Short-term hemodynamic effects of intravenous methyldopa in patients with congestive heart failure

The acute hemodynamic effects of intravenous methyldopa were studied in six patients with chronic congestive heart failure (New York Heart Association class IV) at 4-6 hours after a 750-mg bolus (period A) and 6-12 hours after a maintenance infusion of 1-2 mg/minute (period B). For period A, the most consistent and striking finding was a significant (48%) fall in pulmonary wedge pressure (33 +/- 6 to 17 +/- 2 mm Hg; p less than 0.05). Stroke volume increased 39% (23 +/- 3 to 32 +/- 4 ml/m2; p less than 0.05), while peripheral vascular resistance decreased 15% (3331 +/- 363 to 2841 +/- 241 dynes.s.cm-5; p less than 0.05). Heart rate fell from 97 +/- 7 to 76 +/- 3 beats/minute (p less than 0.05) with a nonsignificant decline in mean right atrial pressure (18 +/- 4 to 9 +/- 1 mm Hg). These hemodynamic changes were either sustained or enhanced during period B. Concomitant clinical improvement was also noted. As an agent with potent vasodilatory and antiadrenergic properties, methyldopa permitted a rise in stroke volume by virtue of unloading and possible inhibition of sympathetic activity that led to increased density of beta-adrenergic receptors of the heart (up-regulation). Significant reduction of ventricular filling pressure was attributed to venodilation and probable improved diastolic function. In selected patients with severe congestive heart failure, particularly underscored by excessive sympathetic tone, methyldopa may be considered as an alternative agent to improve cardiac performance and clinical symptomatology.     

Acute hemodynamic effects of nilvadipine, a new calcium channel blocker, in patients with congestive heart failure.

The acute hemodynamic effects of nilvadipine, a newly synthesized calcium channel blocker, were studied in 12 patients with congestive heart failure. Hemodynamic measurements were made before and 15, 30, and 60 min after oral administration of 6 mg nilvadipine. Substantial reductions in systemic vascular resistance (-28.8 +/- 6.3%, p less than 0.01) and forearm vascular resistance (-52.0 +/- 6.2%, p less than 0.01) after nilvadipine administration were associated with increases in cardiac index (31.1 +/- 8.3%, p less than 0.01) and forearm blood flow (105.2 +/- 27.4%, p less than 0.01). Mean arterial and pulmonary arterial pressures were decreased by 12.2 +/- 3.0% (p less than 0.01) and 14.7 +/- 5.0% (p less than 0.05), respectively, after nilvadipine administration; however, heart rate remained unchanged. Decreases in mean arterial pressure correlated with the baseline arterial pressure (y = 0.58x - 41.6, r = 0.75, p less than 0.01). Pulmonary capillary wedge pressure decreased by 33.1 +/- 9.1% (p less than 0.01) after nilvadipine administration. However, right atrial pressure and the venous stiffness constant remained unchanged, and the venous pressure-volume curve was not shifted significantly. Therefore, the decrease in pulmonary capillary wedge pressure was attributed primarily to afterload reduction. Nilvadipine holds promise as a vasodilator for the therapy of congestive heart failure.     

Regional hemodynamic effects of clonidine in congestive heart failure

Regional and central hemodynamic variables were ascertained in 10 patients with congestive heart failure before and after the oral administration of clonidine. Following the 0.2 mg dose, renal, hepatic, and limb blood flow remained unaltered, whereas a reduction was noted in heart rate (10%), mean systemic (14%), and pulmonary capillary wedge pressures (27%). Cardiac index and systemic vascular resistance fell slightly, however the changes were not statistically significant. Higher dose clonidine (0.4 mg) elicited similar regional hemodynamic effects whereas systemic vascular resistance significantly diminished (21%) and cardiac index remained unchanged. In congestive heart failure, the central antihypertensive agent, clonidine, effects a significant reduction in preload (left ventricular filling pressure) and afterload (systemic blood pressure) without markedly altering other central and regional hemodynamic variables.     

Systemic and regional hemodynamic effects of perindopril in congestive heart failure.

The acute systemic and regional hemodynamic responses to a single oral dose (4 mg) of the angiotensin converting enzyme inhibitor perindopril were investigated in 10 patients with severe congestive heart failure. Perindopril produced significant and long-lasting decreases in systemic vascular resistance (-18%), right atrial pressure (-60%), and mean pulmonary capillary wedge pressure (-28%), whereas it significantly increased cardiac index (+ 12%). Brachial (+ 130%, pulsed Doppler technique) and renal (+ 34%) blood flows were also significantly increased whereas hepatic blood flow remained unchanged. Brachial flow/cardiac output and renal flow/cardiac output ratios increased significantly from 0.8 to 1.6 and from 13.2 to 16.5, respectively. The maximal decreases in forearm and renal (but not in systemic) vascular resistances were correlated with the basal plasma norepinephrine concentrations but not plasma epinephrine concentrations or plasma renin activity. We conclude that in severe heart failure (a) perindopril considerably improves systemic hemodynamics and exerts an inhomogeneous vasodilating effect, resulting in a redistribution of flows toward the forearm and renal territories, (b) norepinephrine is a major determinant of the arteriolar tone in these two vascular beds, and (c) the pulsed Doppler is a particularly suitable method to non-invasively detect and assess hemodynamic improvements in heart failure patients.     

Global and regional hemodynamic effects of ramipril in congestive heart failure

Global and regional hemodynamic changes were assessed in 11 patients with congestive heart failure following the introduction of the novel angiotensin-converting enzyme inhibitor (ACEI), ramipril. All patients were stabilized on digitalis, furosemide, and a fixed diet, central hemodynamics and hormones having been stable over 2 control days. Ramipril resulted in significant falls in converting enzyme activity, angiotensin II, and aldosterone, with a rise in renin. Changes in regional blood flow were assessed 2 h following the first dose of ramipril at the time of maximal increase in global cardiac output (+27%, p less than 0.05), but prior to the maximal fall in systemic arterial pressure. Despite the fall in systemic arterial pressure, blood flow increases were noted in the renal (+93%, p less than 0.05), coronary (+10%), and cerebral (+5%) regions, while forearm blood flow was unchanged. Glomerular filtration rate fell (29%) and was associated with small rises of plasma creatinine and acute sodium retention. After 7 weeks of therapy we noted improvement in functional class (p less than 0.05), exercise time, and left ventricular ejection fraction. We conclude that during inhibition of angiotensin-converting enzyme activity by ramipril in patients with congestive heart failure, blood flow to the kidneys, heart, and brain is increased or preserved despite hypotension. Long-term therapy is associated with beneficial clinical effects.     

Acute hemodynamic effects of piroximone (MDL 19,205) in patients with moderate congestive heart failure: comparison with sodium nitroprusside

Piroximone (MDL 19,205), a new imidazolone derivative, was given intravenously to 14 patients with congestive heart failure (NYHA class II-III), while under constant daily doses of digitalis and diuretics. In the first 3 patients, we determined the dose safely eliciting a favorable hemodynamic response. The subsequent 11 patients received 1 mg/kg of piroximone intravenously, and the hemodynamic effects were compared with those of sodium nitroprusside (SN) at a dose-lowering mean blood pressure by 10-20 mm Hg. Piroximone increased heart rate (13.2 +/- 2.0 beats/min, mean +/- SEM) and lowered mean arterial pressure (9 +/- 2.3 mm Hg). Both agents reduced similarly wedge pressure (6.5 +/- 2.9 and 9 +/- 2.9 mm Hg, respectively, for SN and piroximone) and total peripheral resistance. Cardiac index was increased less by SN (15%) than piroximone (48%) (p less than 0.001), and stroke work index significantly enhanced only by piroximone (p less than 0.001). The changes in loading conditions induced by the two agents being similar, it is likely that piroximone not only acts by peripheral vasodilation, but also possesses positive inotropic properties. Myocardial oxygen demand, assessed indirectly by tension-time index, was not affected by piroximone. Thus, piroximone appears to combine well-balanced vasodilator and inotropic properties which make this new agent potentially very useful for the management of congestive heart failure.     

The hemodynamic effects of ibopamine, a dopamine congener, in patients with congestive heart failure

Ten patients with congestive heart failure underwent noninvasive and invasive hemodynamic testing before and sequentially after the administration of ibopamine to determine the cardiovascular effects of this oral dopamine congener. Single doses of 200, 400 and 600 mg were administered to all patients and 5 repeated doses of 200 or 400 mg were studied in 8. Hemodynamic effects occurred as early as 30 minutes and lasted up to 4 hours after dosing. In general, ibopamine elicited statistically significant dose-related increases in cardiac output and reductions in the derived resistance of the systemic and pulmonary circulations. A biphasic response in central and peripheral pressures was observed; up to 1 hour after administration, ibopamine elevated mean right and left atrial pressures and pulmonary and systemic arterial pressures with a significant reduction of these measurements beyond 1 hour. It did not alter heart rate. Repeated doses qualitatively affected hemodynamics similar to the initial dose and did not appear to be accompanied by short-term tolerance. While oral ibopamine elicits some favorable hemodynamic effects in humans with cardiac failure, the biphasic hemodynamic response is generally undesirable in the majority of these patients.     

Acute hemodynamic and hormonal effects of central versus peripheral sympathetic inhibition in patients with congestive heart failure

Indoramin, an alpha 1 antagonist, and guanabenz, an alpha 2 agonist, were given to 10 patients with severe congestive heart failure to compare the hemodynamic and hormonal effects of a reduction in sympathetic tone obtained through inhibition of postsynaptic alpha 1 receptors versus the decrease in sympathetic activity achieved by stimulating central or presynaptic peripheral alpha 2 adrenoceptors. Both drugs produced similar reduction in systemic arterial pressure. However, only indoramin significantly decreased systemic and pulmonary vascular resistances from 1529 +/- 526 to 1071 +/- 356 and from 721 +/- 422 to 412 +/- 257 dynes X s X cm-5, respectively, and increased stroke index from 26.6 +/- 9.5 to 33.3 +/- 9.5 ml/m2 (all p less than 0.01). Heart rate fell significantly only after guanabenz. Plasma norepinephrine, unchanged after indoramin, fell in each patient after guanabenz; the mean value decreased from 746 +/- 332 to 461 +/- 255 pg/ml (p less than 0.01). Plasma renin activity increased only after indoramin. The data demonstrate: (a) a decrease in sympathetic activity due to blockade of alpha 1 adrenoreceptors produces marked peripheral and pulmonary vasodilation; (b) noradrenergic transmitter release in heart failure is regulated by alpha 2 receptors; (c) an alpha 2-mediated decrease in sympathetic activity and in plasma norepinephrine has a bradycardic effect but does not produce a vasodilator effect. Although the acute hemodynamic effects of indoramin were more prominent than those of guanabenz, the more favorable neurohumoral effects of guanabenz suggest the possibility of long-term benefit in the treatment of heart failure.     

Acute hemodynamic effects of MDL 19205 in mild congestive heart failure

MDL 19205 4-ethyl-1-,3-dihydro-5-(4-pyridinylcarbonyl)-2H-imidazol-2-one, a new cardioactive agent, has been shown to increase myocardial contractile force in animals. It is effective by both oral and intravenous routes. We studied 11 patients with congestive heart failure--in 10 cases owing to coronary artery disease, and in one to cardiomyopathy. All patients had symptoms of NYHA class II or III, left ventricular ejection fractions (LVEF) less than 55%, and left ventricular end-diastolic pressures (LVEDP) greater than 15 mm Hg. Following routine coronary angiography and ventriculography, 0.5 mg/kg MDL 19205 was administered intravenously over 5 min to six patients. Thirty minutes after injection, hemodynamic measurements and ventriculography were repeated. Mean LVEF increased from 42 to 49% (p less than 0.05 for baseline vs. 30 min). In five patients ventriculography was repeated 60 min after placebo administration: LVEF decreased from 45 to 40%. LVEDP decreased from 29 +/- 8 to 16 +/- 8 mm Hg after MDL 19205 administration (p less than 0.05) and remained constant at 24 mm Hg in the placebo group. The small although nonsignificant increase of LVdP/dt after MDL 19205 administration (10 +/- 33%), together with a considerable decrease in LVEDP, was consistent with a positive inotropic effect. LVdP/dt/total pressure developed (VPM), a measure of contractility relatively independent of changes in pre- and afterload, increased from 1.0 +/- 0.3 to 1.3 +/- 0.3 s-1 (p less than 0.05). Neither parameter of contractility (LVdP/dt and VPM) changed significantly in the placebo group.(ABSTRACT TRUNCATED AT 250 WORDS)     

Acute hemodynamic effects of beta-blockers in patients with severe congestive heart failure: comparison of celiprolol and esmolol

The present study was designed to investigate, in patients with severe heart failure, the dose-dependent acute hemodynamic effects of celiprolol versus those of esmolol. Celiprolol is a beta 1 -receptor blocker with vasodilating properties, whereas esmolol is an ultra-short-acting beta 1 -blocker. Included were 14 patients with decompensated chronic heart failure (NYHA class IV) due to coronary heart disease (n = 8) or to dilated cardiomyopathy (n = 6). Each patient received both celiprolol and esmolol in random fashion. The beta-blockers were administered in four dose tiers, with an increase in dosage every 15 min. Hemodynamic measurements were obtained with a Swan-Ganz thermodilution catheter. Administration of celiprolol (5, 10, 20, and 50 microg/kg) took place intravenously. After intravenous administration of a loading dose of 500 microg/kg, we continuously infused esmolol at increasing doses, which were individually titrated for each patient. Mean infusion rates of esmolol were as follows: 40, 75, 140, and 230 micromol/kg per minute. Celiprolol and esmolol induced a comparable dose-dependent decrease in heart rate to a minimum of -10% below baseline. Esmolol caused a significant dose-dependent decrease (-25% below baseline at the highest dose level) in cardiac index (CI). After administration of celiprolol, CI decreased only transiently (-10% below baseline at the second and third dose level) and did not differ from the baseline at the highest dose level. For treatment of severe heart failure, initiation of intravenous beta-blocker therapy with low doses of a beta 1 -blocker with vasodilating effects may have hemodynamic advantages over conventional beta-blockade.     

Beneficial effects of the calcium antagonist PN 200-110 in patients with congestive heart failure

We studied the acute hemodynamic effects of PN 200-110, a newly available calcium antagonist, in 12 patients with severe congestive heart failure. Measurements of cardiac performance were obtained by a right heart catheter before and after administration of 5 and 15 mg of PN. Peak drug effects occurred 1-2 h following the administration of PN 200-110 and were dose related. The 15-mg dose reduced mean arterial pressure (MAP) from 90 +/- 11 to 75 +/- 6 mm Hg (mean +/- SD) (p less than 0.001) and decreased systemic vascular resistance (SVR) from 1,740 +/- 500 to 995 +/- 300 dynes X s X cm-5 (p less than 0.01). Stroke volume index (SVI) increased from 26 +/- 7 to 36 +/- 10 ml/m2 (p less than 0.001), and cardiac index (CI) rose from 2.1 +/- .3 to 2.8 +/- .6 L/m2 (p less than 0.01). Pulmonary arterial wedge pressure (PAW) changed insignificantly. Seven patients performed graded supine exercise at identical workloads before and after treatment. When peak exercise values were compared, the addition of PN 200-110 further reduced SVR from 1,282 +/- 461 to 936 +/- 356 dynes X s X cm-5 (p less than 0.01) and increased CI from 3.3 +/- 1.1 to 4.3 +/- 1.3 L/m2 (p less than 0.01). Only minor, self-limiting side effects were noticed during acute administration. Of the seven patients discharged on PN 200-110 and followed for at least 6 months, six reported substantial relief of symptoms.(ABSTRACT TRUNCATED AT 250 WORDS)     

Acute haemodynamic effects of ibopamine in patients with severe congestive heart failure.

Ten patients with congestive heart failure (CHF), in III and IV NYHA Class, were treated orally with a single dose of ibopamine ranging from 1.2-3.3 mg/kg, and were studied using the Swan-Ganz catheter and thermodilution technique. Cardiac index (CI) and stroke volume index (SVI) were increased, and mean pulmonary pressure (PAP), systemic vascular resistances (SVR) were lowered. Ibopamine increased CI (+33%) and SVI (+26%), and decreased PAP (-17%) and SVR (-24%). All changes were statistically significant. The maximum haemodynamic effect occurred 180 min after ibopamine administration. Blood pressure and heart rate were unaffected. Tolerability was good. This study shows that ibopamine when orally administered to human subjects improves cardiac performance and further investigations on its use as a therapeutic agent in the long term treatment of CHF are recommended.     

Pharmacokinetics of felodipine after intravenous and chronic oral administration in patients with congestive heart failure.

1. In a randomized, parallel, double-blind study felodipine was administered to 11 and placebo to 12 patients with congestive heart failure. The kinetics of felodipine were studied after acute intravenous administration and after chronic oral treatment for 8 weeks. The relationship between cardiac output and pharmacokinetics was analyzed. The pharmacokinetic data were compared with data from young healthy individuals and hypertensive patients. 2. After oral therapy, significant correlations were found between cardiac output and AUC and systemic bioavailability (F). Furthermore, cardiac output before therapy was also significantly correlated with absorption characteristics. No relationship could be demonstrated between cardiac output and i.v. pharmacokinetics. A comparison of patients with heart failure and young healthy individuals revealed that the AUC was three times higher in heart failure patient, while Vss and the ratio of the AUC of the pyridine metabolite to that of felodipine were similar. Oral clearance was reduced by 50% and the terminal half-life was concomitantly increased. Pharmacokinetic data for felodipine are similar in patients with heart failure to published data from elderly hypertensive patients. 3. An increase in liver blood flow during chronic oral therapy, induced by felodipine itself, appears to explain an increase in bioavailability and thus to higher plasma drug concentrations. Thus, it is advisable to start felodipine treatment at a low dosage in patients with congestive heart failure.     

Pharmacokinetic-pharmacodynamic interrelationships of intravenous and oral levosimendan in patients with severe congestive heart failure

OBJECTIVE: To assess the pharmacokinetic-pharmacodynamic (PK-PD) interrelations after a 6-hour continuous infusion and a 2 mg single oral dose of levosimendan in patients with congestive heart failure (CHF). METHODS: This was an open-label, non-randomized Phase II trial in 29 patients with New York Heart Association (NYHA) class III-IV CHF, comprising 2 study days. On the first day, patients were given 6-hour levosimendan infusion with the dose 0.2 microg/kg/min. After a 1-week washout, the patients received a 2 mg single oral dose of levosimendan. Heart rate-corrected electromechanical systole QS2i was the primary variable. Secondary variables were heart rate (HR), systolic (sBP) and diastolic blood pressure (dBP) and 24-hour ambulatory ECG (Holter). RESULTS: QS2i shortened from 515 ms at baseline to 506 ms at the end of 6-hour infusion (p = 0.007). After 2 mg single dose, QS2i shortened at 2 h after drug intake from 532 ms at baseline to 525 ms (p = 0.006). The effect was similar also at 8 h (532 ms vs 526 ms, p = 0.017). Mean of maximum shortening of QS2i observed during the infusion was 22 ms (p < 0.0001) and 17 ms after 2 mg single oral dose (p < 0.0001). The concentration-effect loops for QS2i showed a clear counter-clockwise hysteresis with both modes of administration. sBP and dBP decreased both during infusion and after 2 mg oral dose. HR remained unchanged during both modes of administration. CONCLUSIONS: Both 6-hour infusion and 2 mg single dose of levosimendan showed that levosimendan possesses moderate inotropic and vasodilatory effects in patients with severe congestive heart failure, which could be described as counter-clockwise hysteresis. It seemed that the vasodilatory effect appeared earlier than the inotropic effect.     

Pharmacokinetics of hydrochlorothiazide in patients with congestive heart failure.

1. Hydrochlorothiazide (HCT, 50-75 mg) was administered orally to seven patients with cardiac failure. 2. Plasma levels and urinary concentration of HCT were determined by GLC. 3. The gastrointestinal uptake of the diuretic in three patients was reduced to approximately half that seen in healthy controls. 4. Plasma halflife of HCT was correlated with endogenous creatinine clearance. 5. Pharmacokinetics of HCT are considerably changed in cardiac failure.     

Comparison of hemodynamic effects induced by pentaformilgitoxin and deslanoside in patients with heart failure.

The effect of pentaformilgitoxin and deslanoside on heart rate, blood pressure and cardiac output was compared in six patients with heart failure. Pentaformilgitoxin caused an increase of cardiac output from 3361 ml/min to 4183 ml/min (p less than 0.01). Deslanoside induced a non significant increase of cardiac output from 3617 to 3848 ml/min. Heart rate decreased significantly by both drugs: the reduction was greater after deslanoside (from 93.7 to 77.5 beats/min) than after pentaformilgitoxin (from 92 to 85 beats/min). Both drugs caused a comparable increase in stroke volume.     

川芎嗪对充血性心力衰竭病人的急性血液动力学效应

观察川芎嗪对充血性心力衰竭病人的急性血液动力学效应。于给药 0 ,0 .5 ,1 ,1 .5 ,2 ,3,4 ,5 ,6h经7FSan- Ganz导管 (从右股静脉插至右肺动脉 )测肺毛细血管楔嵌压 ( Pcwp) ,平均肺动脉压 ( m PAP) ,平均右心房压 ( m RAP)、心排血指数 ( CI)及血压 ( BP)。结果表明川芎嗪可降低 m PAP,Pcwp,提高 CI,对 BP,m RAP无显著影响     

Cardiovascular effects of imipramine and bupropion in depressed patients with congestive heart failure

There has been a long-standing concern over the cardiovascular effects of tricyclic antidepressants, particularly in patients with preexisiting cardiac disease. Recent studies have demonstrated that imipramine causes no deleterious effect on ejection fraction as determined by radionuclide angiography in patients with impaired left ventricular function (LVF). However, the high rate of severe orthostatic hypotension induced by imipramine makes use of the drug problematic in these patients. Bupropion is a new antidepressant of the aminoketone class which is structurally unrelated to the tricyclics and which is relatively free of cardiac side effects in healthy depressed patients. We compared imipramine and bupropion in 10 depressed patients with impaired LVF in a random, double-blind crossover study. Neither imipramine nor bupropion adversely affected ejection fraction or other indices of LVF. However, as previously reported, severe orthostatic hypotension requiring discontinuation of drug developed in 50% of patients on imipramine. This difficulty did not occur with bupropion. From a cardiac perspective, bupropion may offer a safe alternative to imipramine in depressed patients with congestive heart failure.     

Cardiorenal effects of an orally active dopamine prodrug (TA-870) in patients with congestive heart failure

The effects of TA-870, a newly synthesized orally active dopamine prodrug, on the cardiorenal functions were investigated in 12 patients with severe chronic congestive heart failure. A single oral dose of TA-870 (1,200 mg) improved left ventricular fractional shortening and mean circumferential velocity on M-mode echocardiography (p less than 0.01 for both). Renal plasma flow and glomerular filtration rate improved with TA-870 (p less than 0.01 and p less than 0.05, respectively); urine volume and sodium excretion increased (p less than 0.01 for both). Blood pressure and heart rate did not change during the 4-h experimental period. Mean plasma free dopamine levels peaked 1 h after dosing. These data suggest that the cardiorenal effects of oral TA-870 are comparable with those of continuous intravenous injections of dopamine. Thus, TA-870 appears to be a useful alternative drug to intravenous dopamine.     

Single-dose effects of ibopamine hydrochloride on renal function in patients with congestive heart failure.

To examine the renal effects of ibopamine HCl we evaluated 15 patients with New York Heart Association Class II-III congestive heart failure and mild renal insufficiency (creatinine clearance [CLcr] = 45-85 ml min-1). Diuretics and vasodilators were withheld and a sodium (Na+)-restricted diet was initiated. All patients exhibited positive Na+ balance at the time of evaluation. Hourly urine volumes, urine chemistries, serum chemistries, PAH and inulin/iothalamate clearances were determined 2 h pre and 4 h post a single 200 mg oral dose of ibopamine. Effective renal plasma flow, creatinine clearance, filtration fraction, and the fractional excretion of sodium and potassium were not significantly altered postdose. A significant increase in urine output and decrease in urine osmolality were seen at all time points postdose. A significant reduction in serum potassium (2 and 3 h) and blood urea nitrogen (1, 3 and 4 h) concentrations occurred. Measurements of glomerular filtration rate by inulin or [125I]-iothalamate produced differing results in the patient groups studied. We conclude that a single dose of ibopamine does not produce significant improvements in renal function in patients with congestive heart failure, mild renal insufficiency and positive sodium balance.