Increase in bicycloprostaglandin E2 metabolite in congestive heart failure in response to captopril

Vasodilating prostaglandins may be increased in patients with chronic congestive heart failure (CHF) to balance out the effects of vasoconstricting forces. Significant increases in plasma levels of bicycloprostaglandin E2 metabolite (PGEm), a chemically stable degradation product of the vasodilating prostaglandin E2, were found in response to captopril (39.4 +/- 7.8 vs. 46.2 +/- 8.2 pg/ml; p less than 0.01). With chronic captopril treatment bicyclo-PGEm remained elevated for 12 h after the last dose after 1 and 2 months (75.5 +/- 5.5; p less than 0.05 and 72.1 +/- 6.3 pg/ml; p less than 0.05, respectively). Upon readministration of captopril during chronic captopril treatment the significant increase of bicyclo-PGEm in response to captopril was sustained, as were changes in plasma renin activity, angiotensin II, and blood pressure. Plasma catecholamines were unchanged with captopril or decreased slightly, vasopressin remained moderately increased throughout. Taken together, the results suggest that vasodilating prostaglandin E2 production might play a part in captopril's beneficial action in chronic congestive heart failure.     

Beneficial hemodynamic response to chronic prazosin therapy in congestive heart failure

Thirteen patients with advanced congestive heart failure (CHF) were treated with prazosin. Following the first dose, cardiac output (CO) (mean ± SD) rose from 3.2 ± 1.2 to 4.3 ± 1.1 L/min, pulmonary artery diastolic pressure (PAD) decreased from 23 ± 12 to 18 ± 11 mm Hg, mean arterial pressure (MAP) decreased from 85 ± 10 to 76 ± 10 mm Hg, and heart rate did not change (92 ± 15 vs 92 ± 14 bpm). At the end of a 48 to 72 hour titration to an optimal regimen, significant effects on CO (3.2 ± 1.1 vs 4.5 ± 1.3 L/min), PAD (24 ± 12 vs 18 ± 8 mm Hg), and MAP (84 ± 10 vs 76 ± 10 mm Hg) were still seen. The patients were restudied after 3 months of treatment. In contrast to reports of rapid development of tolerance to prazosin, we found continued beneficial effects on CO (3.0 ± 1.3 vs 3.8 ± 1.0 L/min) and PAD (23 ± 12 vs 18 ± 10 mm Hg), without significant change in MAP (81 ± 11 vs 78 ± 8 mm Hg). We found wide variability in the CO rise in response to prazosin, which was not accounted for by differences in plasma prazosin concentration. Systemic vascular resistance in the untreated state did correlate with the percentage change in CO. In addition, excessive lowering of the PAD appeared to blunt the CO response in some cases.     

Enalapril in congestive heart failure: acute and chronic invasive hemodynamic evaluation

Following hemodynamic evaluation using invasive and noninvasive methods, 73 patients were treated in an open, uncontrolled, multicenter study with single oral doses of enalapril maleate 1.25 to 40 mg until the optimal dose for each patient (based upon hemodynamic response) was achieved. Diuretics were withheld and reinstituted only if necessary. Hemodynamic measurements were made at 0 (predrug), 1, 2, 3, 4, 6, 8, 10, 12 and 24 hours postdrug. Patients were discharged on their optimal dose, treated 1 to 4 months and then rehospitalized for repeat hemodynamic measurements. The optimal enalapril single dose was associated with the following mean peak responses: increased cardiac index 42% (SE = 6) and decreased pulmonary capillary wedge pressure 40% (SE = 3), systemic vascular resistance 39% (SE = 2), and mean arterial pressure 23% (SE = 1.5). These changes persisted during chronic therapy. Chronic treatment with enalapril also improved exercise capacity 40% (P less than 0.01), ejection fraction 18% (P less than 0.05) and clinical status (N.Y.H.A. functional class, P less than 0.01). Ten and 20 mg/day, taken as once- or twice-daily regimens, were the most commonly effective doses.     

Peripheral hemodynamic effects of captopril in patients with congestive heart failure

In 14 patients with severe congestive heart failure, the effects of captopril on the forearm circulation were evaluated with strain gauge plethysmography. Changes in plasma renin activity, angiotensin II, norepinephrine, epinephrine, bradykinin, prostaglandin E2, and 6-keto-prostaglandin F1 alpha concentrations were also measured. To determine whether the prostaglandins contribute to the peripheral hemodynamic response to captopril, the hemodynamic and hormonal measurements were repeated after pretreatment with indomethacin, an inhibitor of prostaglandin synthesis. Ninety minutes after administering a single dose of captopril (25 mg), mean blood pressure and venous pressure decreased (p less than 0.01 and p less than 0.05, respectively), forearm blood flow and maximum venous volume increased (p less than 0.05 for both), and forearm vascular resistance and forearm venous tone decreased (p less than 0.05 for both). Captopril also improved forearm venous distensibility (p less than 0.05). Pretreatment with oral indomethacin (50 mg) significantly blunted all of these captopril-induced hemodynamic changes. The blockage of the renin-angiotensin system by captopril was unaltered by indomethacin pretreatment. Captopril significantly increased plasma bradykinin, prostaglandin E2, and 6-keto-prostaglandin F1 alpha (p less than 0.05 for each). Indomethacin pretreatment did not affect the captopril-induced increase in bradykinin, but it did completely eliminate the increase in the prostaglandins. Plasma catecholamines did not change with captopril. These data suggest that the vasodilator prostaglandins play a significant role in captopril's peripheral vasodilative effects in congestive heart failure.     

Acute hemodynamic and hormonal effects of ramipril in chronic congestive heart failure and comparison with captopril

Acute hemodynamic and hormonal responses to ramipril in comparison with captopril were studied in 10 patients with moderate to severe congestive heart failure in an open, randomized study. Both drugs were given to 5 patients each in 2 increasing doses on 2 successive days. After 5 mg of ramipril angiotensin converting enzyme (ACE) activity was significantly decreased during 24 hours with a maximum decrease 4 hours after administration. Mean arterial blood pressure decreased from 84 +/- 5 to 62 +/- 5 mm Hg at 4 hours and 71 +/- 4 mm Hg at 12 hours, respectively, after this dose. Capillary wedge pressure decreased from 19 +/- 1 mm Hg to 13 +/- 1 mm Hg at 4 hours with a maximum increase in cardiac output from 3.8 +/- 0.3 liters/min to 4.4 +/- 0.3 liters/min at 2 hours. No significant cardiac effects were present 8 hours after administration. After 10 mg of ramipril, cardiac and hormonal effects showed a quicker onset of action and longer duration compared with the 5 mg dose. Mean arterial pressure decreased to 61 +/- 6 mm Hg. Similar effects were seen after captopril, but with a significantly shorter duration. Mean arterial pressure decreased from 82 +/- 4 mm Hg to 64 +/- 5 mm Hg after 12.5 mg and to 58 +/- 6 mm Hg after 25 mg of captopril. In patients with congestive heart failure ramipril has the hemodynamic profile of a long-acting and potent ACE inhibitor. Significant cardiac effects are present during 4 to 8 hours and ACE activity is still significantly inhibited 24 hours after a single dose of ramipril.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of captopril versus milrinone therapy in modulating the adrenergic nervous system response to exercise in congestive heart failure

The potential adverse consequences of increased adrenergic nervous system activity in patients with heart failure are now recognized. Modulation of the plasma noradrenaline response to submaximal exercise should be desirable. The long-term (9 weeks) effects of milrinone (10 mg 4 times a day) or captopril (50 mg 3 times a day) compared to placebo were evaluated in a double-blind crossover study, in 16 patients with stable, congestive heart failure receiving digoxin and furosemide. After treatment, clinical status (score range 0 to 14 points) improved significantly with both milrinone (4.4 +/- 0.5, p less than 0.01) and captopril (4.1 +/- 0.4, p less than 0.01). Plasma noradrenaline at rest was similar with both drugs and not significantly different from placebo. During submaximal exercise it increased significantly to 1,228 +/- 58 pg/ml with placebo and to 1,295 +/- 174 pg/ml with milrinone; this response was reduced significantly with captopril, to 820 +/- 100 pg/ml (p less than 0.01). Thus, long-term therapy with both captopril and milrinone improved the clinical score, but only captopril reduced the plasma noradrenaline response to submaximal exercise. These findings suggest that angiotensin-enzyme inhibition with captopril will modulate the adrenergic system response to daily activities in patients with chronic congestive heart failure and therefore could have additional salutary effects beyond vasodilatation.     

A cooperative multicenter study of captopril in congestive heart failure: hemodynamic effects and long-term response

The acute hemodynamic effects, long-term clinical efficacy, and safety of the oral angiotensin-converting enzyme inhibitor, captopril, were assessed in a multicenter cooperative study of 124 patients with heart failure resistant to digitalis and diuretics. The cardiac status of most patients was deteriorating prior to the study. Favorable acute hemodynamic effects consistently occurred with captopril. Maximal mean percentage increases in cardiac index, stroke index, and stroke work index were, respectively, 35%, 44%, and 34%. Systemic and pulmonary vascular resistances were each decreased by approximately 40%, as were the filling pressures of the right and left heart. Infusion of nitroprusside in some of the same patients to an end point of a pulmonary capillary wedge pressure of 12 to 18 mm Hg (equivalent to that after captopril) revealed no significant difference in the effect of either drug on the other hemodynamic parameters. Recatheterization after 8 weeks of captopril therapy revealed sustained hemodynamic changes. Significant and sustained improvements in clinical status were observed in most patients as measured by changes in New York Heart Association (NYHA) functional classification and exercise tolerance times. Seventy-nine percent of patients for whom there were adequate NYHA class data improved. Twenty percent remained unchanged and 1% deteriorated. Those patients who had both pretreatment and post-treatment exercise stress testing exhibited a highly significant mean increase in exercise tolerance times of 34% (317 +/- 32 seconds pretreatment to 425 +/- 34 seconds, final measurement). There was no evidence of tachyphylaxis over an 18-month period.(ABSTRACT TRUNCATED AT 250 WORDS)     

Milrinone in congestive heart failure: acute and chronic hemodynamic and clinical evaluation

Acute and chronic hemodynamic and clinical responses to milrinone, a new oral inotrope-vasodilator agent, were evaluated prospectively in 37 patients with severe congestive heart failure. The majority of patients (n = 31) had not responded to prior vasodilator therapy, with a substantial number (n = 8) requiring intravenous inotropic support at the time of initial study. All patients showed acute hemodynamic improvement with oral milrinone, and an optimal maintenance dose was chosen for each patient during dose-ranging studies (average dose 48 mg/day). Milrinone was discontinued before follow-up hemodynamic study in 12 patients (because of worsening congestive heart failure in 6 patients, sudden death in 3 patients, arrhythmia in 1 patient and refusal by 2 patients). Hemodynamic effects of milrinone both acutely and after chronic therapy (average 37 days) were compared in the remaining 25 patients. Acutely, mean cardiac index increased from 1.9 +/- 0.5 to 2.5 +/- 0.5 liters/min per m2 (p less than 0.001), and mean pulmonary capillary wedge pressure decreased from 28 +/- 9 to 18 +/- 8 mm Hg (p less than 0.001). When oral milrinone was readministered after chronic therapy, mean cardiac index increased from 1.9 +/- 0.5 to 2.5 +/- 1.7 liters/min per m2 (p less than 0.001), and pulmonary capillary wedge pressure decreased from 27 +/- 8 to 20 +/- 8 mm Hg (p less than 0.001) at 1 hour. New York Heart Association functional class improved in 18 of the 25 patients treated over a long-term period (mean 5.5 +/- 2.3 months).(ABSTRACT TRUNCATED AT 250 WORDS)     

Activity of the sympathetic nervous system and renin-angiotensin system assessed by plasma hormone levels and their relation to hemodynamic abnormalities in congestive heart failure

Resting hemodynamic measurements and plasma levels of catecholamines and renin activity were studied in 55 hospitalized treated patients with congestive heart failure in clinically stable condition. Plasma norepinephrine (mean ± standard error of the mean 594 ± 51 pg/ml, range 153 to 1,868) and plasma renin activity (mean 12.9 ± 2.4 ng/ml per hr, range 0.6 to 85.2) values were significantly (probability [p] < 0.01) higher than in normal subjects. In 26 of these patients plasma norepinephrine and plasma renin activity measured on 3 successive days including the day of hemodynamic study did not change significantly. In contrast, plasma epinephrine (mean 138 ± 26 pg ml, range 24 to 1,099) increased significantly at the time of invasive studies, probably because of stress-induced adrenal discharge. When baseline plasma norepinephrine was compared with resting hemodynamic values, significant correlations were found with right atrial pressure (correlation coefficient [r] = +0.44), pulmonary arterial pressure (r = +0.45), pulmonary capillary wedge pressure (r = +0.42), pulmonary vascular resistance (r = +0.55), pulmonary arteriolar resistance (r = +0.41), cardiac index (r = ?0.42), systemic vascular resistance (r = +0.30) and heart rate (r = +0.52). Plasma renin activity was only weakly correlated with plasma norepinephrine (r = +0.38) and did not correlate significantly with any hemodynamic measurement.It is concluded that patients with congestive heart failure can be categorized on the basis of neurohumoral activity. The statistically significant correlations between plasma norepinephrine and hemodynamic evidence of cardiac dysfunction suggest that the sympathetic response is either a marker of or a contributor to the hemodynamic derangement. Because hemodynamic abnormalities did not correlate with plasma renin activity despite a statistically significant correlation between plasma norepinephrine and plasma renin activity, it appears that the two systems are independently activated in congestive heart failure but that sympathetic stimulation may be one factor contributing to renin release. Further studies are needed to assess the usefulness of plasma hormone levels in evaluating and treating patients with congestive heart failure.     

Bicyclo-prostaglandin E2 metabolite in congestive heart failure and relation to vasoconstrictor neurohumoral principles

Vasodilator prostaglandins may play a role in maintaining circulatory homeostasis in patients with congestive heart failure (CHF). Plasma levels of bicyclo-prostaglandin E2 metabolite (PGEm), a chemically stabilized degradation product of the vasodilator prostaglandin E2, were determined in 45 patients with chronic CHF (New York Heart Association class II, III or IV). Mean circulating levels of bicyclo-PGEm were significantly elevated in patients with functional class III (72 +/- 8 pg/ml) or IV CHF (77 +/- 10 pg/ml) compared with control subjects (49 +/- 3 pg/ml) and patients with functional class II CHF (49 +/- 4 pg/ml). Bicyclo-PGEm concentrations correlated with plasma renin activity (r = 0.68, p less than 0.001) and plasma angiotensin II (r = 0.56, p less than 0.001) and plasma noradrenalin levels (r = 0.34, p less than 0.05). An inverse correlation was found between serum sodium concentrations and levels of bicyclo-PGEm (r = 0.46, p less than 0.01) as well as plasma renin activity (r = 0.66, p less than 0.001). Thus, prostaglandin E2 levels in plasma are increased in patients with severe CHF.     

Suppression of the renin-angiotensin system by intravenous digoxin in chronic congestive heart failure

Recent studies have demonstrated that therapy with digitalis preparations may be of inconsistent benefit in the treatment of chronic congestive heart failure. One explanation may be a varying effect on vasoconstrictor hormones, as digoxin has been shown to suppress plasma renin activity in normal and hypertensive persons. Therefore, the effect of short-term digoxin administration on plasma renin activity and plasma aldosterone in six patients with compensated, severe, chronic congestive heart failure was evaluated. Intravenous administration of digoxin (0.50 mg) resulted in a reduction of plasma renin activity from 4.3 ± 0.9 to 2.0 ± 0.9 ng/ml per hour and plasma aldosterone from 34 ± 16 to 14 ± 6 ng/dl (both p < 0.05). Maximal response occurred at three hours after administration, with return to baseline by seven hours. Therefore, evaluation of the role of digitalis in chronic heart failure requires consideration of its direct or indirect effect on angiotensin-mediated vasoconstriction and aldosterone-mediated sodium retention, as well as other neurohormonal mechanisms of vasoconstriction.     

Endogenous catecholamine levels in chronic heart failure. Relation to the severity of hemodynamic abnormalities

Plasma free epinephrine, norepinephrine, and dopamine concentrations were determined in 48, 63, and 45 patients, respectively, with overt congestive heart failure, and compared with those in 26 patients with stable angina but without heart failure. Systemic hemodynamic values were determined to assess the severity of heart failure. Arterial epinephrine levels were not different between patients with heart failure (73 +/- 92 pg/ml) and patients without heart failure (55 +/- 73 pg/ml). In patients with congestive heart failure, norepinephrine (665 +/- 510 pg/ml, mean +/- SD) and dopamine (407 +/- 405 pg/ml) levels were significantly higher than in patients with stable angina without heart failure (norepinephrine 184 +/- 136 pg/ml, p less than 0.001, and dopamine 197 +/- 259 pg/ml, p less than 0.02). However, in patients with congestive heart failure, the plasma norepinephrine levels did not correlate with cardiac index (r = 0.21, p = NS), pulmonary capillary wedge pressure (r = 0.11, p = NS), mean arterial pressure (r = 0.11, p = NS), or systemic vascular resistance (r = 0.18, p = NS). Similarly, there was no correlation between dopamine levels and the hemodynamic abnormalities in patients with congestive heart failure. These findings suggest that although endogenous norepinephrine and dopamine levels are frequently elevated in patients with heart failure, reflecting enhanced sympathetic activity, catecholamine levels do not reflect the severity of heart failure.     

Interrelation of electrolytes and renin-angiotensin system in congestive heart failure

Many of the electrolyte derangements seen in chronic heart failure are related to activation of the renin-angiotensin system. Activation of the system may cause the retention of both sodium and water; the former is primarily related to the release of aldosterone and the latter is related to an angiotensin-mediated increase in thirst and decrease in the excretion of free water. The interaction of these mechanisms may explain why patients with chronic heart failure have higher values for total body sodium but lower values for serum sodium concentration than hypertensive patients or normal subjects. Activation of the renin-angiotensin system may also cause potassium depletion, which is manifest clinically by a decrease in both total body potassium and serum potassium concentration. These electrolyte disturbances may play a role in the development of ventricular arrhythmias. The renin-angiotensin system may also contribute to the development of magnesium deficits. These hormone-electrolyte interactions have important implications in the treatment of patients with heart failure, especially those in whom the renin-angiotensin system is pharmacologically inhibited.     

The contributions of sympathetic tone and the renin-angiotensin system to severe chronic congestive heart failure: Response to specific inhibitors (prazosin and captopril)

The contribution of sympathetic tone and the renin-angiotensin system to the pathogenesis of chronic heart failure was evaluated. In 20 paired studies of the same 10 patients, the baseline hemodynamic and humoral correlates of congestive heart failure, and the response to alpha adrenergic blockade (prazosin) and angiotensin converting enzyme inhibition (captopril) were assessed. Despite the extent of failure, baseline plasma renin activity ranged from normal to very high. In contrast, baseline plasma catecholamlne levels were always elevated. Baseline plasma norepinephrine reflected the severity of heart failure, correlating inversely with baseline cardiac index before administration of both drugs. Comparable improvement in left ventricular function was noted after acute therapy. Baseline renin and norepinephrine did not predict the response to prazosin, but baseline renin did predict the response to captopril: pulmonary wedge pressure (r = ?0.776, p < 0.01), stroke index (r = 0.752, p < 0.02), systemic vascular resistance (r = ?0.673, p < 0.05).In summary, elevated levels of plasma norepinephrine were inversely correlated with baseline cardiac function, but norepinephrine levels did not change despite improved hemodynamics with specific prazosin therapy. The renin-angiotensin system exhibited a wide spectrum of activity and hemodynamic improvement with captopril was related to this activity. Absence of a correlation between plasma norepinephrine and plasma renin activity suggested that their contributions to vasoconstriction were not interdependent. Increased sympathetic tone was consistent in severe heart failure, whereas renin-angiotensin activity differed widely. The response to captopril can be used to identify a subset of patients with severe heart failure and adverse angiotensin-mediated vasoconstriction.     

Role of the renin-angiotensin system in the systemic vasoconstriction of chronic congestive heart failure

In 15 patients with severe chronic left ventricular failure, plasma renin activity (PRA) ranged widely, from 0.2--39 ng/ml/hr. The level of PRA was unrelated to cardiac output (CO) or pulmonary artery wedge pressure (PWP), but was slightly negatively correlated with mean arterial pressure (MAP) (r = -0.45) and systemic vascular resistance (SVR) (r = -0.40). After infusion of the angiotensin converting enzyme inhibitor teprotide (SQ 20,881) PWP fell from 26.3 +/- 1.3 (SEM) to 20.3 +/- 1.4 mm Hg (P less than 0.001), CO rose from 3.94 +/- 0.23 to 4.75 +/- 0.31 l/min (P less than 0.001), MAP fell from 87.5 +/- 3.8 to 77.9 +/- 4.1 mm Hg (P less than 0.001) and SVR from 1619 +/- 148 to 1252 +/- 137 dyne-sec-cm-5 (P less than 0.001). The fall in MAP and in SVR was significantly correlated with control PRA (r = 0.68 and r = 0.58, respectively). When subjects were divided on the basis of control PRA the hemodynamic response to teprotide was greatest in the high renin group. PRA rose after teprotide (8.7 +/- 3.4 to 37.9 +/- 7.7 ng/ml/hr, P less than 0.05) but plasma norepinephrine fell (619.1 +/- 103.6 to 449.7 +/- 75.7, P less than 0.05). The renin-angiotensin system thus appears to have an important role in the elevated SVR in some patients with heart failure. Chronic inhibition of converting enzyme should be explored as a possible therapeutic approach.     

Exercise capacity,hemodynamic, and neurohumoral changes following acute and chronic administration of flosequinan in chronic congestive heart failure

Summary We evaluated the responses to 90 minutes and 8 days of therapy with a new long-acting vasodilator flosequinan in ten patients with moderate chronic congestive heart failure in an open, uncontrolled study. Acute administration of 100 mg orally resulted in a decrease of preload, with a reduction of left ventricular end-diastolic volume, left ventricular end-diastolic pressure, pulmonary capillary wedge pressure, and right atrial pressure. Following the acute administration, we found no significant changes of heart rate, cardiac index, stroke volume, peripheral vascular resistance, ejection fraction, and dp/dt. Chronic application for 8 days (100 mg/day) showed persistent effects on preload, with a significant decrease of pulmonary capillary wedge pressure, right atrial pressure, and pulmonary arterial pressure. After 8 days of treatment, cardiac index was significantly increased from 2.2±0.2 l/min/m² to 2.8±0.2 l/min/m² (p=0.013) and stroke volume from 57±10 ml to 74±9 ml (p=0.022). Peripheral vascular resistance decreased by 28%. After 8 days, bicycle exercise capacity increased significantly from 383±44 sec to 422±43 sec (p=0.01) and the patients were able to increase their walking distance over a 6-minute exercise test from 426±46 m to 477±33 m (p=0.007), with a concomitant decrease of dyspnea (p=0.013). Plasma renin concentration showed only a rise 90 minutes after the acute administration on day 8 of the study, and atrial natriuretic peptide and 6-keto-prostaglandin F₁-alpha decreased significantly. Plasma norepinephrine, epinephrine, dopamine, and prostaglandin E₂ did not change. After 8 days body weight was reduced from 76.5±2.1 kg to 75.1±2.4 kg. These data indicate that flosequinan is effective in patients with heart failure during a relatively short duration of treatment, improving cardiac performance and exercise capacity and acting primarily on preload, and it may have cumulative vasodilator effects on arterial vessels during chronic therapy. We observed no substantial stimulation of neurohumoral factors and no fluid retention.     

Acute and chronic effects of ramipril and captopril in congestive heart failure

We studied the acute and long-term effects of ramipril and captopril in 12 patients with moderate to severe congestive heart failure using an open, parallel design. Drug doses were titrated. Compared with baseline values, maximal haemodynamic and humoral effects after the first dose of both angiotensin converting enzyme inhibitors were similar, but the effects of ramipril (5 mg) demonstrated a slower onset of action and a significantly longer duration than captopril (12.5 mg). After 3 months of treatment a single dose of 5 mg ramipril showed the same 24-hour haemodynamic profile as after the first dose, but the hypotensive effect was less marked. There was no plasma accumulation of ramiprilat. Serum creatinine and potassium remained stable, except for one patient whose renal function deteriorated on captopril treatment. Complex ventricular arrhythmias occurred in 11 patients and were unaffected after treatment with ramipril or captopril. Two patients died suddenly during ramipril therapy and one patient during captopril therapy. In summary, ramipril is an effective, long-acting angiotensin converting enzyme inhibitor, producing long-term haemodynamic effects in patients with congestive heart failure. Using an individualised dosage scheme, neither long-lasting hypotension nor deterioration of renal function occurred. No effect on ventricular arrhythmias was seen.