The search for a digitalis substitute II milrinone (Win 47203). Its action on the heart-lung preparation of the dog.

Milrinone (Win 47203) is a dipyridine related to amrinone, which is about 20-50 times as effective as amrinone when assayed on cardiac contractility. In dog heart-lung preparations, milrinone in a concentration of 0.25-0.5 microM produced a near maximal positive inotropic effect on a variety of acute heart failures. This dosage produced a minimal increase in heart rate and reduced the PR interval. Large doses of milrinone did not produce cardiac irregularities and in Nifedipine heart failure with ventricular irregularities, it eliminated these irregularities. Papaverine-induced heart failure was resistant to ouabain, epinephrine and milrinone therapy. In the presence of positive inotropic amounts of papaverine or theophylline, a pentobarbital heart failure was superimposed. This heart failure responded poorly to milrinone, although it responded to both the addition of epinephrine and ouabain. It is thus possible that milrinone, papaverine and theophylline have closely related sites of action.

Issues in the development of subject recruitment strategies and eligibility criteria in multisite trials of matching.

Decision-making in selecting and recruiting subjects for treatment matching research is a complex process involving conceptual, methodological and practical considerations. In selecting clients, concerns arise about whether the criteria will produce a subject population that is (1) relevant to the dimensions associated with the treatment matching, (2) representative of persons typically seen in alcohol treatment settings and, for practical purposes, (3) able or willing to comply with the requirements of the study protocol. Also, in order to fulfill sampling requirements, it may be necessary to employ a variety of creative outreach methods. However, these recruitment mechanisms can pose additional logistical and methodological problems for the research. This article focuses on various issues arising in the selection and recruitment of subjects in matching research. Project MATCH serves to highlight issues related to client eligibility and recruitment and to discuss effective strategies for resolving these matters.

Prospective matching of alcoholic clients to cognitive-behavioral or interactional group therapy.

OBJECTIVE: In earlier work, client sociopathy and global psychopathology were effective variables for treatment matching: clients low on both sociopathy and severity of psychopathology were likely to benefit from interactional group therapy, whereas those scoring high on either of these dimensions benefited more from a coping skills intervention. The present study assessed whether outcomes improve further when clients are assigned to group treatments prospectively based on a matching strategy derived from the previous findings. METHOD: All participants (N = 250, 66% men) met criteria for alcohol dependence or abuse. About half were prospectively assigned to either cognitive-behavioral (CB) coping skills training or interactional therapy, those with higher levels of psychiatric severity or sociopathy were given CB and those who were low on both dimensions were given interactional therapy. The other half were randomly assigned to those treatments, replicating the procedure of the earlier study. Outcome data were collected at the conclusion of treatment and at 3-month intervals for 1 year following. RESULTS: Prospective matching of clients to treatment did not produce superior drinking outcomes compared to random treatment assignment. Randomly assigned clients were more likely to be abstinent at the end of treatment, but this effect disappeared at later follow-ups. Prospectively matched clients had fewer negative consequences of drinking than did those assigned randomly (unmatched). Neither sociopathy nor psychiatric severity was particularly effective for matching. CONCLUSIONS: The matching effects from our previous study were not replicated. Nevertheless, prospective matching did reduce the negative consequences of drinking, consistent with our previous results.

Behavioral and biochemical effects of gradual reductions in cigarette yields in pregnant and nonpregnant smokers.

Smoking-related risks have been well-documented for both the smoker and the pregnant smoker's unborn child, but the risks associated with low tar/nicotine cigarette smoking are still controversial. The present study examined some of the behavioral and biochemical effects of gradual reductions in tar and nicotine yields in six pregnant and six nonpregnant smokers. Over four sessions spanning a 6-week period, smokers switched to cigarette brands progressively lower in tar and nicotine. Examination of the topographical variables assessed both during (cigarette frequency, puff frequency, and cigarette duration) and between sessions (daily cigarette rate and nicotine intake) revealed significant decreases in both pregnant and nonpregnant smokers' cigarette duration and nicotine intake. Also observed were significantly lower and less variable carboxyhemoglobin (COHb) levels among the pregnant smokers when they smoked the lowest tar and nicotine brands. However, even the pregnant smokers' lower mean COHb levels did not drop below the 3% minimal cardiovascular risk level. The pregnant smokers also tended to have lower and less variable salivary thiocyanate (SCN) levels, but these differences were nonsignificant. The results were discussed in terms of implications for controlled smoking treatment programs for pregnant smokers.

Self-control in adult humans: variation in positive reinforcer amount and delay.

In five experiments, choice responding of female human adults was examined, as a function of variations in reinforcer amount and reinforcer delay. Experiment 1 used a discrete-trials procedure, and Experiments 2, 3, 4, and 5 used a concurrent variable-interval variable-interval schedule. Reinforcer amount and reinforcer delay were varied both separately and together. In contrast to results previously reported with pigeons, the subjects in the present experiments usually chose the larger reinforcers even when those reinforcers were delayed. Together, the results from all the experiments suggest that the subjects followed a maximization strategy in choosing reinforcers. Such behavior makes it easy to observe self-control and difficult to observe impulsiveness in traditional laboratory experiments that use adult human subjects.

[Effects of amrinone, a new non-digitalic positive inotropic agent, on the efficiency and coronary circulation of the heart]. / Effectos del amrinone, un nuevo agente inotrópico positivo no digitálico, sobre la eficiencia y el flujo coronario del corazón.

It has been reported recently that 5-amino-34,4'-bipyridine-6(1H)-one is a new positive inotropic agent that appears to offer significant advantages over the cardiac glycosides. The effects of this agent were studied in a modified heart-lung preparation which allows the measurement of coronary flow and oxygen consumption in addition to a controlled study of cardiac contractility. In two models of cardiac insufficiency the administration of 5 mg amrinone caused a marked increase in cardiac output and a considerable decrease in left atrial pressure with complete reversal of the failure. In addition, the drug produces a 78% increase in coronary flow. Amrinone produces in these preparations a proportionally larger increase in cardiac output than in oxygen consumption, thus this agent increases cardiac efficiency. These results suggest that this new compound could be very useful in the treatment of cardiac insufficiency in congestive heart failure.

Electrical responses in cat adrenal cortex: possible relation to aldosterone secretion.

The effects of secretagogues for aldosterone release were studied on the membrane potential of cells in the adrenal cortex of the cat. Adrenal glands were excised, sliced, and continuously superfused. Membrane potentials were recorded from both zona glomerulosa and zona fasciculata-reticularis. Secretagogues, angiotensin II (1 microgram/ml) and 20 mM KCl, were found to depolarize cells rapidly. Ouabain (10(-5) M) also depolarized the membrane potential although the response was sluggish. Samples of the superfusate were collected and analyzed by radioimmunoassay for their aldosterone and cortisol content. Depolarizing concentrations of angiotensin II, KCl, and ouabain seemed to increase aldosterone release. Cortisol output was more variable. Saralasin blocked the effects of angiotensin II on the membrane potential. These experiments suggest that membrane depolarization plays a role in the stimulus-secretion coupling of mineral corticoids.

[Effects of several anti-arrhythmia agents on excitability and conduction depressed by digitalis agents]. / Efectos de diversos agentes antiarrítmicos sobre la excitabilidad y la conducción deprimida por los digitálicos.

Digitalis intoxication is characterized by the appearance of most of the types of severe arrhythmias described and also by important disturbances of cardiac excitability and impulse propagation. Most of the antiarrhythmic agents that are used in the treatment of these conditions also depress excitability and impulse propagation. These characteristics are frequently responsible of severe complications. The purpose of this paper is to determine the type of interactions that exist between digitalis and some antiarrhythmic agents, and compare them with the effects of magnesium. The experiments were done in several groups, of dogs anesthetized with pentobarbital and with the chest open. Excitability, conduction time and functional refractory period were determined using the classical methods. The protocol used consisted in the comparison of the actions of toxic doses of digitalis on excitability and conduction times of the atrial and ventricular tissues, under control conditions and in the presence of therapeutic doses of procainamide, lidocaine and magnesium. The results showed that procainamide worsened the depression of excitability and conduction produced by digitalis intoxication, while lidocaine does not add to the digitalis effects and in some cases it produces a partial improvement of these parameters. Magnesium completely reverts the effects on excitability and conduction. These results provide us with rational pharmacological bases for the treatment of digitalis intoxication and suggest that magnesium could be very useful in the management of patients with severe digitalis intoxication.

[Automatism: an intrinsic property of cardiac tissues]. / Automatismo: una propiedad intrínseca de los tejidos cardíacos.

Automaticity is an intrinsic property of some types of cardiac tissues, like the nodes and the conducting fibers. Automatic cells are characterized by the appearance, during diastole, of a slow depolarization which is capable of reaching threshold and generate an action potential. This depolarization is the so-called slow diastolic depolarization, or pacemaker potential. Tissues with automaticity do not have the same intrinsic firing frequency, which determines the existence of a true pacemaker; normally this role is assumed by the sinus node and several latent, or subsidiary pacemakers. The latter do not give any manifestation, because, since they have a slower firing frequency than that of the true pacemaker, the impulses generated by the latter will activate them before they can reach threshold. The ionic mechanisms that originate the pacemaker potential are just some of the processes that constitute the electrophysiological properties of the cardiac cell membranes. The mechanism includes the slow inactivation of an outward current combined with a constant inward current. Recently published evidence suggests that the pacemaker potential could be the resultant of an inward current that is slowly activated during the final part of the repolarization, but these data are still controversial and difficult to interpret. The factors that regulate heart rate modify the electrophysiological characteristics of the membrane by means of three major mechanisms: the slope of the pacemaker potential, the voltage of the threshold potential and, the maximum diastolic potential. Some of the most important factors that modulate heart rate include the neurotransmitters of the automatic nervous system, the plasmatic levels of some ions, like potassium and calcium, and changes in the intrinsic properties of the membrane, like the influence of heart rate on the activity of the sodium pump.

The effects of milrinone (Win 47203) on the coronary blood flow and oxygen consumption of the dog heart-lung preparation.

Milrinone is a new bipyridine-positive inotropic agent that is closely related to amrinone. In the nonfailing heart, coronary blood flow was increased and coronary bed resistance was decreased by milrinone, most probably by a direct action of milrinone on the coronary vasculature. Oxygen consumption was increased at the lower workloads. In the failing heart milrinone (0.1 to 0.5 mg/L of blood) increased cardiac output and coronary blood flow and reduced coronary vascular resistance. With the 0.1 mg dose oxygen consumption was reduced, especially at the high workloads, and was not significantly changed at the low work levels. With higher doses of milrinone oxygen consumption of the heart was not changed significantly while external work was increased. These data show that milrinone can increase the work of the heart with a decrease or no significant change in oxygen consumption of the isolated failing heart. The use of this drug in heart failure accompanied by restricted blood flow may thus be indicated.

Cardiac effects of ethacrynic acid, a Na+, K+-ATPase inhibitor.

To test hypotheses relating positive inotropic effects of cardiac glycosides (CG) to inhibitory effects on Na,K-ATPase, cardiac actions of other inhibitors were examined. Ethacrynic acid was studied using microelectrode recordings of dog Purkinje fibers (DP) and cat papillary muscle (CP), and isometric recordings of CP at Lmax stimulated at 1/sec (36.5 degrees C). Results with all doses (20-200 gamma/ml) were similar, differing only in latency. Actions of ethacrynic acid on electrical activity of DP and CP were, chronologically: increase in duration of the action potential (AP), and decrease in dV/dt, overshoot, and resting potential. In CP an initial increase (2-5 min) in contractility (10-15 percent) was followed by decreased in active tension and dP/dt with parallel increases in resting tension and duration of contraction. ATP levels were unchanged, eliminating the possibility of ethacrynic acid acting as a metabolic poison. Simultaneous recording of contractions and AP in CP showed that the positive inotropic effect was always associated with a lengthening of the AP. In a series of CP, ouabain (2 gamma/ml) always increased contractility when ethacrynic acid had already reduced it by 75 percent. These results suggest that Na,K-ATPase inhibition is not responsible for the inotropic effects of CG.

[Mechanisms of conduction disorders in digitalis poisoning]. / Mecanismos de los trastornos del automatismo en la intoxicación digitálica.

Ever since the first papers on the mechanism of the arrhythmias of digitalis were first published, during the first two decades of this century, the issue has been a controversial one. Since the automaticity induced by digitalis intoxication has different characteristics when compared to normal automaticity, it has been suggested that probably the mechanisms for these two types of spontaneous activity are different. It has been recently proposed that the automaticity induced by digitalis intoxication could be secondary to the after potential oscillations described in isolated conducting fibers. In order to test this hypothesis we used two experimental models which allow for a careful analysis of the ectopic activity, without the interference of the sinus rhythm. These studies were done in two groups of animals: one, with electrically isolated atria, was used to analyze supraventricular arrhythmias. The other, with chromic atrioventricular block, was used to study ventricular arrhythmias. The results obtained from these experiments show: 1. High therapeutic doses of digitalis enhance the postpacing inhibition of normal pacemakers; 2. When the ectopic rhythms of digitalis intoxication appear, they show postpacing stimulation; 3. Ectopic activity shows a direct relationship with the rate of the conditioning stimulation, and both the coupling period and the number of premature beats depend on this rate. In view of the similarity between the behavior of these arrhythmias and that of the after potential oscillations, we conclude that these oscillations are responsible for the ectopic automaticity of digitalis intoxication.

Ouabain uptake by endocytosis in isolated guinea pig atria.

Mammalian cells specifically internalize some molecular species through receptor-mediated endocytosis (RME). We have used four different experimental protocols to investigate whether ouabain enters cardiac cells of guinea pig atrium through this pathway. First, by electron microscope morphometry we found that ouabain increased endocytic vesicles in atrial cells. Second, by scintillation counting we found that [3H]ouabain uptake by the tissue is decreased by three treatments that decrease RME, i.e., NH4Cl, trifluoperazine, and 16 mM [K+]0. Third, by radioautography at the electron microscope level, we checked that in preceding experiments [3H]ouabain was washed out of plasma membrane after 60-min rinse and interiorized into the cardiac cells. Fourth, isometric tension recordings showed that the positive inotropic effect of ouabain was diminished in the presence of inhibitors, whereas that of a hydrophobic analogue, ouabagenin, was not affected. These results suggest that ouabain enters cardiac cells through RME and also that an intracellular site may, at least in part, be responsible for its inotropic effect.

[Manufacture of valvular prostheses from bovine pericardium, their evaluation and the initial results of the 1st group of implants]. / Manufactura de protésis valvulares de pericardio bovino, su valoración y resultados iniciales del primer grupo de implante.

The results obtained with some types of bioprostheses together with the present economical situation of the country pointed out that the manufacture of another type of bioprostheses was necessary. After a careful analysis of the results that had been reported in the literature with the diverse types of bioprostheses had been made, it was concluded that pericardial valves were the best choice for our specific requirements. The first problem that had to be solved was the identification of the adequate fraction of purified glutaraldehyde that would provide for adequate tissue fixation. This was determined using several types of biophysical and biochemical techniques. The next step was to find the adequate manufacturing techniques that would provide us with optimal function valves. This was achieved by testing the functional characteristics of these valves on a cardiac cycle simulator. The first group of 132 patients that received this type of valve includes 9 multiple valve replacements, 24 aortic, 98 mitral and 1 pulmonary valve replacements. All the surviving patients have shown a clear improvement and they all show adequate function of their bioprostheses. The function of the valves has not been involved in any of the patient deaths. Since there has not been any evidence of disfunction, these results show that the manufacturing techniques and the design of these bioprostheses is adequate. Naturally to long-term durability of these valves will have to wait before it can be valorated.

[Design and evaluation of a duplication of the cardiac for the evaluation of valvular prostheses]. / Deseño y evalucación de un duplicado de ciclo cardíaco para la valoración de prótesis valvulares.

Recently, several different models of valvular prostheses have been developed in which biological material, like duramater and perycardium, is being used for their manufacturing. Since these valves have to be manufactured one by one, the possibility of obtaining heterogeneous results is very high, thus it is very important to have a system to evaluate the behavior of these prostheses. The objective of this project was to design and evaluate a cardiac cycle duplicator to test the function of valvular prostheses. The system consists of a double plexiglass chamber, separated by the valvular prosthesis being studied. The superior "auricular" chamber is connected to a reservoir where the height of the column of saline can be modified. The interior "ventricular" chamber is connected to a pump that generates pressure pulses at constant intervals which simulate ventricular systoles. The other end of the pump connects with an artificial Starling's resistance. The data obtained from this system allows the quantification of the following: 1) Functional diameter, form and area of maximal opening; 2) valve motility; 3) sufficiency of the prostheses; 4) velocity of valve opening and closing; 5) rigidity of the valves; 6) optimal pressure gradient for adequate valvular function. The system makes possible the evaluation and comparison of the function of these valvular prostheses.