Haemodynamic dose-response effects of intravenous amrinone in left ventricular failure complicating acute myocardial infarction

The haemodynamic dose-response effects of intravenous amrinone were measured in 16 male patients, aged 40-65 years, with radiographic and haemodynamic evidence of left ventricular failure 4-18 h after acute myocardial infarction. After a l-h control period to confirm stable haemodynamic baseline variables, patients were randomised to either low-dose (200-400-800 micrograms/kg/h) or high-dose (800-1600-3200 micrograms/kg/h) intravenous amrinone. Each of the three infusions was given consecutively over 30 min (total infusion time 90 min) in each group, and haemodynamic measurements were made at the end of each infusion step. No arrhythmias or other untoward side effects, including haematological changes, were observed during the infusions. In both groups, intravenous amrinone reduced the pulmonary artery-occluded pressure (PAOP) (p less than 0.01), increased the cardiac output (p less than 0.05), and reduced the systemic vascular resistance (p less than 0.05). The reductions in PAOP and systemic arterial diastolic pressure and the increase in heart rate were directly dose-related, but the changes in cardiac output and systemic vascular resistance were not. These results suggest that peripheral vasodilation, particularly of venous capacitance vessels, as well as positive inotropic stimulation, may play a role in the haemodynamic changes induced by intravenous amrinone in acute ischaemic left ventricular failure.     

Haemodynamic dose-response effects of intravenous nisoldipine in coronary artery disease.

The circulatory consequences of slow-calcium channel blockade with a new dihydropyridine nisoldipine were evaluated at rest and during exercise-induced angina in 16 patients with angiographically proven coronary artery disease. In 10 patients resting cardiac stroke output (thermodilution) and pulmonary artery occluded pressure were determined following four intravenous nisoldipine injections (cumulative dosage of 1, 2, 4 and 8 micrograms kg-1). The exercise effects of nisoldipine were evaluated by comparing the effects of the 8 micrograms kg-1 cumulative dosage with a control exercise period at the same workload. At rest nisoldipine reduced systemic vascular resistance and mean arterial pressure, and increased heart rate, cardiac and stroke volume indices. During 4 min supine-bicycle exercise nisoldipine reduced systemic mean arterial pressure and vascular resistance; this resulted in augmented cardiac and stroke volume indices at an unchanged pulmonary artery occluded pressure. In six additional patients rest and exercise ejection fractions were measured using a nonimaging nuclear probe. Nisoldipine (4 micrograms kg-1) resulted in a small trend to increase left ventricular rest and exercise ejection fraction. These data demonstrated improved rest and exercise cardiac performance following nisoldipine in patients with severe coronary artery disease.     

Haemodynamic dose-response effects of a transdermal nitrate delivery system in acute myocardial infarction with and without left heart failure

The haemodynamic effects of a transdermal nitroglycerin delivery system (NTG-TTS) were investigated in 67 patients with a recent myocardial infarction. The study objectives were to define the dose-response effects of NTG-TTS and to examine the influence of baseline haemodynamic status on subsequent response. Therefore, patients with normal cardiac function [pulmonary artery occluded pressure (PAOP) less than 18 mm Hg, n = 40] and those with acute heart failure (PAOP greater than 18 mm Hg, n = 27) were studied after one of three regimens (TTS-10, TTS-20, or TTS-40) with the intention of securing 10 evaluable patients in each group. In patients with acute heart failure, all three doses reduced the left ventricular filling pressure with a modest decrease in systemic arterial pressure; cardiac index and heart rate were unaltered. The systemic vascular resistance was significantly reduced from 120 min. In patients with normal left ventricular function, there were small but significant reductions in systemic arterial pressure and vascular resistance with limited increases in heart rate; the cardiac stroke work index was reduced. These results are compatible with actions of NTG-TTS mainly on capacitance vessels; PAOP fell with limited impact on systemic arterial pressure and vascular resistance index. This mode of nitrate delivery resulted in a low incidence of hypotension and side-effects; comparison with other delivery methods in myocardial infarction seems indicated.     

Haemodynamic dose-response effects of i.v. metoprolol in coronary heart disease

Summary The haemodynamic effects of intravenous metoprolol, over the dose-range 2.5–20 mg, were studied in 12 patients with coronary heart disease. The pharmacodynamic activity of the drug was confirmed by the suppression of exercise systolic pressure and tachycardia. There were statistically significant dose-response reductions in systolic and diastolic pressures, heart rate and cardiac output together with a dose-related increase in pulmonary wedge pressure. In patients with coronary heart disease intravenous metoprolol should probably not exceed the doses used in this study and should be administered with caution in patients with impairment of pumping function.     

Haemodynamic dose-response effects of i.v. nicardipine in coronary artery disease

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). 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 micrograms/l) resulted in a linear decrease in systemic blood pressure and vascular resistance with significant increase in cardiac index (maximum delta CI + 1.6 l min(-1) m(-2); P less than 0.01), stroke index (maximum delta SI + 11 ml/m2; P less than 0.01) and in pulmonary artery occluded pressure (maximum delta PAOP + 2 mm Hg; P less than 0.01). There was a significant increase in heart rate; the stroke work index was unchanged. 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 less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)     

Haemodynamic dose-response effects of intravenous oxprenolol in coronary heart disease

The haemodynamic dose-response effects of intravenous oxprenolol over the range of 2--64 mg were measured in 28 patients with coronary heart disease. At rest there were statistically significant dose-response trends, linear or quadratic, between the cumulative doses of oxprenolol and reductions in systolic pressure, heart rate, and cardiac output and increases in stroke volume and pulmonary wedge pressure. The magnitude of the changes was uninfluenced by the degree of left ventricular functional disability as judged by the level of the pulmonary wedge pressure. During dynamic exercise the haemodynamic changes induced by oxprenolol were significantly greater in patients with more marked left ventricular disability than in those less severely affected. These observations define the immediate effects of intravenous oxprenolol over a relatively wide dose range and confirm its relative haemodynamic safety in patients with stable coronary heart disease.     

The effects and dose-response relationship of xamoterol in patients with ischaemic heart disease.

1. In a double-blind placebo controlled four-way crossover study the effects and dose response relationships of xamoterol were studied in nine patients with angina and dyspnoea secondary to chronic left ventricular dysfunction. The duration of exercise on a treadmill and heart rate were measured at the end of each phase of the study at 2 h and 24 h after dosing. 2. Xamoterol at 200 mg and 400 mg orally once daily had no effect on the mean resting heart rate but there was a small (5.7 beats min-1) but significant reduction in resting heart rate on 600 mg at 2-2.5 h after dosing. All three doses of xamoterol significantly reduced the maximum exercise heart rate at 2-2.5 h after dosing. 3. Xamoterol at all three doses significantly increased exercise duration at 2-2.5 h after dosing but not at 24 h. 4. Mean plasma xamoterol concentration at both 2-2.5 h and 24 h after dosing were dose related. The EC50 for xamoterol is 33.5 ng ml-1, where EC50 is the effective plasma concentration required to produce 50% of the maximum effect on exercise heart rate.     

Effect of UK-52,046, an alpha 1-adrenoceptor antagonist, on baroreflex function in man.

1. In a placebo controlled study (six healthy male subjects), the effects of UK-52,046 (0.4 microgram kg-1 i.v.) and prazosin (0.25 mg i.v.) on baroreflex function were compared, at doses which produced antagonism to phenylephrine, but which had no effect on supine blood pressure. 2. Baroreflex function [delta R-R interval ms mm Hg-1 change in SBP] was assessed following increases in systolic blood pressure (SBP) with phenylephrine and during the Valsalva manoeuvre. 3. At these doses neither UK-52,046 nor prazosin had an effect on supine SBP or heart rate; however following prazosin, standing SBPs at 5 s (69.7 +/- 7.6 mm Hg) and at 3 min (65.5 +/- 11.7 mm Hg) were less than the respective pre-treatment (P less than 0.05) values (96.0 +/- 2.9, 110.3 +/- 6.2 mm Hg) and placebo (82.7 +/- 5.6, 98.7 +/- 11.1 mm Hg). UK-52,046 had no significant effects on standing SBP at 5 s or 3 min. At 5 s, pre- and post-treatment R-R intervals (584 +/- 26, 541 +/- 27 ms respectively) were not significantly different with prazosin, but at 3 min the post-treatment R-R interval following prazosin (519 +/- 17 ms) was less (P less than 0.05) than the pre-treatment value (658 +/- 36 ms). 4. UK-52,046 had no effect on baroreflex sensitivity (12.7 +/- 1.3 ms mm Hg-1) compared with placebo (17.9 +/- 2.7 ms mm Hg-1).(ABSTRACT TRUNCATED AT 250 WORDS)     

Duration of action and effect on baroreflex function of the anti-arrhythmic alpha 1 antagonist UK-52,046.

The effects of acute and chronic oral administration of UK-52,046 (25 micrograms kg-1) on baroreflex function and its duration of action, were studied in conscious dogs. It was found that UK-52,046 had no effect on blood pressure and heart rate following acute and chronic administration. UK-52,046 shifted the phenylephrine dose response curve to the right, and the PE50 (measure of alpha 1-adrenoceptor antagonism) was increased (P less than 0.05) compared to placebo on day 1 (2, 4, 8 and 24 h) and day 8 (2, 4, 8 and 12 h). The antagonism was increased (P less than 0.05) on day 8 (0, 8 and 12 h) compared with day 1. Evaluation of the effects of UK-52,046 on baroreflex function using phenylephrine to increase blood pressure indicated no significant difference from placebo. It was concluded that at an antiarrhythmic dose, UK-52,046 has no effect on blood pressure, heart rate or baroreflex function. The pressor response curve was shifted to the right indicating a duration of action of at least 12 h on chronic oral administration.     

Beneficial effects of L-carnitine in dialysis patients with impaired left ventricular function: an observational study

BACKGROUND: Recent studies have shown that L-carnitine may improve clinical status and reduce the need for erythropoietin in dialysis patients with cardiovascular diseases. In this observational study, we investigated whether the addition of L-carnitine to conventional therapy might improve cardiac function (as assessed by M-mode and two-dimensional echocardiography) and clinical status in dialysis patients with left ventricular dysfunction. METHODS: Eleven dialysis patients with reduced left ventricular function (EF < 45%) were treated with L-carnitine for 8 months. Two-dimensional (2-D) echocardiography was performed at baseline and every 2 months up to the end of the treatment period. The dosage of erythropoietin was also monitored during the study and the patients' clinical status was assessed by a questionnaire. RESULTS: Carnitine increased mean LV ejection fraction from 32.0% to 41.8% (p < 0.05 vs baseline). There was also a slight reduction of erythropoietin dosage and an improvement of clinical status. CONCLUSIONS: Eight months' therapy with carnitine appears to improve LV function and clinical status in dialysis patients with impaired LVF.     

Haemodynamic dose-response effects of i.v. penbutolol in angina pectoris.

The haemodynamic dose-response effects of intravenous penbutolol, a newer beta-adrenoceptor antagonist with intrinsic sympathomimetic activity but without cardioselectivity, were evaluated in 10 patients with angiographically documented coronary artery disease. Following four logarithmetically cumulative i.v. boluses (0.5-4 mg dosage range) there was a log linear increase in plasma penbutolol concentration; the levels achieved (51 +/- 8 to 219 +/- 19 ng/ml) were in the therapeutic range (12 to 250 ng/ml). Penbutolol resulted in a linear decrease in heart rate (maximum delta HR - 4 beats/min; P less than 0.01); there was a small increase in pulmonary artery occluded pressure which reached its maximum at the lower doses (maximum delta PAOP + 1 mm Hg; P less than 0.01). The resting cardiac output, blood pressure and calculated systemic vascular resistance were unchanged. During 4 min steady-state supine bicycle exercise there was attenuation of exercise cardiac output (delta C.I. - 0.6 1 min-1 m-2; P less than 0.01) and systolic pressor response (delta SBP - 13 mm Hg; P less than 0.01) compared with control observations without change in other measured or derived variables. The haemodynamic profile of penbutolol compared favourably with other beta-adrenoceptor antagonists previously evaluated under similar conditions in patients with ischaemic heart disease. Over the i.v. dose-range evaluated penbutolol attenuated exercise-induced angina with a relatively modest depression of cardiac performance; the small change induced in resting haemodynamic variables may, in part, have been contributed to by the intrinsic sympathomimetic activity of penbutolol.     

Haemodynamic effects of salbutamol in patients with acute myocardial infarction and severe left ventricular dysfunction

The haemodynamic effects of salbutamol infusions at rates of 10,20, and 40 micrograms/min were measured in 11 patients with acute myocardial infarction complicated by left ventricular failure. Four patients also had cardiogenic shock. Consistent increases were observed in cardiac outputs at all doses (up to 56% at 40 micrograms/min), while the mean systemic arterial pressure fell slightly (average 5 mm Hg), implying a reduction in peripheral vascular resistance. Changes in right atrial pressure and indirect left atrial pressure (measured as pulmonary artery end-diastolic pressure) were small and not significant. Analysis of data from individual patients showed that the greatest increment in cardiac output was reached at 10 micrograms/min in two cases, 20 microgram/min in three, and 40 micrograms/min in the remaining six. Heart rate at these doses increased by an average of only 10 beats/min. Salbutamol failed to reduce left ventricular filling pressure and cannot be recommended for the treatment of pulmonary oedema in acute myocardial infarction. The increase in cardiac output, however, was considerable, so that the drug may be important in the management of low-output states. This action is probably a result of peripheral arteriolar dilatation (itself a result of beta 2-adrenoreceptor stimulation) and is achieved with little alteration in the principal determinants of myocardial oxygen requirement.     

Haemodynamic effects and kinetics of concomitant intravenous disopyramide and atenolol in patients with ischaemic heart disease

Summary The haemodynamic effects of concomitant intravenous administration of disopyramide (Norpace) and atenolol (Tenormin) were studied in a cross-over trial in 7 patients with ischaemic heart disease. Following 150 mg disopyramide i.v. the cardiac index (CI) and stroke volume index (SVI) decreased by 14% and 26%, respectively and the heart rate (HR) and preejection period index (PEPI) increased by 13% and 19%, respectively. A decrease in CI of 14% and HR of 21%, respectively were noted after intravenous administration of 7.5 mg atenolol; PEPI increased by 10% whereas SVI remained unchanged. The cardiac Index (CI) fell by 33% following the administration of both drugs. The effect on CI of the two drugs was additive. The effect of disopyramide and atenolol on HR, SVI and PEPI was not significantly modified by coadministration of the other drug. No change in blood pressure was observed after disopyramide or atenolol. A correlation () of 0.540 and 0.387 was observed between the change in PEPI and the log free and total serum concentrations of disopyramide, respectively. Combined intravenous use of the two drugs in patients with incipient or overt heart failure is not recommended, unless it is due to the arrhythmia to be treated.     

An acute study of the electrophysiological and haemodynamic effects of intravenous UK-52,046, a novel alpha 1-adrenoceptor antagonist.

The acute electrophysiological and haemodynamic effects of UK-52,046, a novel alpha 1-adrenoceptor antagonist (0.5 microgram kg-1) were studied in 10 patients. Resting and paced conduction intervals, refractory periods, Wenckebach cycle length and sinus node recovery time were measured and compared with baseline values. Haemodynamic measurements including cardiac output were measured before and after drug administration. Changes in QRS interval (83 to 105 ms) and QRS duration during sinus rhythm (83 to 105 ms) or during constant atrial pacing (85 to 109 ms), were not significant (P greater than 0.05). Myocardial refractoriness and sinus node recovery time were not altered by the drug. Slight increases in mean heart rate (72.5 to 78.8 beats min-1), mean right atrial pressure (4.5 to 5.5 mm Hg) and mean cardiac output (5.4 l min-1 to 5.7 l min-1), were not significant (P greater than 0.05). Systolic and diastolic arterial pressure, cardiac work indices, and vascular resistance remained unchanged. These results demonstrate the safety of this drug given intravenously in a non-ischaemic setting, and warrant its further investigation as an antiarrhythmic agent in myocardial ischaemia.     

Enhanced external counterpulsation improves endothelial function and exercise capacity in patients with ischaemic left ventricular dysfunction

Enhanced external counterpulsation (EECP) therapy decreases angina episodes and improves quality of life in patients with left ventricular (LV) dysfunction (LVD). However, studies have not elucidated the mechanisms of action and overall effects of EECP in patients with LVD. The purpose of the present study was to investigate the effects of EECP on endothelial function in peripheral conduit arteries and exercise capacity (peak Vo ₂) in patients with LVD. Patients with ischaemic LVD (ejection fraction (EF) 34.5 ± 4.2%; n = 9) and patients with symptomatic coronary artery disease (CAD) and preserved LV function (EF 53.5 ± 6.6%; n = 15) were studied before and after 35 sessions (1 h) of EECP. Brachial and femoral artery flow‐mediated dilation (bFMD and fFMD, respectively) were evaluated using high‐resolution ultrasound. Enhanced external counterpulsation elicited similar significant improvements in the following FMD parameters in the CAD and LVD groups (P ≥ 0.05 between groups for all): absolute bFMD (+53% and +70%, respectively), relative bFMD (+50% and +74%, respectively), bFMD normalized for shear rate (+70% and +61%, respectively), absolute fFMD (+33% and +21%, respectively) and relative fFMD (+32% and +17%, respectively). In addition, EECP significantly improved plasma levels of nitrate/nitrite (+55% and +28%) and prostacyclin (+50% and +70%), as well as peak Vo ₂ (+36% and +21%), similarly in both the CAD and LVD groups (P ≥ 0.05 between groups for all). Despite reduced LV function, EECP therapy significantly improves peripheral vascular function and functional capacity in CAD patients with ischaemic LVD to a similar degree to that seen in CAD patients with preserved LV function.     

Dose-dependent alpha 1-adrenoceptor antagonist activity of the anti-arrhythmic drug, abanoquil (UK-52,046), without reduction in blood pressure in man.

1. The dose-dependency of the alpha 1-adrenoceptor antagonist activity of the anti-arrhythmic abanoquil (UK-52,046) was investigated in 10 healthy male subjects who received serially increasing infusions of phenylephrine before and 2, 4, 8, 12, 24 and 48 h after single oral doses of abanoquil 0.25, 0.5 and 1 mg and placebo in a double-blind randomised manner. 2. The doses of phenylephrine required to increase systolic BP by 20 mm Hg (PS20) were calculated using a quadratic fit to the individual dose-response curves. 3. Abanoquil 0.25, 0.5 and 1 mg increased the PS20 in a dose-dependent manner with effects which were maximal at 2 to 8 h and lasted for 24 to 48 h (P less than 0.05). Maximal dose ratios were: abanoquil 0.25 mg 2.0 +/- 0.9, 0.5 mg 2.4 +/- 1.3, 1 mg 3.4 +/- 1.1. 4. No change occurred in supine BP but a small increase (P less than 0.01) occurred in supine HR 8 h post-dosing (64 +/- 9, 58 +/- 6 beats min-1 for abanoquil 1 mg and placebo respectively). 5. Therefore abanoquil 0.25, 0.5 and 1 mg showed dose-dependent alpha 1-adrenoceptor antagonist activity with no effect on supine BP.     

Hemodynamic effects of intravenously administered celiprolol in patient with coronary heart disease and depressed left ventricular function

Hemodynamic changes after intravenous application of 10 mg celiprolol-HCl (3-[3-acetyl-4-(3-tert-butylamino-2-hydroxy-propoxy)-phenyl]-1,1-diethyl urea hydrochloride. Selectol; in the following briefly called celiprolol) were investigated over an interval of 30 min in 15 patients with angiographically determined coronary heart disease and depressed left ventricular function (ejection fraction less than 60%, left ventricular end-diastolic pressure (LVEDP) greater than 12 mmHg). One patient suffered from severe left ventricular failure with lung edema and could not be evaluated. The heart rate was not influenced, the arterial pressure was significantly reduced (p less than 0.01), similarly LVEDP (p less than 0.001), and pulmonary pressure (p less than 0.01). Cardiac output and total peripheral resistance were not changed significantly. The hemodynamic working profile of celiprolol in patients with depressed left ventricular function is that of a beta 1-receptor blocker with a strong intrinsic sympathomimetic activity (ISA = Intrinsic Sympathetic Activity) and vasodilating properties--even on preload. The intravenous application of celiprolol in patients with severely depressed left ventricular function can cause pump failure.     

Improvement of bradykinin endothelium-mediated vasodilation of forearm resistance circulation by quinaprilat in patients with coronary artery disease with or without left ventricular dysfunction.

Angiotensin-converting enzyme (ACE) inhibition potentiates bradykinin and acetylcholine endothelium-mediated vasodilation. Three groups were studied. Group I (n = 10) was the reference group; group II was composed of nine patients with coronary artery disease; and group III of seven patients with coronary artery disease and left ventricular dysfunction. Forearm blood flow was measured with plethysmography. Acetylcholine and bradykinin were administered in a random order in the brachial artery at infusion rates of 40 and 80 microg/min and 10, 30, 100 pmol/min, respectively. Then quinaprilat was infused alone at the rate of 50 microg/min and then coinfused with acetylcholine and bradykinin. Five of the reference subjects were pretreated with acetylsalicylate. Acetylcholine and bradykinin increased forearm blood flow in a dose-dependent manner in the three groups. However, the vasodilator responses to both agents were significantly lower in the two groups of patients than in the reference group. Quinaprilat significantly enhanced the vasodilator response to acetylcholine only in subjects of the reference group, whereas it enhanced the vasodilator response to each dose of bradykinin, both in subjects of the reference group and in patients. Pretreatment with aspirin did not change the vasodilator responses in any group. In healthy persons, quinaprilat had no effect on its own on forearm blood flow but enhanced the response to bradykinin and even acetylcholine. In patients with coronary disease, short-term administration of quinaprilat was able to improve the impaired response to bradykinin. The response to acetylcholine, however, could not be significantly enhanced in contrast to that in healthy subjects.