Digitalis Drugs Research Articles

The effect of interferon on cardiac function and autoimmune antibody in dilated cardiomypathy

To observe the effect of interferon-a and conventional medicines on cardiac function and autoimmune antibodys in DCM patients and compared with conventional therapy alone. Fifty two cases coincided with the DCM standard-were selected from Ott, 1997 to Apr, 2OCtO. Randomly divided into 2 groups, 31 in interferon group and 21 in conventional group. Conventional therapy inccluded digitalis, diuretic, ACE1 and antiarrhythmic drugs, In addition of conventional drugs, interferon 300 million n intramuscular injection on every other day were given in interferon group, the treatment lasted 3-6 monthes. The grade of cardiac function, the frequency of ventricular ventricular rematnre beat, failure and cold were recorded clinically; and I t receptor-antibody, Ma receptor-antibody. TNFo , peripheral lencocyte EVSRNA, CVB viral neutralization antibody were detected before therapy, 1 month, 3 months and 6 months after therapy. The detection of B rand M2 receptor-antibody were used synthsis peptide ELISA; TNFa was assayed by doubleantibody ELISA; peripheral leucocyte EVsRNA was detected by RT-PCR; CVB viral neutralization antibody was tested by viral neutralization test. Interferon combined with conventional treatment was showed more effective than conventional therapy alone in cardiac function, decreasing ventricular premature beat, decreasing times of heart failure, and decreasing times of common cold in DCM. In first 3 aspects, significant difference appeared 6 month after therapy, while the significant different in decreasing times of common cold was appeared in 1, 3 and 6 month after therapy between 2 groups. The size of left ventricle were not decreased obviously in control and interferon groups after treatment. The increase of LVEF of interferon group was more markedly in interferon group than that in control group in 6 month after treatment. The interferon was showed beneficial on the changes of autoimmune antibodys and EVsRNA in DCM patients. There was significant difference between in positive rate of TNFo and EVsRNA after 6 month interferon treatment between 2 groups. Negative correlation was showed between cardiac function and TNF.

Ouabain resistance of a human trophoblast cell line is not related to its reactivity to ouabain

Ouabain is a specific inhibitor of sodium, potassium-dependent adenosine triphosphatase (Na,K-ATPase), a P-type ion-transporting ATPase which is essential for the maintenance of adequate concentrations of intracellular Na+ and K+ ions. The present study describes the establishment of a ouabain-resistant mutant, TLouaR, from a human trophoblast cell line TL. Morphologically TL and TLouaR are indistinguishable, but, TLouaR is about 1000 times more resistant to the cytotoxic effect of ouabain and > 2000 times to that of bufalin and yet ouabain can retard the growth of the TLouaR cells and in parallel reduce its cloning efficiency in a time- and dose-dependent manner. Furthermore, Na,K-ATPase activity from TLouaR cells is inhibitable by ouabain albeit with lower efficiency. [3H]ouabain binding studies reveal that TLouaR cells have less (P < 0.05) ouabain binding sites (1.7 +/- 0.15 x 10(4)/cell vs. 2.3 +/- 0.115 x 10(4)/cell in the control). However, affinities (dissociation constants Kd) to ouabain for TL and TLouaR cells are not significantly different. Lastly, Na,K-ATPase activity (1.375 +/- 0.25 micromole ATP/min mg protein) of TLouaR cells is significantly higher (P < 0.05) than that of the TL cells (0.895 +/- 0.12 micromole ATP/min x mg protein). These studies show that the interactions between ouabain and Na,K-ATPase can be mediated through different pathways resulting in diverse phenotypic characteristics. In addition, ouabain resistance does not necessarily reflect the lack of response to the digitalis drug. The exact mechanisms of ouabain resistance observed in the present study remain to be determined but the TLouaR cells may be the best tool to uncover the many functional characteristics of Na,K-ATPase.

Digoxin and Its Related Endogenous Factors

The digitalis drugs are plant-derived cardenolide compounds used medicinally for several hundred years. These drugs elicit inotropic and chronotropic effects on the heart, but they also affect many other tissues. The mechanism of action involves inhibition of the ion-transport activity of a membrane-associated protein called Na,K-ATPase (sodium pump). Present theory holds that the sodium pump is the principal molecular receptor for the digitalis drugs. Recent evidence indicates the presence of naturally occurring digitalis-like compounds in mammals. It is believed these compounds, collectively known as either digitalis-like (DLF) or ouabain-like (OLF) factors, may be endogenous hormones regulating the biological activity of the sodium pump and its isoforms. The presence of deglycosylated and other congeners of one specific DLF, the digoxin-like immunoreactive factor (DLIF), has very recently been described in humans. Digoxin as a drug is the most widely prescribed digitalis in the U.S., and its measurement in serum has established a model for present-day therapeutic drug monitoring (TDM). Historically, the accurate measurement of digoxin in blood has been difficult. This article focuses on the present understanding of the clinical use of digoxin, factors that affect the accuracy of measuring digoxin, the principle of measuring metabolically active species of digoxin, and the effects of DLIF and other interfering substances in digoxin immunoassay.

Role of aging on electrical, mechanical, and coronary modifications induced by ouabain and epinine in isolated rat heart

The contractile response to digitalis and beta adrenoceptor agonists is lower in the senescent than in the adult myocardium, while the development of ventricular arrhythmias is increased. The aim of this study was to examine the effects of aging on cardiac response to digitalis and an adrenergic agonist used clinically. The electrical and mechanical responses were tested in isolated and perfused hearts from 3-24 month old rats receiving 15 min infusion of digitalis drug (ouabain, 6 x 10(-5) M) alone, and after 5 min of beta adrenoceptor agonist drug (epinine, 1.5 x 10(-7) M). Ouabain action was associated with a rise in left ventricular end diastolic pressure (p < 0.01) which increased progressively with aging, and with an elevation of left ventricular developed pressure (p < 0.01) which decreased progressively with aging. Epinine induced a reduction of left ventricular end diastolic pressure (p < 0.01) and a rise in left ventricular developed pressure (p < 0.01) but both effects decreased progressively with aging. Ouabain reduced coronary flow and this decrease was more pronounced with aging (p < 0.01), while epinine caused an increase (p < 0.01) that diminished in older hearts. Ouabain given after epinine resulted in a greater increase in left ventricular end diastolic pressure than epinine (p < 0.01) but lower than that caused by ouabain alone (p < 0.01), a greater increase in left ventricular developed pressure than epinine and ouabain (p < 0.01), and a smaller reduction of coronary flow rate than ouabain alone (p < 0.01). All these effects, however, diminished progressively with aging. Arrhythmia scores were higher during ouabain than in control (p < 0.01) and in epinine treated hearts (p < 0.01); pretreatment with epinine did not modify arrhythmia score during ouabain administration. The number and severity of arrhythmias, however, increased with aging in all groups. Aging has a negative effect on both the positive inotropic and the arrhythmogenic effects of ouabain and epinine, although these phenomena are more pronounced during ouabain administration. However, when the two drugs are given simultaneously, epinine does not modify the arrhythmogenic effect of ouabain but reduces some of its deleterious haemodynamic effects.

Endogenous factors with immunological and biological activity similar to cardiac glycosides: biochemical and pathophysiological implications.

Endogenous factors with properties similar to digitalis drugs (Endogenous Digitalis-Like Factors, EDLF) have been found in several tissues and body fluids of animals and humans. Detectable EDLF concentrations were found in blood and urine extracts of adults (normal healthy controls, hypertensive patients and salt loaded healthy subjects), while higher levels were generally observed in plasma samples of pregnant women, newborns and patients with renal insufficiency. The chemical characteristics of this endogenous factor are, at the present, unknown, although it has been suggested that EDLF could be a substance with low molecular weight. Experimental studies and theoretical considerations suggest that EDLF, in addition to the ability to react with antibodies anti-digitalis drugs (such as digoxin and ouabain), might also bind to the specific cellular receptor of the cardiac glycosides and thus inhibit the membrane Na+/K+-ATPase (sodium pump). Therefore, it has been suggested that EDLF is an endogenous modulator of the membrane sodium-potassium pump and it could play a role in the regulation of fluids and electrolytes, muscular tone of myocardium, and also in pathogenesis of hypertension.

Effect of Congestive Heart Failure Treatment on Incidence and Prognosis of Ventricular Tachyarrhythmias

The prognosis for patients with congestive heart failure (CHF) is poor, with a mortality exceeding 50% within 5 years from diagnosis. This poor prognosis remains despite improved pharmacological therapy. Because the prevalence of sudden death among these patients is high, reported to exceed 40%, the prognostic importance of ventricular tachyarrhythmias has attracted much interest. Long-term electrocardiographic monitoring of patients with CHF reveals a high prevalence of ventricular premature beats, which in many patients occur frequently or are complex according to Lown criteria. Ventricular tachycardia (three or more consecutive beats) has been recorded in 40% or more of the patient population. Whether the occurrence and/or severity of ventricular tachyarrhythmia detected on Holter electrocardiograms relates to the subsequent prognosis is, however, debated. The occurrence of ventricular tachyarrhythmia may just be an expression of severely compromised left ventricular function, which, in turn, decides the subsequent outcome of the disease. Besides myocardial injury, patients with CHF have many factors that may contribute to the high prevalence of ventricular arrhythmias. Among these are elevated levels of plasma norepinephrine. Angiotensin II may increase the sensitivity to sympathetic nervous system arousal but also promotes renal loss of potassium and magnesium. Treatment with digitalis and diuretic drugs may provoke arrhythmias as well. Heart failure therapy may, however, also improve ventricular arrhythmias. Accordingly, it has been demonstrated that captopril therapy significantly reduces ventricular prematurity, compared with digitalis. In contrast, however, enalapril improvement of mortality was due to a reduction of progressive heart failure, with no difference seen in the incidence of sudden cardiac death (the CONSENSUS study).(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of Whole Season CO2 Enrichment on the Cultivation of a Medicinal Plant, Digitalis lanata

AbstractA versatile method was developed for the application of 1000 ppm CO2 during the whole growth period of plants. Temperature controlled water cooling and ventilation of the greenhouse resulted in a monthly CO2 enrichment time of 60 to 90 % of the total light period. Digitalis lanata, grown in greenhouses with CO2 enrichment during the whole growth phase from April to November, produced twice as much biomass as field cultivated plants.The relative yield of the glycoside digoxin per gram Digitalis drug dry weight was 0.4% in field grown and 0.7% in greenhouse cultivated plants. The production of digoxin per hectare in the greenhouse at 1000 ppm CO2 was almost 3.5‐fold that by field cultivation. Drug yield and secondary metabolite production in D. lanata were remarkably influenced by increased temperature and elevated CO2 partial pressure in the greenhouse.

Specific binding of cardiac glycoside drugs and endogenous digitalis-like substances to particulate membrane fractions from human placenta.

We studied the characteristics of binding of cardiac glycosides to particulate membrane fractions from human placenta, to demonstrate that placental tissue is a suitable source of receptors for digitalis drugs. Moreover, we performed preliminary experiments with 125I-labeled digoxin and placental particulates to develop a radioreceptor assay for measurement of endogenous substances with activity similar to cardiac glycoside drugs (EDLS). Placental membrane fractions were incubated with [3H]ouabain (10 nmol/L) or 125I-labeled digoxin (50 pmol/L). With both ligands, binding followed a pseudo-first-order reaction kinetics and was saturable. Scatchard analysis revealed a single class of sites [for ouabain, KD = 20.2 +/- 5.8 nmol/L (mean +/- SEM), Bmax = 3.1 +/- 0.9 nmol per gram of protein; for digoxin, KD = 29.7 +/- 1.9 nmol/L, Bmax = 24.3 +/- 1.1 nmol per gram of protein]. As expected, digoxin was less potent than ouabain in displacing both tracers from digitalis drugs receptors; progesterone, cortisone, digitoxose, furosemide, bumetanide, and propranolol had no or little effect. Specific 125I-labeled digoxin binding was competitively inhibited by plasma and (or) urine extracts from newborns, adults, pregnant women, and patients with renal insufficiency. Inhibition of binding and volume of plasma and urine assayed were linearly related. These findings support the hypothesis that cardiac glycosides and EDLS can interact with the human placenta and suggest placental tissue to be a suitable source of receptors for cardiac glycosides.

Long-Term Therapy of Chronic Congestive Heart Failure with Ibopamine

The present multicenter open investigation was designed to provide information on the adverse reaction rate, drug interaction, and survival in a group of 544 cardiac patients treated for 1 year with ibopamine either alone or in association with digitalis, diuretics, and other drugs. Some efficacy parameters were also considered. Heart failure was due to idiopathic dilated cardiomyopathy (21%), ischemic heart disease (32%), hypertensive heart disease (31%), and others (16%). Ibopamine was given alone to 39 patients; the others were given the drug in association with digitalis, diuretics, and vasodilators. One hundred forty patients did not complete the trial (25.7%). The most common causes of discontinuation were death (12.5%), noncompliance with the protocol (5%), and adverse events (3.9%). The clinical conditions and NYHA functional class improved in most patients. The cardiothoracic ratio decreased on average. The 1-year mortality rates associated with NYHA class II, III, and IV were 4.4, 13.8, and 37.2%, respectively. Survival tended to be shorter in a small group of 22 patients with hyponatremia, thus confirming some previous reports. Adverse experiences were mainly related to cardiovascular and gastrointestinal systems; the symptoms were considered severe only in 1 of 544 patients enrolled. Ibopamine seems not to induce dangerous arrhythmias. Blood pressure and heart rate did not change over time during ibopamine treatment. Laboratory tests were not significantly affected; fluctuations observed in some tests were related to concomitant variations in the severity of the primary disease. No tolerance to ibopamine seems to be observed during this long-term therapeutic trial.

Electrical and mechanical effects of new aminosteroids on guinea-pig isolated ventricular muscle.

1. LND 623 and LND 796 are two aminosteroid derivatives which exert similar positive inotropic effects to digitalis. Their electrophysiological, toxic and inotropic effects were investigated in both normal and partially K+-depolarized ventricular muscle. 2. In guinea-pig myocardial fibres, LND 623 and LND 796 required tenfold higher concentrations than digoxin to induce the same signs of toxicity; e.g. triggered activities generated from delayed afterdepolarizations, leading to the marked depression of action potential characteristics and inexcitability. These abnormal rhythms and delayed afterdepolarizations were abolished by 1 mM caffeine. The toxic effects were reversed by washout, particularly in the case of LND 796. 3. In normal-K+ solution, LND 623 and LND 796 exhibited concentration-dependent positive inotropic effects on guinea-pig papillary muscle and increased concomitantly resting membrane potential and action potential amplitude. The range of active concentrations (0.1 to 1 microM) of LND 623 was larger than that of digoxin (0.3 to 1 microM). Like digoxin, LND 796 exerted negative inotropic effects at the lowest concentrations (0.01 to 0.03 microM) and positive inotropic effects at high concentrations (1 and 3 microM). 4. In partially K+-depolarized papillary muscle, in the presence of 2 microM histamine, LND 623 (3 and 10 microM) and LND 796 (10 and 30 microM) enhanced the two components P1 and P2 of the contraction and increased slow action potential amplitude, resting potential and maximal rate of depolarization. Low concentrations (0.03 to 0.3 microM) of LND 796 induced negative inotropic effects. beta-Adrenoceptor blockade with atenolol (1 microM) did not modify the activity of LND 623 but significantly enhanced the negative inotropic effect on P2 induced by 1 and 3 microM LND 796 and reduced the positive inotropic effect on P1 and P2 of the highest concentration (30 microM) studied. 5. In the presence of either caffeine (1 mM) or Ca2+-free, Sr2+-rich (3.6 mM) solution, LND 623 and LND 796 produced a positive inotropic effect which was stronger with LND 623. 6. It is suggested that two mechanisms are involved in the inotropic effects of these aminosteroids: (i) an enhanced Ca2 + entry via the slow calcium channels partially brought about by a local release of endogenous catecholamines in the case of LND 796, (ii) an inhibitory effect on Na+-K+ ATPase which, at the highest concentrations, lead to similar signs of cellular toxicity to those described for digitalis drugs. Because of their enlarged positive inotropic range, both aminosteroids may be of interest in the treatment of congestive heart failure.

Hemodynamic effects of intravenous digoxin in patients with severe heart failure initially treated with diuretics and vasodilators

The purpose of this study was to assess the hemodynamic effects of intravenous digoxin in patients with New York Heart Association class IV heart failure, who had never previously been treated with digitalis drugs, and who were initially treated only with diuretics and systemic vasodilators to clinical end points of compensation. Eleven male patients, 5 with idiopathic and 6 with ischemic cardiomyopathy, had sinus rhythm and were hospitalized with congestive heart failure not precipitated by an acute ischemic event. All 11 patients were treated with intravenous furosemide and various vasodilators without invasive hemodynamic monitoring for a mean period of 4.3 +/- 2.1 days. This therapy resulted in subjective and objective improvement in all patients as reflected by a significant decrease in heart failure score from 9.5 +/- 2.2 to 2.7 +/- 2.3 (p less than 0.001). When compensation was achieved by clinical criteria, the patients were instrumented and hemodynamics obtained before and serially thereafter for 6 hours after the intravenous administration of digoxin given in two 0.5 mg doses 2 hours apart. In response to digoxin, cardiac index increased from 2.6 +/- 0.7 liters/min per m2 to a peak of 3.3 +/- 0.6 liters/min per m2 (p less than 0.005); left ventricular stroke work index (g X m/m2) increased from 27 +/- 16 to 43 +/- 23 (p less than 0.005) and the ejection fraction (eight patients) increased from 21 +/- 13% to 29 +/- 11% (p less than 0.04). Mean pulmonary capillary wedge pressure decreased from 24 +/- 7 to a minimum of 17 +/- 4 mm Hg (p less than 0.02).(ABSTRACT TRUNCATED AT 250 WORDS)

Antiarrhythmic drug interactions: are they important?

Most cardiac patients who have cardiac arrhythmias and are treated by antiarrhythmic agents will receive other cardiovascular drugs to treat coexistent problems, for example heart failure, angina or hypertension. Also, two antiarrhythmic drugs may be simultaneously prescribed to these patients in the search for better efficacy and fewer side effects. Finally these patients may well take noncardiovascular drugs such as cimetidine for the treatment of peptic ulcer disease or other hypersecretory disorders. In all cases, complex pharmacodynamic and pharmacokinetic drug interactions are likely to occur. These interactions have been extensively reviewed by Bigger and Giardina. The purpose of this work is to focus on the potentially important interactions with antiarrhythmic drugs. It is of interest for the cardiologist to be aware of the most common and meaningful drug interactions in order to prevent lack of efficacy or a risk of drug toxicity that could result from the simultaneous administration of different drugs to a patient. In this regard the interactions of antiarrhythmic drugs with digitalis, cimetidine, beta-blocking agents and other antiarrhythmic drugs will be briefly reviewed.

Effects of acetyl-strophanthidin on left ventricular function and ventricular arrhythmias

Digitalis drugs can suppress ventricular arrhythmias. It is uncertain whether this effect results from improved left ventricular (LV) function. We utilized radionuclide scanning techniques to evaluate changes in LV ejection fraction (EF) after an infusion of acetyl-strophanthidin in 43 patients with frequent ventricular premature beats (VPBs) (44 to 2400/hr). Acetyl-strophanthidin suppressed ventricular arrhythmia in 17 patients, but LVEF increased in only six of these patients (57% to 67%), while it was unaltered in 11 patients (28% to 30%). In 26 patients ventricular arrhythmia was not suppressed. Fifteen of these patients had an increase in LVEF (60% vs 71%), while this was unchanged in 11 patients (27% vs 29%). Thus no correlation was observed between the positive inotropic and antiarrhythmic action of acetyl-strophanthidin nor was there any correlation between the type of heart disease and the effect of acetyl-strophanthidin on ventricular arrhythmia and LVEF. We conclude that the suppression of VPBs by acetyl-strophanthidin is independent of the drug's effects on LV function. Evidence is reviewed suggesting that the antiarrhythmic effect of acetyl-strophanthidin on ventricular ectopic activity is due to its vagotonic action.

Efficacy of amiodarone for refractory supraventricular tachyarrhythmias

Amiodarone was administered to 121 patients (82 males, 39 females; average age 59 years) with refractory atrial tachyarrhythmias. All patients had experienced recurrent atrial fibrillation, atrial flutter, or reentrant supraventricular tachycardia previously refractory to digitalis drugs, β-adrenergic blocking agents, and an array of membrance-active preparations. Seventy-four of 121 patients (61.2%) had no evidence of organic heart disease, whereas 17 patients experienced arrhythmia as a result of coronary heart disease, nine had preexcitation syndromes, 16 had primary valvular heart disease, and five patients, had congenital heart disease. Atrial fibrillation alone or in combination with atrial flutter was the primary dysrhythmia in 95 of 121 patients (78.5%), whereas in 26 patients (21.5%) supraventricular tachycardia was the primary refractory dysrhythmia. Fifty-one patients (42%) had experienced tachyarrhythmias for more than 10 years prior to the use of amiodarone. During an average follow-up of 27.3 months, complete suppression of atrial arrhythmias occurred in 98 of 121 patients (81%), and partial suppression occurred in seven (5.8%). In 16 patients (13.2%) the drug was deemed ineffective, and in eight patients (6.6%) amiodarone was discontinued because of intolerable side effects. The average blood serum concentration among successfully treated patients was 1.9 μg/ml, whereas the average concentration for those with side effects was 2.3 μg/ml. Thus, amiodarone is an extremely effective (85%) agent for refractory atrial tachyarrhythmias. Once daily administration, generally tolerable side effects, and excellent patient tolerance render this agent an attractive option for the management of these dysrhythmias.

Prognosis of medically treated patients with coronary-artery disease with profound ST-segment depression during exercise testing.

Reproducible and profound (greater than 2 mm) ST-segment depression during exercise testing in patients with coronary heart disease is associated with multivessel involvement. In these patients, coronary-artery bypass surgery has been recommended even when symptoms are absent. However, there are few long-term follow-up data regarding the prognosis when such patients are treated medically. Among 212 men with coronary-artery disease in whom profound ST-segment depression could be reproduced with exercise, 142 who had no other type of heart disease and were not receiving digitalis drugs had a mean ST-segment depression of 2.9 mm. Follow-up has lasted an average of 59 months: 11 patients have died (annual mortality, 1.4 per cent), and nine have had bypass operations (1.3 per cent per year). Survival correlated with exercise tolerance but not with degree of ST depression, peak heart rate, or peak blood pressure during exercise. We conclude that such ST-segment depression is not associated with a poor prognosis. There is rarely a need to resort to cardiac surgery; medical management is highly successful and associated with a low mortality.

Effects of chronic digitalization on cardiac and renal Na+ + K+-dependent adenosine triphosphate activity and circulating catecholamines in the dog.

To extend our understanding of the mechanism of action of digitalis drugs, we studied electrocardiograms (ECGs), renal function, plasma concentrations of catecholamines, and myocardial and renal Na+ + K+-dependent adenosine triphosphate (Na+ + K+ ATPase) activity in chronically digitalized dogs. Five healthy, male, mongrel dogs received a therapeutic regimen of digoxin (0.1 mg/kg on day 1 in three divided doses followed by 0.025 mg/kg per day) orally for 2-4 months. This resulted in plasma digoxin concentrations of 1.1 to 4.7 ng/ml as determined by radioimmunoassay. Six control dogs received daily gelatin capsules by mouth. ECGs monitored throughout the study showed no changes. Digitalized dogs had elevated plasma norepinephrine concentrations (347 vs. 137 pg/ml in controls) and no change in plasma epinephrine concentrations. Digitalized dogs had elevated glomerular filtration rates (0.74 vs. 0.94 ml/min per g of kidney) without significant changes in renal handling of electrolytes and water. All of the above studies were done without the aid of restraining drugs or infusions. The animals were killed with an overdose of pentobarbital for in vitro studies. In digitalized dogs, microsomal Na+ + K+ ATPase-specific activity was 26 to 33% lower in the renal cortex, medulla, and papilla, and 46% lower in the cardiac left ventricle than in control dogs. Digitalization did not alter the osmolalities of renal tissues. We conclude that chronic reduction Na+ + K+ ATPase activity by one-third dose does not cause abnormalities in renal handling of electrolytes and water, and inhibition of Na+ + K+ ATPase in the left ventricular muscle by one-half is associated with no obvious ECG changes in the dog. Further, elevated plasma norepinephrine concentrations may contribute to both the therapeutic and the toxic effects of digitalis.

The effect of drugs on the cardiovascular response to exercise.

Anti-hypertensives, diuretics, digitalis, beta-blockers, nitrates, anti-arrhythmics, and psychiatric drugs are reviewed for their effects on the cardiovascular response to exercise, in particular work capacity, heart rate, blood pressure, anginal threshold, and exertional arrhythmias. The limitations of these measurements to assess changes in the various aspects of cardiovascular performance in the presence of drugs becomes evident, emphasizing the need for an understanding of the relationship between drug effects on specific target organs and the altered integrated exercise response. The variable response of individuals to drug therapy, depending on the pathophysiological effects of their disease, demonstrates the value of exercise testing in selecting optimal drug regimens.

Digitalis drugs and vulnerability to ventricular fibrillation

The effect of acetylstrophanthidin (AS), a rapid-acting digitalis-like agent, on the ventricular fibrillation (VF) threshold was examined in normal and denervated chloralose-anesthetized dogs. In neurally intact dogs an intravenous bolus of AS (0.075 mg/kg) increased the VF threshold up to a maximum 50% (P < 0.01) within 30 min after injection. The augmented VF threshold following intravenous administration of AS was not altered by vagotomy. Bilateral stellectomy in vagotomized dogs, as well as carotid sinus and aortic arch denervations, however, prevented the AS induced increase in VF threshold. In neurally intact dogs β-adrenergic blockade with propranolol (0.25 mg/kg) precluded AS effects. These data suggest that the increase in the VF threshold resulting from AS administration in the normal canine ventricle is due to withdrawal of sympathetic tone mediated via the baroreceptor reflex. The direct effect of AS on the myocardium is to decrease the VF threshold.

Effect of arrhythmogenic doses of deslanoside on the uptake of monoamines in brain tissue and in cardiac tissue

The purpose of our study was to determine whether a toxic arrhythmogenic dose of digitalis administered to an in vivo preparation would affect the neuronal uptake of norepinephrine, serotonin and dopamine in brain tissue and norepinephrine in cardiac tissue. This was investigated by intoxicating anesthetized cats with deslanoside, removing cardiac and brain tissue at the onset of ventricular fibrillation, and examining the ability of brain tissue to accumulate [ 3H]-NE, [ 3H]-5-HT and [ 3H]-DA and cardiac tissue to accumulate [ 3H]-NE. It was found that deslanoside inhibited uptake of [ 3H]-NE into the left ventricle and [ 3H]5-HT into the area postrema. These selective effects may reflect greater blood flow to these regions or different sensitivities of the transport mechanisms for these amines. This inihibition of uptake into both left ventricular tissue and area postrema may contribute to some of the cardiovascular and emetic effects seen with digitalis drugs.

Neural Actions of Digitalis

Neural actions of digitalis drugs have been well documented but their role in the cardiovascular effects of this group of agents is a subject of considerable con­ troversy. Information concerning neural actions of these drugs, as related to their cardiovascular effects, can be grouped into the following three categories: conduction, automaticity, and refractory period; ventricular arrhythmias; and inotropic and hemodynamic effects. The first are examples where firm evidence from both animal and human studies indicates a major role for the nervous system in determining the response produced by digitalis drugs. The second is an example where impressive evidence has been obtained from some but not all animal studies indicating an important role for the nervous system in the toxic response of these agents. The third are examples where present data suggest a role for the nervous system in the well-known actions of digitalis drugs on the heart and vasculature, but more experimentation is needed to confirm present findings and to further elucidate the extent to which the nervous system partici­ pates in these responses.