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The first reports of cardiac Na/K-ATPase signaling, published 20 years ago, have opened several major fields of investigations into the cardioprotective action of low/subinotropic concentrations of cardiotonic steroids (CTS). This review focuses on the protective cardiac Na/K-ATPase-mediated signaling triggered by low concentrations of ouabain and other CTS, in the context of the enduring debate over the use of CTS in the ischemic heart. Indeed, as basic and clinical research continues to support effectiveness and feasibility of conditioning interventions against ischemia/reperfusion injury in acute myocardial infarction (AMI), the mechanistic information available to date suggests that unique features of CTS-based conditioning could be highly suitable, alone /or as a combinatory approach.

Endogenous cardiotonic steroids (CTS), also called digitalis-like factors, have been postulated to play important roles in health and disease for nearly half a century. Recent discoveries, which include the specific identification of endogenous cardenolide (endogenous ouabain) and bufadienolide (marinobufagenin) CTS in humans along with the delineation of an alternative mechanism by which CTS can signal through the Na(+)/K(+)-ATPase, have increased the interest in this field substantially. Although CTS were first considered important in the regulation of renal sodium transport and arterial pressure, more recent work implicates these hormones in the regulation of cell growth, differentiation, apoptosis, and fibrosis, the modulation of immunity and of carbohydrate metabolism, and the control of various central nervous functions and even behavior. This review focuses on the physiological interactions between CTS and other regulatory systems that may be important in the pathophysiology of essential hypertension, preeclampsia, end-stage renal disease, congestive heart failure, and diabetes mellitus. Based on our increasing understanding of the regulation of CTS as well as the molecular mechanisms of these hormone increases, we also discuss potential therapeutic strategies.

Introduction: Plantain, a herbal remedy, has been reported to interfere with therapeutic drug monitoring of digoxin. We evaluated three commercially available plantain products for potential interference with therapeutic drug monitoring of digoxin and 13 other common drugs., Method: Dry content of plantain capsule or plantain leaf was extracted with either methanol or ethanol:water (60:40 by volume), added to drug-free serum and apparent digoxin was measured by both fluorescence polarization immunoassay and microparticle enzyme immunoassay. Using immunoassays, we also measured apparent concentrations of 13 other drugs (tobramycin, procainamide, tricyclic antidepressants, quinidine, carbamazepine, phenytoin, theophylline, valproic acid, amikacin, gentamycin, phenobarbital, salicylate and acetaminophen [paracetamol]) due to the presence of plantain. In separate experiments, a serum pool prepared from patients receiving digoxin was further supplemented with plantain and observed digoxin values were compared with original digoxin concentration. The presence of any cardiac glycoside in plantain was also investigated using thin layer chromatography (TLC)., Results: We observed no apparent digoxin in the presence of plantain in serum. Moreover, when aliquots of digoxin serum pool were supplemented with various amounts of plantain, the observed digoxin concentrations in the presence of plantain compared well with original digoxin concentration. TLC analysis did not show the presence of either digoxin or digitoxin in plantain products studied. Moreover, plantain did not affect immunoassay results of the 13 other drugs studied., Conclusions: The plantain products studied did not interfere with therapeutic drug monitoring of digoxin as well as 13 other commonly monitored drugs.

In a series of papers the authors analyze literature data on the use of cardiac glycosides for long term treatment of chronic heart failure. Data obtained in prospective placebo controlled trial DIG show that digoxin significantly increases mortality of all patients with sinus rhythm and intact left ventricular systolic function (ejection fraction > 45%) and of women with left ventricular systolic dysfunction (ejection fraction < or = 45%). Men with left ventricular systolic dysfunction represent the only category of patients with chronic heart failure in sinus rhythm in whom long term administration of digoxin is justified. Digoxin does not affect mortality of these patients however it reduces requirements in hospitalizations due to worsening of heart failure.

In a series of papers the authors analyze literature data on the use of cardiac glycosides for long term treatment of chronic heart failure. Part 1 is devoted to clinical pharmacology of glycosides with special emphasis on digoxin. In low doses digoxin produces no substantial effect on contractility of left ventricular myocardium but can cause worsening of its diastolic function. Favorable action of digoxin on clinical course and outcomes of chronic heart failure is most probably related to modulation of neuro-humoral systems. Data on factors influencing sensitivity to glycosides in various categories of patients with heart failure, their interaction with other drugs, and contraindications for digoxin are also presented.

The highly conserved cardiotonic steroid (CS) binding site present on the ubiquitous membrane sodium pump, sodium, potassium-ATPase, appears to have been conserved by no force other than its capacity to bind CS: a family that includes plant-derived cardiac glycosides and putative endogenous vertebrate counterparts. Binding of ligand is inhibited by increased extracellular potassium. This implies functional coordination because inhibition of the sodium pump would be counterproductive when extracellular potassium is elevated. The interesting biology of the CS binding site continues to stimulate investigations into the identity of endogenous ligands, their role as pump regulators at the cellular level, and as mediators of body fluid balance and blood pressure regulation. In addition to inhibition of sodium and potassium transport, there is considerable recent evidence suggesting that the sodium pump may act as a cell signaling receptor activated by CS binding and responding by coordination of intracellular signaling pathways that can be dependent on and also independent of the reduction in transmembrane ion flux resulting directly from pump inhibition. This signaling may influence cell survival, growth, and differentiation. Recent insight into the biology of pump regulation by CS is reviewed.

Pharmacology is integrated in all areas of nursing practice. From the most basic entry level to the most advanced clinical practice, nursing curriculums are not complete without pharmacology. The word "pharmacology" often makes nurses and other health care professionals feel uneasy. Pharmacology implies complicated words and formulas that seem foreign, recalled only from one's most distant recollections of college years. For many health care providers, courses in pharmacology are taken before they care for patients, leaving them with little practical experience from which to relate. Education involves not simply learning and doing, but also applying knowledge. A basic understanding of pharmacology is needed to break down the barriers of pharmacologic communication and put the clinician at ease with terminology so often used by the medical community.

Newly developed Ca2+ sensitizers possess different mechanisms of action on contractile machinery. Increasing maximal Ca(2+)-activated force in addition to enhancing Ca2+ sensitivity (MCI-154, EMD 53998, and EMD 57033) could exert pronounced positive inotropy and may provide a mechanoenergetic advantage over the classic Ca2+ mobilization in the chronically failing heart. EMD 53998 and EMD 57033 prolong crossbridge attachment time, resulting in negative lusitropy. In contrast, pimobendan, levosimendan, and MCI-154 accelerate left ventricular relaxation in heart failure, because Ca2+ sensitizing action of these agents may be prominent during the early phases of contraction. Therefore, Ca2+ sensitizers can avoid the legacy of problems associated with conventional inotropic interventions and may break through "reservation" to "preservation" in the treatment of chronic heart failure.

Inotropic support is an important therapeutic modality in the intensive care unit. There are three classes of agents available to the clinician: catecholamines, bipyridines, and cardiac glycosides. Each class increases inotropy by a different mechanism and each agent has distinct physiological and pharmacological actions. It is important to understand the underlying pathophysiology involved so the appropriate inotrope can be chosen on a rational basis. Prior to and during therapy invasive hemodynamic monitoring is required to ensure proper titration of the chosen agent. If an undesirable effect ensues, therapy can then be modified.

Treatment of chronic heart failure with ACE-inhibitors has greatly improved the prognosis. In addition to ACE-inhibitors, diuretics seem to be necessary to decrease mortality, whereas the importance of cardiac glycosides has not been demonstrated unequivocally. Nevertheless, modern treatment of chronic heart failure in all stages should be a combination of diuretics, digitalis, and ACE-inhibitors rather than a stepwise addition of drugs depending on the severity of the disease. An increased heart rate leads to increased myocardial O2-consumption, decreased O2-supply, ischemia, and reduced contractility. Betablocker-induced reduction of heart rate does, however, not necessarily improve symptoms or hemodynamic conditions. The optimal heart rate in large failing hearts is not known yet. Probably, it is dependent on the type and severity of myocardial disease or impairment. In this respect, the sarcoplasmatic release and uptake of Ca2+ plays the most important role in the disordered force-frequency-relation in chronic heart failure.

The effects of pimobendan (UD-CG 115) on hemodynamics and exercise capacity after acute (single dose) and chronic (6 month) oral treatment, as well as acute treatment after 6 months were investigated in 67 patients with chronic heart failure of NYHA classes II or III, which had persisted in spite of treatment with diuretics and digitalis. They were treated with pimobendan (2.5 mg bid or 5 mg) or placebo in a randomized, double-blind multicenter trial. With a single administration before and after 6 months' treatment there was-compared to placebo-a significant fall in pulmonary capillary pressure (PCP) at rest (R) and during exercise (E) of 7% to 24%. Right atrial pressure (R) and pulmonary arterial pressure (PAP) (R, E) decreased after pimobendan on day 1; cardiac index (E) increased significantly. All other parameters were not influenced. After chronic therapy, PCP (E), PAP (E), LV stroke work index (E), and pulmonary resistance (R and E) values were significantly lowered by pimobendan when compared to day 1. Exercise duration was prolonged after 6 months by 83 s and 47 s after 5 and 10 mg/day, resp., compared to the placebo group (group difference not significant). Subjective wellbeing was improved in all three groups (no group difference). Clinical symptoms were not altered; six patients (two in each group) died suddenly. Another nine patients discontinued the trial prematurely because of poor efficacy or adverse events (no group difference). Overall, pimobendan was well-tolerated and had favorable effects on both acute and chronic hemodynamics and on exercise capacity. There was no evidence of any tolerance development.

An increased understanding of the pathophysiologic changes underlying CHF, advanced monitoring technology, and a wider array of drug therapy have improved the prognosis of patients with this disorder. These advances allow for greater individualization of therapy, improve patient compliance, and lower the incidence of undesirable side effects. Of course, with the increase in complexity of treatment choices comes the need for more knowledgeable practitioners who can select the most appropriate therapeutic approach. All practitioners also must make every effort to educate the patients about their disease, treatments, and necessary lifestyle changes so that optimal benefits can be realized.

Several extensive reviews concerning the actions of new positive inotropic agents in the treatment of congestive heart failure, often with reference to their mechanism of action, have recently been published. Each of them has presented specific points of view. This review will place special emphasis on the significance of intracellular sodium activity for the modulation of myocardial inotropy; the continuing importance, after a 200 year history, of the use of cardiac glycosides as strong inotropic agents; the emerging significance of the phosphoinositide (PIP2) pathway to provide additional second messengers for the modulation and regulation of cardiac inotropy; the contribution of the alpha 1-adrenergic system to cardiac inotropy; the increasing awareness of the significant involvement of adenosine and its antagonists in cardiac function; and the increasing realization that myocardial tissues are not homogeneous, i.e., that in many species the atrial and ventricular tissues are using different, even opposite mechanisms in the generation of their functional responses.

The author begins with the physiological and pathophysiological requirements. He also deals with the way the heart changes with age, and with cardio-active medicines.

In 210 newly detected untreated diabetics of type IIA or B from 4 districts of the county of Neubrandenburg who were admitted to hospital in 1982 their behaviour in taking medicaments was analysed. Cardiac remedies strictly speaking and in the wider sense were classified into the drug groups cardiac remedies (glycosides), antihypertensive agents, beta-receptor blockers, other coronary therapeutic agents and diuretics. At the same time the prevalence of the cardiovascular risk signs overweight (75.7%), hypertension (69.1%), hypertriglyceridaemia (54.8%), hypercholesterolaemia (43.3%), hyperuricaemia (21.0%) and inhalation of cigarette smoke (greater than or equal to 5 cigarettes a day: 12.9%) was established. The proportion of obese persons diminished with growing age, also the percentage of smokers was in the same proportion. In the inverse ratio to this the proportion of diabetics with hyperuricaemia increased according to age. 62.9% of the newly detected diabetics were treated with cardiac glycosides and 49.1% with antihypertensive agents. Only every 4th to 5th patient did not receive a medicament from the drug groups investigated. With the exception of the cardiac remedies in all other groups of substances the proportion of patients treated increased with the enlarging number of cardiovascular risk signs.