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The haemodynamic effects of intravenous frusemide (1 mg/kg) were studied in 22 male patients with left ventricular failure following acute myocardial infarction. Radiographic pulmonary oedema was present in all patients and their average left heart filling pressure was 20 mmHg. Bolus injection of the drug was followed by immediate increases in systemic arterial pressure (P less than 0.05) and heart rate (less than 0.05); these declined to pre-injection values after 60 min. Following frusemide there were progressive reductions in left heart filling pressure (P less than 0.01), thermodilution cardiac output (P less than 0.01) and stroke volume (P less than 0.05) and a progressive increase in the derived systemic vascular resistance (P less than 0.05). There was an average diuresis of 860 ml during the 90 min following the frusemide injection. The influence of frusemide on left ventricular performance was studied by comparing the circulatory effects of passive leg raising in the control period with those at 30, 60 and 90 min after the drug. In the control period this manoeuvre increased left heart filling pressure, but not heart rate, cardiac output, stroke volume or systemic vascular resistance. Ninety minutes after frusemide, but not before, passive leg raising resulted in a significant increase in cardiac output (P less than 0.01) and stroke volume at a similar increment in filling pressure and a significant reduction in the systemic vascular resistance (P less than 0.05). These circulatory actions of intravenous frusemide are compatible with initial arteriolar constriction and venodilatation followed by depletion of blood volume with subsequent change in left ventricular pumping performance.

1 The haemodynamic dose-response effects of the slow channel blocking agent nicardipine were evaluated in 10 male patients with angiographically confirmed coronary artery disease. At rest, following a similar control saline period, four doses of the drug (log cumulative dosage: 1.25, 2.5, 5.0 and 10.0 mg) were administered by i.v. infusion over a total duration of 40 min; haemodynamic variables were recorded in the 3-5 min following each 5 min infusion. During steady-state exercise the haemodynamic effects of the drug were evaluated by comparison of a control exercise period with observations made at the same workload (200-500 kpm) following the maximum cumulative dose (10 mg).2 Following the four i.v. infusions, the plasma nicardipine level increased log-linearly with the infused dose (r = 0.68). Compared with control measurements at rest after saline, these plasma concentrations (35 + 8 to 141 + 24 ,ug/l) resulted in a linear decrease in systemic blood pressure and vascular resistance with significant increase in cardiac index (maximum ACI + 1.6 1 min1 m-2; P < 0.01), stroke index (maximum ASI + 11 mlIm2; P < 0.01) and in pulmonary artery occluded pressure (maximum APAOP + 2 mm Hg; P < 0.01). There was a significant increase in heart rate; the stroke work index was unchanged. 3 During upright bicycle exercise the reduction in systemic blood pressure was accompanied by an increased exercise cardiac output without change in stroke index. The exercise pulmonary artery occluded pressure was unchanged compared with control observations, the stroke work index fell significantly (P < 0.05). 4 The changes in resting haemodynamic variables following nicardipine reflect the influence of a reduction in left ventricular afterload favourably modifying cardiac performance in ischaemic heart disease. During exercise, with near maximal vasodilatation, the additional reduction in systemic vascular resistance on nicardipine did not further improve exercise haemodynamics. However, nicardipine, over a wide intravenous dose-range, did not result in undue depression of cardiac function; thus it would appear to be haemodynamically safe, even in relatively severe coronary artery disease.

Clinical concern still exists regarding the potentially deleterious results of the combined negative inotropic effects of cardiac beta-adrenoceptor and slow calcium channel blockade in patients with impaired left ventricular function due to coronary heart disease. The haemodynamic effects of sublingual nifedipine (20 mg) and intravenous metoprolol (10 mg) singly and in combination were therefore studied in 20 patients with severe angina pectoris associated with angiographically documented coronary artery disease. The plasma concentrations of each drug at the time of the haemodynamic measurements were within the range associated with relief of exercise-induced anginal pain. Sitting at rest, nifedipine was associated with reductions in systemic arterial pressure (P less than 0.05), systemic vascular resistance (P less than 0.001), and increases in heart rate (P less than 0.01) and cardiac output (P less than 0.05) without significant change in the left heart filling pressure. In contrast, sitting at rest, metoprolol was associated with reductions in systemic blood pressure (P less than 0.05), heart rate (P less than 0.001) and cardiac output (P less than 0.05) and an increase in left heart filling pressure (P less than 0.01). After both drugs, similar directional changes were observed during upright bicycle exercise compared to the control exercise measurements. In combination, the negative inotropic effects of metoprolol were largely offset by the reduction of the systemic vascular resistance due to nifedipine. Conversely the reflex tachycardia following nifedipine was countered by metoprolol. Thus the combination reduced two of the major determinants of left ventricular oxygen consumption, namely heart rate and systemic blood pressure, at the expense of a small increase in left heart filling pressure. This may have explained the subjective improvement in anginal symptoms noticed by the majority of the patients. The combination of nifedipine and metoprolol was haemodynamically more advantageous both at rest and during exercise than either drug alone in our patients with depressed left ventricular function due to the coronary heart disease.

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