Preface Inotropic stimulation of the myocardium, as well as vasodilation and diuresis as essential principles in the treatment of congestive heart failure have recently met with considerable criticism and reevaluation. It is generally agreed that unloading of the heart, either through vasodilation and/or diuresis, improves the working conditions of the dilated, failing heart. It reduces myocardial oxygen consumption through reduction of chamber radius and, thereby, wall tension as the major determinants of myocardial oxygen consumption. Inotropic stimulation, quite in contrast, does not conserve oxygen. It rather consumes energy and that may be disadvantageous in situations of compromised oxygen supply and energy metabolism of the working myocardium. However, under conditions of sufficient oxygen supply and metabolic support inotropic stimulation may bring about increased pumping and subsequent improvement of myocardial failure. In recent years it could convincingly be demonstrated that vasodilation leads to symptomatic improvement of congestive heart failure, improvement of exercise tolerance, and it prolongs life - especially in the case of ACE-inhibitors and the combination of hydralazine with long-acting nitrates. Quite in contrast, equally beneficial effects could not be demonstrated for inotropic agents in congestive heart failure. Only for the cardiac glycosides has it been shown that beneficial effects can be achieved, especially if atrial fibrillation with absolute arrhythmia is present. The influence of the cardiac glycosides on the latter represents an effect which is independent of the inotropic action. As far as inotropic stimulation as a therapeutic factor by itself in acute and/or chronic congestive heart failure is concerned, statistical proof is lacking that therapeutic benefit can be achieved. On the other hand, clinical experience shows that inotropic stimulation may be of considerable value, especially in cardiogenic shock, where beta- and alpha-adrenergic catecholamines find widespread application. It is not clear, however, to what extent vasoactivity of these substances accounts for the therapeutic effect. Pathophysiological studies suggest inotropic stimulation to be highly desirable after ventricular unloading, accomplished either through vasodilation or diuresis. Evaluation of inotropic drugs has met with difficulty, because virtually all inotropic drugs exhibit vasoactivity. Beta-adrenergic agents are characterized by vasodilation. This group of drugs includes substances such as isoproteronol, dobutamine, dopexamine or fenoterol. Partial agonists, such as xamoterol or prenalterol will also have to be included. The balance between beta-1 (inotropic) and beta-2 (vasodilating) properties may vary dependent on dosage (dobutamine) and the individual situation. In chronic congestive heart failure with beta-1 receptor downregulation, beta-2 effects, and hence vasodilation, may dominate; Noradrenalin induces arterial vasoconstriction. Stimulation of the alpha-receptors will probably induce some inotropism, but the predominant effect is vasoconstriction. This evidently will counteract any myocardial stimulant effect and must be considered undesirable in heart failure, unless we are dealing with situations with inadequate peripheral vasoconstriction (early shock, septic shock). Dopaminergic receptors seem to exhibit inotropic properties to a certain degree. Their predominant action, however, is a peripheral vasoconstriction through secondary noradrenaline release and renal vasodilation brought about by specific dopaminergic recep-

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tors in the renal parenchyma. Dopamine has been widely used in intensive care medicine. More recently, oral preparations have been tested in congestive heart failure, for example levodopa and ibopamine. The latter drug is a prodrug and is transformed into epinine, the active substance. Here inotropic stimulation and renal vasodilation are achieved simultaneously. Phosphodiesterase inhibitors are characterized by vasodilator activity as well as inotropic stimulation. It is this group of drugs which has recently received the most attention (amrinone, milrinone, enoximone). The vasodilating properties are so pronounced that hypotension may occur. The very pronounced vasodilation is apt to mask oxygen-consuming properties of inotropic stimulation. The effectiveness of these drugs seems to be seriously impaired in chronic heart failure, as soon as receptor downregulation and, probably, impairment of receptor/effect-coupling occurs. Here not only beta1-adrenergic activity, but also inotropism mediated through phosphodiesterase inhibition seems to be inhibited. Adenylate cyclase activators such as forskoline, have recently been studied. Experience has been disappointing; they do not seem to offer a new approach. Histamine agonists are also dependent on a functioning receptor mechanism at the membrane level. Experience with these drugs has been insufficient so far. Calcium agonists are currently not considered drugs for the treatment of heart failure, because they combine inotropic stimulation and vasoconstriction. This can, at most, be considered desirable in cases of early septic shock, but applicability on a wider range cannot be claimed. The evaluation of inotropic drugs with regard to their influence on myocardial oxygen consumption and myocardial contractile economy has so far been widely neglected. It may well be that the clue to a more logical evaluation of inotropic drugs rests with the definition of the "energetic profile". In the past it has been very difficult to differentiate vasoactivity and inotropism in regard to myocardial energetics. Recently this differentiation has become possible. For these reasons we have choosen to attempt a reevaluation ofinotropic stimulation. For some of the currently used drugs an oxygen-wasting effect can be shown. This applies to sympathomimetic amines as well as to the phosphodiesterase inhibitors. On the other hand, cardiac glycosides and some new inotropic drugs which have additional "calciumsensitizing" effects, seem to be able to bring about inotropic stimulation with proportionate cost in terms of oxygen consumption. The second Gargellen-Conference held June 16, 1988, in Gargellen/Montafon, Austria, was dedicated to the evaluation of inotropic drugs under the aspect of myocardial energetics. The previous Gargellen-Conference of June 1986 addressed the contractile process and the energetic costs of myocardial contraction and thereby laid the basis for this symposium. We are very grateful to our sponsors, Dr. Karl Thomae GmbH, Biberach/Riss (represented by Dr. Benedikter), Bayer AG, Leverkusen (represented by Dr. Kubitz), and Fisons AG (represented by Dr. Roloffs). We also gratefully acknowledge the support of G6decke AG, Freiburg; Beiersdorf AG, Hamburg; Winthrop AG, Wedel/Holstein; and of our publishers Dr. D. Steinkopff-Verlag, Darmstadt, for expert help and efficiency. We hope that this book will help to improve our understanding of inotropic stimulation substances and thereby improve our therapeutic armamentarium for the frequent and serious syndrome of congestive heart failure. Hi. Just Ch. Holubarsch H. Scholz