper evaluation of the cardiotoxicity of certain types of compounds. Therefore, the cardiotoxicity of a prodrug of 5-FU was assessed in closed-chest animals, and it was found to be less cardiotoxic than 5-FU.

Technique for producing heart block in closed-chest dogs without electrical recording

An instrument and technique have been devised for the production of complete atrioventricular heart block in anesthetized, closed-chest animals. The instrument is inserted into the right atrium via the right external jugular vein. Localization of the atrioventricular node region by the visualization of intracardiac landmarks with fluoroscopy makes electrical recording unnecessary. Discrete injections of a radiopaque necrosing solution produces the heart block. Procedure time is under 30 min a success rate of 90%.

Age-related effects of digoxin on myocardial contractility and Na-K pump in sheep.

The age-dependent effects of an acute nontoxic, positively inotropic dose of digoxin on myocardial monovalent cation active transport were determined in fetal, newborn, and adult sheep. Thirty-five lightly sedated, closed-chest animals were instrumented to record electrocardiogram, left ventricular (LV) pressure, and rate of change of LV pressure (LV dP/dt). Ouabain-inhibitable uptake of Rb+ (86Rb+) was measured in both right ventricular (RV) and LV slices from control animals and in animals infused with [3H]digoxin (0.04 mg/kg) sufficient to cause an increase in LV dP/dt without toxicity. Sixty minutes after digoxin, LV dP/dt increased 123% over base-line values in fetuses, 131% in newborns, and 165% in adult animals. RV and LV myocardial digoxin concentrations were similar in all groups. Rb+ active transport was significantly reduced in both RV and LV tissue from all animals 60 min after digoxin. Control animals showed no significant changes in contractility or Rb+ active transport among the control group of fetal, newborn, or adult sheep. Acute infusions of digoxin increased LV contractility in each age group and was accompanied by digoxin-induced inhibition of myocardial Rb+ active transport. No age-related differences in the extent of Rb+ active transport among control or among digoxin-treated animals were observed under these experimental conditions. These studies suggest that the differential response to the therapeutic and toxic effects of digoxin in sheep of various ages does not reside in an age-dependent response of the myocardial sodium pump to digoxin.

Effects of physical training on myocardial vascularity and perfusion.

Physical training is thought to be a stimulus for coronary vascular growth and coronary collateral development. This report is a summary of knowledge in the area. Studies in experimental animals with normal hearts indicate that physical training promotes increased myocardial capillary density and also causes enlargement of the surface coronary vessels. The physiologic effect of these changes on coronary vascular reserve and protection of segments of the heart against myocardial ischemia has not been established. Physically trained dogs and pigs do not appear to be protected against the effects of coronary occlusion, in that the ischemic area appears to be as large in trained animals as in untrained animals for any given coronary lesion. One study in physically trained rats appears to show protection against myocardial infarction, but whether this is related to coronary vascular changes has not been established. Experiments in dogs subjected to chronic narrowing or gradual occlusion demonstrate that physical training in these models does promote collateral blood flow as measured by retrograde flow in open-chest experiments. Studies using the microsphere technique in closed-chest animals confirms increased collateral flow to ischemic areas in some animals, but the magnitude of the increases appears to be small and varies greatly from animal to animal. Studies in athletes suggest that myocardial blood flow is lower at any submaximal level of training in athletes than in sedentary persons. Studies in patients with coronary artery disease have generally failed to show an increase in coronary blood flow or in perfusion of ischemic areas after physical training programs, but the techniques used might not have been sensitive enough to detect changes. The evidence in the experimental animals is sufficiently promising to indicate that the search should be continued to define physical training programs that will most stimulate myocardial vascularity and coronary collaterals in humans.

Experimental myocardial infarction in the closed-chest dog: a new technique.

The reliable and safe production of myocardial infarction in closed-chest animals is of paramount research interest. To date, the injection of particulate matter and the introduction of occlusive solid plugs have been described. Because of the limited size of the catheter, only small branches could be occluded, which resulted in a high incidence of mortality. A new simple technique is described that allows occlusion of a major coronary artery at a preselected site. An Ivalon (polyvinyl alcohol) plug compressed around the tip of an introducing wire is advanced through a selectively placed catheter into the coronary artery. It is felt in place for 5 minutes and assumes its original size upon contact with blood. Once the plug is re-expanded, the wire is withdrawn. The new technique was carried out successfully on nine dogs with no immediate fatality and myocardial infarction as demonstrated by cine ventriculography and histopathologic examination.

A closed chest animal model for the study of reversible ischemia.

An experimental methodology consisting of partial coronary occlusions, pacing-induced myocardial ischemia and photokymography-aided fluoroscopic study of segmental left ventricular motion, was verified in 14 closed chest dogs. A partial intracoronary occluder device was found suitable for single or multiple coronary arterial stenosis, and remained patent up to 10 h with 10/cm3 heparin administration. With 38% proximal left circumflex coronary artery stenosis, pacing up to 220 beats/min produced no significant regional or global left ventricular dysfunction. In contrast, a 68.5% stenosis which was not associated with dysfunction in the resting state produced significant derangements of segmental motions at a pacing rate of 150 beats/min. Photokymography probes placed at several segments of the left ventricular epicardial and endocardial interface delineated by fluoroscopy or ventriculography allowed monitoring of regional contractions in both pacing-induced ischemic and remote nonischemic zones. The methodology is considered ready for further applications in experimental studies of ischemic states and treatments, simulating clinically meaningful coronary stenosis in the animal without requiring prior thoracotomy and pericardiotomy for implanting occluders.

Distension of pulmonary vein--left atrial junction: heart rate responses in conscious and anesthetized dogs.

The cardiac chronotropic effects of distension of pulmonary vein-left atrial junction were investigated in conscious dogs and in dogs anesthetized with intravenous alpha-chloralose (100 mg/kg) or pentobarbital (30 mg/kg). All the experiments were made on trained, chronically instrumented, closed chest animals held in horizontal position. Inflation of a single small balloon in the junction elicited a tachycardic response both in conscious and chloralose-anesthetized dogs, while in pentobarbital anesthesia no change in heart rate was found. Contrary to reports of other investigators, no transient bradycardia was found, nor any correlation between predistension heart rate and the increase in heart rate due to the distension. It is suggested that the choice of anesthetic can be done only after its modifying effect on the parameter studied is known. Only the use of trained, chronically instrumented and conscious dogs will reveal this effect.

Canine electrophysiology of encainide, a new antiarrhythmic drug

Encainide, a new benzanillide derivative with high potency and a good therapeutic/toxic ratio, was evaluated with the use of standard His bundle recording techniques to determine its effects on the cardiac conduction system in closed chest animals. Twenty mongrel dogs weighing 18 to 29 kg were anesthetized with 4 percent chloralose and classified into groups: group 1, a control group and groups 2,3, and 4, which were given 0.3, 0.9 and 2.7 mg/kg body weight, respectively, of encalnide In an intravenous infusion over a 15 minute period. Plasma concentration, blood pressure, surface electrocardiogram and atrlal and His bundle electrograms were recorded before, during and after drug infusion for a total of 120 minutes. Heart rate, A-H and H-V intervals, the QRS complex and Q-Tc interval were measured every 5 minutes during sinus rhythm and with constant atrial pacing. In addition, sinus nodal recovery time and atrial, atrioventrlcular (A-V) nodal and left ventricular refractory periods were measured before and immediately after infusion and every 30 minutes for 2 hours. Peak plasma concentration averaged 450 ng/ml in group 2,1,300 ng/ml in group 3 and 4,000 ng/ml in group 4. Blood pressure was not altered at any dose level throughout the study. The QRS complex and H-V interval were significantly prolonged ( P < 0.005) at doses of 0.9 mg/kg and greater. These effects correlated well with plasma concentration. There was no significant change in heart rate, corrected sinus nodal recovery time, A-H interval, Q-Tc Interval atrial, A-V nodal or left ventricular refractory period. It is concluded that, unlike other antiarrhythmic agents, encainide prolongs His-Purkinje system conduction without significantly affecting conduction or refractoriness of other parts of the cardiac conduction system in animals.

The effect of vagus nerve stimulation upon vulnerability of the canine ventricle: role of sympathetic-parasympathetic interactions.

The effect of vagus nerve stimulation (VNS) upon ventricular vulnerability was studied in 30 mongrel dogs subjected to varying levels of adrenergic stimulation. Vulnerability was assessed both by determining the minimum current required to produce ventricular fibrillation (VF threshold) and by plotting VF threshold throughout the vulnerable period (VF zone). Chloralose-anesthetized animals were studied by means of sequential pulses applied to the apex of the right ventricular endocardium. Testing was carried out in closed-chest dogs, in open-chest dogs with and without left stellate ganglion stimulation (LSGS), and in open- and closed-chest dogs pretreated with propranolol. In the absence of adrenergic stimulation. VNS was without significant effect on either the VF threshold or the VF zone under closed- or open-chest conditions. During LSGS, however, VNS was associated with a 93 +/- 22% (mean +/- SE) increase in VF threshold (P less than 0.01) and constriction of the VF zone. Vagus nerve stimulation combined with LSGS raised VF threshold to the control value, but not beyond. After beta-adrenergic blockade with propranolol, VNS was without effect on VF threshold in either open- or closed-chest animals. It is concluded that augmented sympathetic tone is a precondition for a VNS-induced elevation in VF threshold. The vagal effect is indirect and is expressed by opposing the effects of heightened adrenergic tone on ventricular vulnerability.

A method of closed-chest cannulation of the left atrium for left atrial-femoral artery bypass

A large-bore polyvinyl catheter was devised for passage into the left atrium by means of a modified transseptal catheterization technique. This was performed without difficulty using both pulsatile and nonpulsatile bypass in the closed-chest animal as well as in 3 terminally ill patients. Blood was drained from the left atrium and returned to the femoral artery through an extracorporeal circuit. The shock syndrome produced by coronary embolization in dogs was successfully managed in this fashion. The results of the clinical trials were encouraging. Assisted left heart circulation using a closed-chest left atrial-femoral artery bypass seems feasible by this technique.

Regional vascular response to hypoxia in the lungs of anaesthetised sheep.

The pulmonary vascular response to hypoxia was studied in open and closed chest anaesthetised sheep. Control distributions of pulmonary blood flow were significantly different between the open and closed chest animal, and changes in total pulmonary vascular resistance during hypoxia were identical in the two preparations. There were, however, marked regional differences in the response of the pulmonary vasculature to hypoxia in both preparations, there being greater increases in vascular resistance in the central zone of the lungs between the dorsal and ventral surfaces of the supine animal.

Cannula-tip coronary blood flow transducer for use in closed-chest animals.

Cannula-tip coronary blood flow transducer for use in closed-chest animals.

Closed chest model of intracoronary occlusion for study of regional cardiac function

A new closed chest animal technique permits selective intracoronary balloon occlusion and measurement of hemodynamic and regional metabolic function before and during occlusion and reperfusion. The distal end of the double lumen balloon catheter provides information about the nature and extent of flow distal to the occlusion and permits blood sampling or administration of pharmacologic agents directly into the ischemic zone. Independent blood sampling from the great cardiac vein by means of a specially designed balloon catheter and from the coronary sinus by cannula allows simultaneous biochemical and regional blood flow measurements from the occluded and nonoccluded segments of the heart. Simultaneous intracoronary epicardial electrocardiograms permit electrophysiologic correlation with regional hemodynamic and metabolic events. The administration of oxygen by tracheal airway can increase partial oxygen tension in the circulation distal to coronary occlusion. When intracoronary pressures distal to occlusion are markedly reduced, the frequency of ventricular fibrillation is much greater.

The effects of nitroglycerin on coronary collaterals and myocardial contractility.

Nitroglycerin (TNG) causes a prolonged dilatation of coronary collaterals. To demonstrate a functional significance of this dilatation we measured the effect of TNG on myocardial contractile force in dogs 2(1/2)-4 wk after the left anterior descending coronary artery (LAD) had been embolized in closed-chest animals. Development of collaterals was documented by angiography. Via a left thoracotomy the main left coronary artery (LCA) and LAD distal to the embolized plug were cannulated. Coronary flow and perfusion pressure were recorded. Contractile force was measured with gauges sutured to epicardial areas supplied by the left circumflex coronary artery (LCf) and occluded LAD. Coronary perfusion pressure in the LCA was gradually decreased until the contractile force recorded by the LAD gauge diminished while the LCf gauge was unaffected. Under these conditions, with coronary perfusion pressure held constant with the aid of a Starling resistance, TNG (18 mug) injected into the LCA increased peripheral LAD pressure by 3-12 mm Hg and contractile force in the LAD region by 36% (range 20-90%), returning it to near-normal levels, while having minimal effect in the LCf area. These changes persisted for 5 min. When LCf and LAD areas were both ischemic, intracoronary TNG had minimal effect on peripheral LAD pressure and contractile force. Thus, TNG causes prolonged dilatation of coronary collaterals and presumed increased collateral flow with subsequent enhancement of myocardial contractile force in ischemic areas. This effect is seen only when ischemia is limited to an area supplied by the collaterals. When the whole heart is ischemic, collaterals are unresponsive to TNG, suggesting that these collaterals dilate fully when the regions from which they originate become ischemic.

Sympathetic cerebral vasoconstriction blocked by adrenergic alpha receptor antagonists.

Alpha receptor adrenergic antagonists were used in chloralose-anesthetized dogs to block cerebral vasoconstriction elicited by stimulation of the sympathetic innervation of the cerebral vessels. A venous outflow technique was used to measure cerebral blood flow with an electromagnetic flow transducer. The brain's arterial supply was left undisturbed. The experiments were performed in both open and closed chest animals and in animals with open and closed craniums. The left sympathetic stellate ganglion was stimulated for 60 seconds at 15 Hz, 3 msec pulse duration, and 3 to 9 v intensity. Control stimulation produced a 65.8% decrease in cerebral blood flow. Dibozane, 1 or 2 mg/kg, or phentolamine, 2 mg/kg, was then administered, and stimulations were repeated with the same stimulus parameters. After alpha receptor blockade, cerebral blood flow decreased only 3.5% with sympathetic stimulation. The effective blockade by two different alpha receptor antagonists, of a different structure, indicated that an alpha receptor was responsible for the sympathetically mediated cerebral vasoconstriction. In conclusion, stimulation of the sympathetic innervation of the cerebral vessels results in a marked decrease in cerebral blood flow which is blocked by alpha receptor antagonists.