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.     

Implication of the central nervous system in the systemic and regional hemodynamics of two centrally acting hypotensive drugs, flesinoxan and clonidine, in the rat.

The systemic and regional hemodynamic effects of the selective 5-HT1A receptor agonist flesinoxan (3-300 micrograms/kg, i.v., in cumulative doses) were investigated in normotensive anesthetized and pithed rats using a pulsed Doppler system and were compared to those of the alpha 2-adrenoceptor agonist clonidine. In anesthetized rats, flesinoxan and clonidine induced dose-dependent decreases in blood pressure and heart rate. Total peripheral resistance and hindquarters vascular resistance dose-dependently decreased after flesinoxan administration whereas cardiac output remained unchanged. Clonidine dose-dependently decreased cardiac output and did not change total peripheral resistance. These results indicate that the decrease in blood pressure induced by flesinoxan is due to a reduction in total peripheral and hindquarters vascular resistance. In contrast, clonidine decreased blood pressure by reducing cardiac output. In the pithed rat, the systemic and regional hemodynamic effects of flesinoxan were abolished whereas those of clonidine were reversed. These results provide evidence for the participation of the central nervous system in the systemic and regional hemodynamic effects of flesinoxan. However, direct administration into the central nervous system remains to be performed in order to strengthen this conclusion.     

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.     

Hemodynamic Responses to Indoramin at Rest and During Exercise in Congestive Heart Failure

Twenty patients with congestive heart failure underwent hemodynamic studies before and over 10 hours after the administration of 25, 50, and 75 mg of indoramin, an alpha₁-adrenergic antagonist. Hemodynamic studies were repeated during exercise after the administration of the optimal dose of indoramin. The drug reduced resting and exercise pulmonary capillary wedge pressure, right atrial pressure, systemic blood pressure and vascular resistance, and pulmonary artery pressure and vascular resistance. Resting and exercise stroke volume and cardiac output rose in response to the fall in vascular resistances. Heart rate was not altered at rest or during exercise. The first dose of the alpha₁ blocker indoramin elicits a significant reduction in ventricular preload and afterload and augmentation of ventricular performance in patients with congestive heart failure.     

Hemodynamic effects of nisoldipine in chronic congestive heart failure

The hemodynamic effects of 10 and 20 mg isobutyl methyl 1,4-dihydro-2,6-dimethyl-4-(2-nitrophenyl)-3,5-pyridinecarboxylate (nisoldipine, Bay k 5552) p.o. were studied in 15 patients with chronic congestive heart failure due to ischemic heart disease or cardiomyopathy. The dose of 10 mg elicited only a decrease of pulmonary wedge pressure during exercise, all other parameters remained unaffected. After 20 mg nisoldipine arterial blood pressure was reduced already at rest. During exercise, arterial as well as pulmonary artery and wedge pressures were significantly reduced. Heart rate remained unaffected and cardiac index increased slightly. It is concluded, that nisoldipine improves the hemodynamic situation in chronic congestive heart failure by simultaneously reducing cardiac pre- and afterload.     

Intravenous captopril in congestive heart failure

Hemodynamic and neurohumoral effects of intravenous captopril were studied in ten patients with severe chronic congestive heart failure (NYHA Functional Class III and IV). Incremental bolus doses of captopril, titrated to a maximum cumulative dose of 15 mg, were given at 10-minute intervals. Systemic arterial pressure, mean pulmonary capillary wedge pressure, systemic vascular resistance, mean pulmonary artery pressure, and heart rate decreased (P less than .05). Cardiac index and stroke volume index increased (P less than .05). Maximum hemodynamic effects occurred after cumulative doses of 7 mg and were seen within 30 minutes after initiation of therapy; responses persisted for 30-90 minutes after the last dose. Plasma renin activity increased, and plasma atrial natriuretic factor concentration decreased. No adverse effects were observed with the use of intravenous captopril. Thus, intravenous captopril produces rapid and favorable hemodynamic improvement in advanced heart failure patients.     

Cumulative hemodynamic response to short-term treatment with flosequinan (BTS 49465), a new direct-acting vasodilator drug, in severe chronic congestive heart failure

Pharmacologic tolerance develops rapidly to the hemodynamic effects of many vasodilator drugs used in the treatment of congestive heart failure. We evaluated the responses to 3 days of therapy with a new long-acting vasodilator drug, flosequinan (BTS 49465), in 16 patients with severe chronic heart failure. On each of the 3 days, flosequinan (100 or 150 mg orally) produced marked increases in cardiac index and decreases in left ventricular filling pressure, mean right atrial pressure, and systemic vascular resistance (all p less than 0.01) without significant changes in heart rate. Whereas the effects of flosequinan on right and left ventricular filling pressures on the first and third days were similar, cardiac index was higher and systemic vascular resistance was lower after the third dose than after the first dose of the drug, indicating the occurrence of a cumulative vasodilator effect on arterial resistance vessels. Since all hemodynamic changes persisted for longer than 24 h after each dose of the drug, the daily administration of flosequinan also produced a progressive improvement in the hemodynamic state recorded before each dose of the drug. These data indicate that pharmacologic tolerance does not develop to the effects of flosequinan during short-term therapy with the drug in patients with severe chronic heart failure. Instead, further hemodynamic improvement may occur because of a cumulative vasodilator effect that results from the drug's prolonged duration of action.     

The dopamine congener, ibopamine, in congestive heart failure

The hemodynamic effects of the dopamine congener, ibopamine, were investigated in nine patients with chronic congestive heart failure. A placebo-controlled design was utilized. Placebo and ibopamine in doses of 100, 200, and 300 mg were given orally as a single dose to each patient on 4 successive days. Dopamine at 1, 2, 4, and 6 micrograms/kg/min intravenously, was used as an internal standard. Ibopamine did not significantly change heart rate, systemic and pulmonary arterial pressures, pulmonary capillary wedge pressure, or mean right atrial pressure. Significant decreases of systemic arterial resistance (19%) and total pulmonary arterial resistance (21%), and significant increases of cardiac index (20%) and stroke volume index (16%) were elicited by ibopamine at doses of 200 and 300 mg. Peak effects occurred at 1 to 2 h with a duration of action of less than 4 h. The 2 changes were comparable with those obtained by dopamine 2-4 micrograms/kg/min. Except for mild changes at 30 min postdosing, the inotropic indices of the systolic time intervals were not altered significantly by ibopamine. Ibopamine elicits significant hemodynamic effects in patients with chronic congestive heart failure; in large part, these effects appear to be mediated through vasodilatory properties rather than direct positive inotropy.     

Characterization of the dose-concentration-dependent hemodynamic effects of nifedipine in heart failure

The hemodynamic effects of increasing oral doses of nifedipine (10 to 30 mg) were studied in 12 patients who had low output heart failure. With each set of hemodynamics, serum concentrations of nifedipine were measured to determine the concentration/response relationships. Eleven of twelve patients responded acutely to nifedipine, defined as a reduction in systemic vascular resistance (SVR), and an augmentation in cardiac index (CI) and stroke volume index (SVI). The differential dose effects (X +/- SD) for SVR and SVI for baseline (N = 11), 10 mg (N = 10), 20 mg (N = 3) and 30 mg (N = 4) were: 1913 +/- 486, 1102 +/- 221, 1128 +/- 166, 803 +/- 176 and 17.9 +/- 4.8, 23.8 +/- 4.5, 31 +/- 0.42, 33 +/- 3.5, respectively. All nifedipine doses reduced SVR and increased CI and SVI compared with baseline (P less than .001). The increase in CI and SVI was significantly correlated to the mg/kg dose of nifedipine (r = 0.79; P less than .001). Nifedipine administration resulted in no significant change in central venous pressure, pulmonary capillary wedge pressure, or pulmonary vascular resistance. No relationship could be demonstrated between serum concentrations of nifedipine and any hemodynamic effect. Conclusions drawn were: (1) the afterload reduction effects of nifedipine are acutely efficacious in a large portion of patients with heart failure and this activity supercedes the negative inotropic effects of the drug at doses between 10 and 30 mg; (2) the magnitude of the hemodynamic effects are dose dependent.(ABSTRACT TRUNCATED AT 250 WORDS)     

Haemodynamic evaluation of two regimens of molsidomine in patients with chronic congestive heart failure

We investigated the extent and duration of the haemodynamic effects of two regimens of molsidomine, i.e. two tablets of a standard regimen consisting of 4 mg given 6 h apart and one tablet of 16 mg in sustained-release form once daily in 13 patients with chronic congestive heart failure using a placebo-controlled, randomized, double-blind and crossover protocol over a period of 12 h. Both regimens significantly affected systolic, mean and diastolic pulmonary arterial pressure (reductions of up to 15%), right atrial pressure (reductions of up to 35%) and total pulmonary resistance (reductions of up to 18%). The lower dose achieved its maximum action after about 1 h and remained effective for 2 h, whereas the higher dose in sustained-release form showed maximal efficacy at 2 h and remained active even at 12 h. In contrast, only minor changes in arterial blood pressure, systemic vascular resistance and cardiac output were observed on both regimens, almost exclusively at 2 h. Heart rate was not affected by either of the regimens tested. Neither regimen led to any untoward adverse effects. Thus, molsidomine is a potent vasodilating agent which, apart from its effects on preload, also acts on pulmonary arterial and right atrial pressures, leaving systemic circulation largely unaffected on the regimens tested. Administered on its own, it is therefore suitable for treatment of congestive heart failure.     

Hemodynamic and neurohumoral responses to intravenous nicorandil in congestive heart failure in humans.

Nicorandil is a vasodilator drug that combines potassium channel opening properties with nitrate effects. The resulting potent and unique vasodilating properties suggest a potential therapeutic role in congestive heart failure. We therefore studied the acute hemodynamic and neurohumoral responses to nicorandil, given as single intravenous bolus doses of 158, 251, 398, or 630 micrograms/kg, to 22 patients with chronic congestive heart failure (ejection fraction less than 40%). Hemodynamic responses occurred within 5 min of dosing and terminated within 240 min. The heart rate was significantly increased only at 5 min after the 158 micrograms/kg dose, and was unchanged after all other doses. The mean arterial pressure was reduced only by the 398 and 630 micrograms/kg doses. The pulmonary capillary wedge pressure and right atrial pressure were significantly reduced by all doses within the initial 30 min; this reduction in pulmonary capillary wedge pressure was better sustained over time by the two larger doses, whereas the reduction in right atrial pressure was sustained only by the 158 micrograms/kg dose. The cardiac index was reduced by the 158 micrograms/kg dose, but increased after 251, 398, and 630 micrograms/kg of nicorandil. Plasma nicorandil concentrations were positively correlated with changes in cardiac index, systemic arterial pressure, pulmonary capillary wedge pressure, heart rate, and systemic vascular resistance. When measured 1 h after dosing, plasma immunoreactive ANF decreased, norepinephrine concentrations did not change, and plasma renin activity increased, but only at the 630 micrograms/kg dose level.(ABSTRACT TRUNCATED AT 250 WORDS)     

Bosentan improves renal regional blood flow in rats with experimental congestive heart failure

The effects of the mixed endothelin receptor antagonist bosentan on renal regional haemodynamics were investigated in rats with aorto-caval fistula, an experimental model of congestive heart failure. A matched group of normal rats served as control. Injection of bosentan (10 mg/kg i.v.) to the rats with decompensated congestive heart failure produced an increase in cortical (+20%) and medullary (+12%) blood flow, and a decrease in vascular resistance in the cortex (−30%) and medula (−23%), while reducing mean arterial pressure by approximately 10 mm Hg. In rats with compensated congestive heart failure and in normal animals, infusion of bosentan did not affect blood pressure and cortical perfusion. These findings indicate that 1) endothelin receptor blockade produces beneficial effects on renal haemodynamics in rats with experimental congestive heart failure and 2) endothelin-1 may be involved in the pathogenesis of renal hypoperfusion only in decompensated congestive heart failure.     

Invasive Pharmacodynamic Characterization of Combined Ibopamine and Calcium Blocker Therapy for Heart Failure

Study Objective . To determine the acute hemodynamic response of single-dose coadministration of ibopamine plus nifedipine or diltiazem in patients with New York Heart Association functional class (NYHA FC) II—III congestive heart failure. Design . A single-blind, placebo-controlled, two-paired, crossover study. Setting . Cardiology clinics at two large teaching hospitals. Patients . Eight patients with NYHA FC II—III congestive heart failure who met the inclusion criteria were selected randomly. Interventions . All patients underwent right heart catheterization. Day 1 consisted of concomitant calcium channel blocker plus placebo, with cardiac and peripheral hemodynamic recordings from 30 minutes–24 hours. The design was equivalent on day 2, with single-dose administration of ibopamine plus calcium channel blocker. Measurements and Main Results . Single-dose nifedipine-diltiazem augmented cardiac output and stroke volume secondary to decreasing systemic vascular resistance. The nifedipine-ibopamine and diltiazem-ibopamine subgroups demonstrated relatively equal hemodynamics, augmenting cardiac index (nifedipine 43%, p<0.05; diltiazem 40%, p<0.05 vs baseline) while decreasing systemic vascular resistance (nifedipine 41%, p<0.05; diltiazem 28%, p NS vs baseline) 30 minutes after the dose. In contrast to single-dose diltiazem, the diltiazem-ibopamine subgroup exhibited an increased left ventricular filling pressure (122%, p<0.05 vs baseline) and mean pulmonary artery pressure (43%, p<0.05 vs baseline) at 30 minutes after the dose. One patient experienced a transient episode of chest pain associated with increased heart rate and blood pressure with diltiazem-ibopamine. Conclusion . Diltiazem and ibopamine should be coadministered with caution in patients with coronary artery disease and left ventricular dysfunction.     

The acute hemodynamic, hormonal, and pharmacokinetic properties of oral spirapril in patients with moderate to severe heart failure.

The acute hemodynamic, hormonal, and pharmacokinetic responses to the oral angiotensin-converting enzyme (ACE) inhibitor spirapril were studied in 15 patients with moderate to severe congestive heart failure in a baseline controlled dose-ranging study. Doses of 0.3, 1.0, 1.5, 3.125, and 6.25 mg were investigated for 24 h in three groups of five patients each. All doses demonstrated a significant reduction in serum ACE, even after 24 h. Significant reductions in mean arterial pressure, systemic vascular resistance, and pulmonary capillary wedge pressure were observed with doses greater than 1.0 mg spirapril. Maximal significant hemodynamic effects occurred approximately 4-6 h after drug administration. The plasma concentrations of spirapril and its metabolite spiraprilate were dose-dependent. After administration of spirapril, the quick rise to the peak level of spiraprilate suggests rapid metabolism of spirapril into spiraprilate and a slow elimination of this metabolite. No severe hypotension or other serious side effects occurred in the patients studied. The results indicate that spirapril may be expected to be an effective drug in the treatment of congestive heart failure. From our findings we conclude that 1.5 mg spirapril is an optimal starting dose in patients with moderate to severe congestive heart failure.     

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.     

Beneficial effects of fenoldopam on systemic and regional hemodynamics in rabbits with congestive heart failure

Fenoldopam (SKF 82526 J) is a selective DA-1 receptor agonist and thus of a potential benefit for promoting afterload reduction, renal vasodilatation, and diuresis in congestive heart failure. To examine the acute effects of fenoldopam in heart failure, studies were performed in control rabbits (n = 6) and in rabbits with chronic congestive heart failure (CHF, n = 6) induced by adriamycin treatment. Cardiovascular variables and regional blood flows were determined before and after an infusion of fenoldopam (150 micrograms/kg total dose). Resting hemodynamics differed in CHF and control groups. In the CHF group, mean arterial pressure (MAP), cardiac output (CO), and stroke volume (SV) were reduced and right atrial pressure (RAP), left ventricular end-diastolic pressure (LVEDP), and total peripheral resistance (TPR) were increased. Renal blood flow was much reduced in the CHF as compared with the control group (5.1 +/- 0.8 vs. 9.1 +/- 0.6 ml/min.g, p less than 0.05). Similar falls in MAP were noted after fenoldopam in CHF (-13 +/- 2%) and control rabbits (-12 +/- 3%) due to falls in TPR. An increase in CO was observed in both groups, the rise being more pronounced in the CHF group (22 vs. 12%). Heart rate was unchanged by fenoldopam in CHF rabbits but increased in controls. After fenoldopam, CHF rabbits exhibited significantly greater increases in blood flow to each of the three vascular beds studied: renal (113 +/- 27% vs. 7 +/- 13%), mesenteric (249 +/- 60% vs. 15 +/- 19%) and cerebral (145 +/- 13% vs. 12 +/- 12%). Plasma renin and norepinephrine (NE) levels increased after fenoldopam in both control and CHF rabbits. These results show that acute administration of fenoldopam produces favourable systemic and regional hemodynamic responses in rabbits with low output heart failure. However, long-term benefit remains to be demonstrated, particularly considering the hormonal responses.     

Systemic and regional hemodynamic effects of the putative 5-HT1A receptor agonist flesinoxan in the cat

The systemic and regional hemodynamic effects of the centrally acting putative 5-HT1A receptor agonist flesinoxan (3, 10, 30, and 100 micrograms/kg) were investigated in the anesthetized cat and compared with those of 8-hydroxy-2(di-n-prophylamino) tetralin (8-OH-DPAT 3, 10, 30, and 100 micrograms/kg) and clonidine (0.3, 1, 3, and 10 micrograms/kg). Cardiac output (CO) was measured with a precalibrated electromagnetic flow probe placed on the ascending aorta, and regional blood flows and conductances were measured with radioactive microspheres. Flesinoxan and 8-OH-DPAT caused a decrease in blood pressure (BP 44 and 37%, respectively, at 100 micrograms/kg) mainly resulting from an increased peripheral vascular conductance; in the case of 8-OH-DPAT, however, a reduction in CO (34%) also contributed. Clonidine decreased BP (12% at 10 micrograms/kg) by reducing CO (31%). All three drugs decreased heart rate (HR). Flesinoxan and 8-OH-DPAT decreased tissue perfusion in the heart, lungs, gastrointestinal tract, eyes, and skin, but both renal and cerebral blood flows were preserved as a result of increased vascular conductances. These two drugs also redistributed intrarenal blood flow from the outer cortex toward the inner cortex and medulla. Low doses of clonidine tended to increase but higher doses decreased organ blood flows, especially to the heart, lungs, liver, and eyes. Clonidine did not redistribute intrarenal blood flows. These results establish that the 5-HT1A receptor agonists flesinoxan and 8-OH-DPAT elicited a systemic and regional hemodynamic profile that differs from that of the alpha 2-adrenoceptor agonist clonidine.     

Effects of converting-enzyme inhibition on cardiorenal hemodynamics in patients with chronic congestive heart failure

The role of the renin-angiotensin system in cardiorenal function in patients with severe chronic congestive heart failure was investigated. A single oral dose of captopril in 16 patients significantly increased cardiac index and reduced arterial blood pressure and total systemic vascular resistance. These changes were significantly greater in subjects with higher baseline plasma renin activity (PRA). During 7-day captopril therapy, renal plasma flow distinctly increased in 10 patients in whom renal function was followed. The increase found in renal plasma flow was greater in subjects with higher PRA. Yet, the reduction in renal vascular resistance was much greater than that of total systemic vascular resistance, even in patients with lower PRA. Simultaneous infusion of aprotinin in eight of these subjects did not affect the captopril-induced increase in renal plasma flow, despite the suppression of plasma bradykinin levels; these responses were the same in both PRA subgroups. The results suggest that captopril reduces total systemic vascular resistance in patients with chronic congestive heart failure through inhibition of the renin-angiotensin system and that the preferential renal vasodilator effect of captopril might be the sole result of this inhibition, with the kallikrein-kinin system or kinin-mediated prostaglandins not playing a major role.     

Long-term clinical, hemodynamic, angiographic, and neurohumoral responses to vasodilation with felodipine in patients with chronic congestive heart failure.

Twenty patients on conventional therapy for severe congestive heart failure (CHF) were randomly assigned to adjunctive treatment with felodipine (n = 10) or placebo (n = 10) and followed over a 6-month period. Baseline clinical, hemodynamic, angiographic, and neurohumoral estimates of CHF were comparable in the two treatment groups. These estimates remained virtually unchanged at 6 months in patients on placebo therapy, but circulating noradrenaline levels were further augmented. In patients on felodipine therapy, substantial reductions in left ventricular end-systolic pressure, mean arterial pressure, and systemic vascular resistance were observed at 6 months. This afterload reduction led to a preferential increment in the stroke volume (36%) which increased cardiac output (30%), whereas heart rate tended to decrease. The improved hemodynamics during felodipine treatment were paralleled by marked improvements in the angiographic left ventricular ejection fraction and regional segmental wall motion score. The enhanced contractile state of the left ventricle was accompanied by significant reductions in the augmented plasma levels of catecholamines, and the patient clinical status improved. The 6-month mortality rate in the 20 patients was 40% and indicated a closer relation to baseline noradrenaline plasma levels than to hemodynamic or angiographic estimates of CHF. Despite the limited number of patients, the long-term clinical efficacy of felodipine is thus evidenced in patients with CHF and is related to sustained arteriolar dilatation and improved neurohumoral profile by this vasoselective calcium antagonist.     

Cardiovascular profile of UDCG 115 BS-pimobendane and reversibility of catecholamine subsensitivity in severe congestive heart failure secondary to idiopathic dilated cardiomyopathy

The pyridazoline derivative UDCG 115 BS (pimobendane) is a new, noncatecholamine, nonglycoside inotropic compound with potent vasodilative properties which exerts its stimulatory myocardial effect by increasing the Ca2+ affinity of cardiac contractile proteins and thus improving Ca2+ utilization. The aim of this study was to characterize and quantify the hemodynamic profile of oral UDCG 115 BS in 25 patients suffering from idiopathic congestive cardiomyopathy (NYHA III) and compare these effects with the action of the beta 1-receptor agonist dobutamine. UDCG 115 BS 5 mg p.o. increased cardiac output, cardiac index, and stroke volume index by approximately 60%. With only minor changes in heart rate, ventricular filling pressures decreased by 40%. A decline in pulmonary and systemic vascular resistance (-50%), as well as in systolic, diastolic, and mean pulmonary artery pressures (-35%) were also observed. The effects of 5 mg UDCG 115 BS were comparable to those that occurred with the optimal dose of dobutamine, whereas 10 mg UDCG 115 BS induced significantly more pronounced hemodynamic changes. The effects of UDCG lasted for at least 12 h. No major side effects were observed. Continuous treatment with 10 mg UDCG 115 BS/day for greater than 5 days resulted in a significantly improved response in beta-adrenoceptor stimulation as well as a drop in endogenous plasma catecholamines to nearly normal values. We therefore conclude that UDCG 115 BS, with its unique receptor-independent mechanism of action, may represent a new therapeutic approach in the management of patients with congestive heart failure (CHF).