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Congestive heart failure is a clinical syndrome in which the capacity of the heart to maintain cardiac output is impaired. As a consequence, blood pressure is threatened and endocrine and paracrine mechanisms are activated to preserve circulatory homeostasis and to maintain blood pressure. At terminal stages, a complex multiorgan syndrome develops with severe pump failure, intense systemic vasoconstriction, and avid water and sodium retention. Increasing evidence points to humoral circulating or locally synthesized substances as one of the causes of the terminal consequences of heart failure. Therefore, the hypothesis that the syndrome of heart failure is, at least in part, a humoral disease has developed and is obtaining scientific credibility. Consequently, the neuroendocrine response to heart failure is no longer viewed as a compensatory beneficial mechanism. Instead, we have learned through the years that pharmacological treatment aimed at reducing the effect of the neuroendocrine response is indeed clinically and prognostically advantageous for the patient.

There are several potential outcomes of myocardial ischemia. When ischemia is severe and prolonged, irreversible damage occurs and there is no recovery of contractile function. Interventions aimed at reducing mechanical activity and oxygen demand, either before ischemia or during reperfusion, have been shown to delay the onset of ischemic damage and to improve recovery on reperfusion. When myocardial ischemia is less severe but still prolonged, myocytes may remain viable but exhibit depressed contractile function. Under these conditions, reperfusion restores complete contractile performance. This type of ischemia, leading to a reversible, chronic left ventricular dysfunction, has been termed hibernating myocardium. Depression of mechanical activity is, actually, a protective mechanism whereby the hibernating cells reduce their oxygen demands in the setting of reduced oxygen supply. A third possible outcome after a short period of myocardial ischemia is a transient postischemic ventricular dysfunction, a situation termed stunned myocardium. As in the case of hibernating myocardium, the depressed contractile function occurring during stunning could be a protective mechanism, allowing the reperfused cells to gradually recover their metabolism and function.

The majority of calcium antagonists used clinically belong to three distinct chemical classes: the phenylalkylamines, the dihydropyridines, and the benzothiazepines. In recent years their mode of action has been unravelled, their limitations recognized, and their efficacy and use in the management of patients with a broad spectrum of cardiovascular and other disorders defined. It is clear, however, that these drugs are not all alike, providing an explanation for their differing effects. The final therapeutic effect in humans depends on the mechanisms of action at the molecular level, the tissue selectivity, and the hemodynamic changes of each agent. All these aspects are examined in detail in this article. Concepts that are highlighted are as follows: (a) Molecular biology has allowed recognition of the polypeptide components of the alpha 1 subunit of the L-type Ca2+ channel and the finding of peptide segments covalently labelled by all three classes of drugs. (b) The location of these segments within the peptides is different: Binding sites for dihydropyridines are located externally, whereas those for verapamil and diltiazem are located internally, in the cytosolic part of the membrane. (c) Dihydropyridine binding is voltage dependent. This explains the selectivity of this class of drugs for vascular smooth muscle, which is more depolarized than cardiac muscle. (d) Phenylalkylamines and benzothiazepines reach their receptors at the internal surface of the sarcolemma through the channel lumen. Their binding is facilitated by the repetitive depolarization of atrioventricular and cardiac tissue, a phenomenon described as use dependence. This explains why these drugs are not highly selective, but equipotent for the myocardium, the atrioventricular conducting tissue, and the vasculature. (e) Dihydropyridines act through selective vasodilatation and may increase heart rate and contractility via a reflex mechanism. On the contrary, phenylalkylamines and diltiazem act through a combination of effects, including reduction of afterload, heart rate, and contractility. When taken together, all these differences distinguish the preferential clinical utilization of one of these compounds for a given cardiovascular pathology.

The acute and chronic effects of the dihydropyridine calcium antagonist nisoldipine were studied in patients with chronic heart failure (LV EF

Cicloprolol is a new beta-blocking agent with high selectivity for beta 1 receptors and high intrinsic sympathomimetic activity. We studied the acute hemodynamic effects of cicloprolol in nine subjects with no evidence of left ventricular dysfunction who underwent cardiac catheterization for the evaluation of chest pain. All patients had normal coronary angiography and left ventriculography. Left ventricular pressure was determined throughout the cardiac cycle using a Millar 8Fr Minotip catheter; an echocardiogram, phonocardiogram, and ECG were simultaneously recorded to obtain left ventricular pressure-diameter loops. All the measurements were repeated before and after the intravenous administration of cicloprolol. Cicloprolol was administered at increasing doses of 0.05, 0.10, and 0.25 mg/kg until a cardiac output increase of at least 15% over basal values was achieved. A decrease of mean arterial pressure or cardiac output after cicloprolol was not observed in any patient. Cicloprolol administration significantly increased cardiac output (24%), stroke volume (22%), and peak positive dP/dt (25%); no significant changes in heart rate, systemic blood pressure, right atrial pressure, or pulmonary artery pressures were observed. No significant change in the echocardiographic parameters occurred. Among the indices of left ventricular diastolic function, the time constant of isovolumetric relaxation was significantly decreased (-43%) after cicloprolol; moreover, the left ventricular pressure-diameter loop in the protodiastolic phase was shifted to the left following cicloprolol infusion. This study confirms that in subjects with normal left ventricular function cicloprolol can improve resting left ventricular systolic function, and it shows that this action can also be attended by a more rapid isovolumetric relaxation, similar to what has been observed with other sympathomimetic amines.

To assess whether pretreatment with the calcium antagonist anipamil protects the heart against ischemic and reperfusion damage and to establish how long the protection persists after cessation of the therapy, rabbits were injected subcutaneously twice daily for 5 days with 2 mg/kg body weight of this drug. The heart was then isolated 2, 6, or 12 hours after the last injection and was perfused by the Langendorff technique during a control period and 90 minutes of total ischemia (37 degrees C), followed by 30 minutes of reperfusion. Diastolic and developed pressure was monitored; coronary effluent was collected and assayed for creatine phosphokinase (CPK); mitochondria were harvested and assayed for respiratory activity, ATP production, and calcium content; and tissue concentration of adenosine triphosphate (ATP) and creatine phosphate were determined. The data obtained with anipamil were compared with those obtained with verapamil administered to the rabbit at the same dose and following the same procedure. Pretreatment with anipamil induced a negative inotropic effect under normoxic conditions; reduced the rate and extent of depletion of ATP and creatine phosphate during ischemia, with an incomplete restoration of the nucleotides after reperfusion; maintained mitochondrial function and calcium homeostasis during ischemia and reperfusion; reduced the rate of CPK release; and improved the recovery of ventricular function on reperfusion. The protective effects of anipamil persisted for as long as 12 hours after the last administration. In contrast, the protective and negative inotropic effects of verapamil were no longer apparent in heart isolated 6 or 12 hours after the last dose of the drug.(ABSTRACT TRUNCATED AT 250 WORDS)

The two dihydropyridine calcium antagonists, nicardipine and nifedipine, were compared in 12 patients with both stable angina pectoris and systemic hypertension using a double-blind, crossover protocol. After a 2-week placebo run-in period, each patient was randomized to either nicardipine or nifedipine; each drug was titrated up to either blood pressure normalization, appearance of adverse effects, or maximal dosage (40 mg, three times a day with nicardipine and 30 mg, three times a day with nifedipine) and then administered for 4 weeks. Maximal symptom-limited exercise tests were performed at the end of the placebo run-in and each treatment period, 3 and 8 hours after drug administration. Nicardipine and nifedipine were used at the mean doses of 100±20 mg/day and 57±20 mg/day, respectively. Both drugs reduced, significantly and similarly, standing and supine blood pressure, frequency of anginal episodes, and nitroglycerin consumption. At 3 hours after drug administration, exercise duration and time to 1-mm ST depression increased significantly from 402±84 and 306±108 seconds, respectively, with placebo; to 533±135 and 442±138 seconds during nicardipine; and to 518±118 and 437±133 seconds during nifedipine, with a concomitant reduction of peak ST depression. Both submaximal and maximal exercise diastolic blood pressure were significantly reduced by the two calcium antagonists whereas systolic blood pressure was decreased only at submaximal but not at maximal exercise; the heart rate was not significantly modified by the two drugs at any exercise stage. The rate-pressure product decreased from 169±17 to 151±25 with nicardipine and 152±24 with nifedipine at submaximal exercise, but was not significantly modified at the onset of 1-mm ST depression and maximal exercise. Thus, nicardipine and nifedipine showed a similar hypotensive and antianginal activity; the only important difference between the two drugs emerged from the exercise tests performed 8 hours after drug administration; although nifedipine still maintained a slight antianginal activity, nicardipine showed a significantly greater anti-ischemic and hemodynamic activity at that time.

We studied the acute effects of intravenous nifedipine on hemodynamics and left ventricular function of CAD patients without previous treatment (group 1) and of 10 CAD patients receiving acebutolol (9 mg/kg daily) and who had been shown to be adequately beta blocked (reduction in heart rate by 25%) (group 2). Intravenous nifedipine (15 micrograms/kg) significantly reduced systemic peripheral resistances in both groups: this was associated with decreased systolic blood pressure and increased left ventricular cardiac output with a slight nonsignificant increase of ejection fraction. There was a significant increase in heart rate in both groups, the chronotropic response to nifedipine being attenuated in patients receiving acebutolol. Left ventricular end-diastolic pressure did not change in the first group, but it was significantly decreased in the second group, with a concomitant increase of end-diastolic left ventricular volume, suggesting an amelioration of diastolic compliance. The effect of nifedipine on intrinsic myocardial contractility was quite different, depending on the presence of beta adrenergic blockade. When given to patients of group 1, nifedipine significantly increased dP/dtmax, Vcemax, and Vmaxd. The same indices, however, were significantly depressed when nifedipine was given to the patients of group 2 receiving acebutolol. This study shows that intravenous nifedipine can be usefully administered to patients with coronary artery disease who have been on adequate beta-blocking doses of acebutolol with relative safety. Under these conditions nifedipine increases cardiac output in association with arterial dilation, despite evidence for a negative inotropic effect. These data also suggest that such an intrinsic negative inotropic effect would normally be masked by compensatory sympathetic activity.