Hemodynamic and renal excretory effects of human brain natriuretic peptide infusion in patients with congestive heart failure. A double-blind, placebo-controlled, randomized crossover trial.

BACKGROUND: The pharmacological effects of infusion of human brain natriuretic peptide (hBNP) in patients with severe congestive heart failure have not been characterized previously. METHODS AND RESULTS: Twenty patients with severe congestive heart failure were randomized in a double-blind, placebo-controlled, crossover trial to receive incremental 90-minute infusions of hBNP (0.003, 0.01, 0.03, and 0.1 microgram/kg per minute) or placebo on 2 consecutive days. At the highest completed dose of the hBNP, mean pulmonary artery pressure decreased from 38.3 +/- 1.6 to 25.9 +/- 1.7 mm Hg; mean pulmonary capillary wedge pressure decreased from 25.1 +/- 1.1 to 13.2 +/- 1.3 mm Hg; mean right atrial pressure decreased from 10.9 +/- 1 to 4.8 +/- 1.0 mm Hg; mean arterial pressure decreased from 85.2 +/- 2.0 to 74.9 +/- 1.7 mm Hg; and cardiac index increased from 2.0 +/- 0.1 to 2.5 +/- 0.1 L/min per square meter (all P < .01 versus placebo). Urine volume and urine sodium excretion increased significantly during hBNP infusion when compared with placebo infusion (90 +/- 38 versus 67 +/- 27 mL/h and 2.6 +/- 2.4 versus 1.4 +/- 1.2 mEq/h, respectively, both P < .05 versus placebo), whereas creatinine clearance and urinary potassium excretion did not change. CONCLUSIONS: Infusion of incremental doses of hBNP is associated with favorable hemodynamic and natriuretic effects in patients with severe congestive heart failure.

Changes in plasma endothelin-1 levels reflect clinical response to beta-blockade in chronic heart failure.

Plasma levels of endothelin-1 are elevated in patients with chronic heart failure; however, it is unknown whether changes in plasma endothelin-1 levels accurately reflect clinical response to therapy in these patients. To determine this, we measured plasma endothelin-1 in addition to functional, hemodynamic, and other neurohormonal parameters as part of a double-blind, placebo-controlled study of the beta-blocker vasodilator carvedilol in patients with moderate to severe chronic heart failure. Patients were assigned (2:1 randomization) to receive carvedilol (25 mg twice daily, n = 10) or placebo (n = 5) for 14 weeks, with evaluations made before and after therapy. Compared to patients receiving placebo, patients receiving carvedilol improved significantly as assessed by the parameters described. These changes were paralleled by significant falls in endothelin-1 with carvedilol (-2.1 + 3.8 pg/ml) in comparison to placebo (2.2 + 3.9 pg/ml; p < 0.05 for between-group differences). Changes in endothelin-1 after treatment in both groups correlated significantly with changes in symptom severity, New York Heart Association class, 6-minute walk distance (r = 0.64 to 0.80; p < 0.05), hemodynamic parameters (ejection fraction, right atrial pressure, pulmonary artery diastolic pressure, pulmonary wedge pressure, right atrial pressure, and stroke volume index; r = 0.54 to 0.86; p < 0.05), and neurohormonal parameters (serum aldosterone and plasma norepinephrine (r = 0.74 to 0.76; p < 0.05). By stepwise regression analysis, change in endothelin-1 was an independent, noninvasive predictor of functional and hemodynamic responses to therapy in these patients. These findings suggest that endothelin-1 accurately reflects functional, hemodynamic, and neurohormonal responses to beta-blocker therapy in patients with congestive heart failure. Measurement of endothelin-1 may therefore be a useful, noninvasive approach to the evaluation of clinical response to drug therapy in these patients.

Double-blind, placebo-controlled study of the long-term efficacy of carvedilol in patients with severe chronic heart failure.

BACKGROUND: Clinical trials have shown that beta-adrenergic blocking drugs are effective and well tolerated in patients with mild to moderate heart failure, but the utility and safety of these drugs in patients with advanced disease have not been evaluated. METHODS AND RESULTS: We enrolled 56 patients with severe chronic heart failure into a double-blind, placebo-controlled study of the vasodilating beta-blocker carvedilol. All patients had advanced heart failure, as evidenced by a mean left ventricular ejection fraction of 0.16 +/- 0.01 and a mean maximal oxygen consumption of 13.6 +/- 0.6 mL.kg-1.min-1 despite digitalis, diuretics, and an angiotensin-converting enzyme inhibitor (if tolerated). After a 3-week, open-label, up-titration period, 49 of the 56 patients were assigned (in a double-blind fashion using a 2:1 randomization) to receive either carvedilol (25 mg BID, n = 33) or matching placebo (n = 16) for 14 weeks, while background therapy remained constant. Hemodynamic and functional variables were measured at the start and end of the study. Compared with the placebo group, patients in the carvedilol group showed improved cardiac performance, as reflected by an increase in left ventricular ejection fraction (P = .005) and stroke volume index (P = .010) and a decrease in pulmonary wedge pressure, mean right atrial pressure, and systemic vascular resistance (P = .003, .002, and .017, respectively). In addition, compared with placebo, patients treated with carvedilol benefited clinically, as shown by an improvement in symptom scores (P = .002), functional class (P = .013), and submaximal exercise tolerance (P = .006). The combined risk of death, worsening heart failure, and life-threatening ventricular tachyarrhythmia was lower in the carvedilol group than in the placebo group (P = .028), but carvedilol-treated patients had more dizziness and advanced heart block. CONCLUSIONS: Carvedilol produces clinical and hemodynamic improvement in patients who have severe heart failure despite treatment with angiotensin-converting enzyme inhibitors.

Lymphocyte G proteins reflect response to treatment in congestive heart failure.

Congestive heart failure is associated with chronotropic and inotropic hyporesponsiveness to adrenergic stimulation. A decrease in Gs alpha or an increase in Gi alpha is associated with a decrease in adenylyl cyclase activity. The current study assessed G proteins in response to treatment with direct-acting vasodilators and correlated changes in lymphocyte beta-adrenergic receptor components with changes in hemodynamic variables. Twenty-three patients with severe chronic congestive heart failure (New York Heart Association functional classes III and IV) were studied. Patients were grouped as responders (n = 10) or nonresponders (n = 13) on the basis of clinical assessment of functional status from questionnaires. Therapy was associated with an increase in cardiac index, a decrease in mean arterial pressure, and a decrease in systemic vascular resistance in all patients. Left ventricular filling pressure significantly decreased in responders (26 +/- 2 mm to 13 +/- 3 mm, p < 0.05) but did not change significantly in nonresponders. Similarly, mean right atrial pressure significantly decreased in responders (11 +/- 2 mm Hg to 4 +/- 1 mm Hg, p < 0.05) but did not change in nonresponders. Plasma norepinephrine increased significantly only in nonresponders (679 +/- 100 pg/ml to 1233 +/- 201 pg/ml, p < 0.05). Whereas lymphocyte beta-adrenergic receptor density and Gs did not significantly change, Gi increased after treatment only in the nonresponder group (23 +/- 5 to 51 +/- 11 fmol/mg, p < 0.05). A poor response to direct-acting vasodilators can be distinguished by reactive increases in plasma norepinephrine and lymphocyte Gi in the absence of a decrease in either left- or right-sided filling pressures.

Sustained hemodynamic response to flosequinan in patients with heart failure receiving angiotensin-converting enzyme inhibitors.

OBJECTIVES: We evaluated the short- and long-term effects of flosequinan in 47 patients with severe heart failure despite ongoing captopril treatment. BACKGROUND: There have been no previous evaluations of the long-term hemodynamic effects of any direct-acting vasodilator in patients with heart failure receiving an angiotensin-converting enzyme inhibitor. Flosequinan is an arterial and venous vasodilator with actions similar to those of the hydralazine-isosorbide dinitrate combination. METHODS: After baseline hemodynamic measurements using balloon-tipped pulmonary artery and radial arterial catheters, patients were randomized to receive 50, 100 or 150 mg of flosequinan daily. Hemodynamic variables were measured immediately before and after short-term flosequinan administration and after 8 weeks of therapy. RESULTS: With short-term flosequinan administration, mean arterial, right atrial and left ventricular filling pressures decreased by 6.4 +/- 1.1, 3.8 +/- 0.5 and 7.3 +/- 0.7 mm Hg, respectively (all p < 0.001). Cardiac index increased by 0.5 +/- 0.1 liters/min per m2, systemic vascular resistance decreased by 616 +/- 105 dynes.s.cm-5 and heart rate increased by 4 +/- 1 beats/min (all p < 0.001). After 8 weeks of long-term flosequinan administration, the vasodilator effect of a dose of flosequinan persisted. Compared with pretreatment baseline values, mean arterial, right atrial and left ventricular filling pressures at the peak effect of flosequinan were decreased by 3.5 +/- 1.3, 2.8 +/- 0.7 and 5.1 +/- 1.3 mm Hg, respectively (all p < 0.01). Systemic vascular resistance had decreased by 585 +/- 95 dynes.s.cm-5, cardiac index had increased by 0.5 +/- 0.1 liters/min per m2 and heart rate had increased by 10 +/- 2 beats/min (all p < 0.001). CONCLUSIONS: The arterial and venous vasodilator flosequinan exerts both short- and long-term sustained hemodynamic effects in patients with heart failure receiving angiotensin-converting enzyme inhibitors.

Hemodynamic effects of renin inhibition by enalkiren in chronic congestive heart failure.

Previous efforts to block the renin-angiotensin system in patients with chronic congestive heart failure (CHF) have focused on 2 distal sites in the system, the angiotensin-converting enzyme and the angiotensin II receptor. Recent work, however, has led to the development of agents that directly inhibit renin, the proximal step in the cascade. In this study, we investigated the hemodynamic effects of renin inhibition in 9 patients with chronic CHF by using enalkiren, a primate-selective, dipeptide renin inhibitor, which has been previously shown to suppress plasma renin activity and to lower blood pressure in hypertensive patients. The acute intravenous administration of enalkiren (1.0 mg/kg) produced increases in cardiac index (2.0 +/- 0.3 to 2.3 +/- 0.1 liter/min/m2) and stroke volume index (26 +/- 3 to 34 +/- 4 ml/m2) and decreases in left ventricular filling pressure (31 +/- 3 to 25 +/- 3 mm Hg), mean right atrial pressure (15 +/- 1 to 13 +/- 2 mm Hg), heart rate (78 +/- 5 to 72 +/- 6 beats/min) and systemic vascular resistance (2,199 +/- 594 to 1,339 +/- 230 dynes.s.cm-5) (all p less than 0.01 to 0.05). These observations indicate that renin inhibition produces hemodynamic benefits in patients with chronic CHF and could potentially provide a novel approach to interfering with the renin-angiotensin system in patients with this disorder.

Comparative hemodynamic effects of procainamide, tocainide, and encainide in severe chronic heart failure.

Many of the newer antiarrhythmic agents are said to cause minimal myocardial depression, but their hemodynamic effects have not been invasively evaluated and compared in patients with severe chronic heart failure. In a randomized, crossover study, the hemodynamic responses to single oral doses of procainamide (750 mg), tocainide (600 mg), and encainide (50 mg) given to 21 patients with severe chronic heart failure were compared. Cardiac performance decreased with all three drugs, but the magnitude of deterioration differed among the three agents. Stroke volume index decreased with procainamide (-5 +/- 1 ml/m2, p less than 0.001), tocainide (-7 +/- 1 ml/m2, p less than 0.001), and encainide (-8 +/- 1 ml/m2, p less than 0.001), but the decline was significantly greater with encainide than with procainamide (p less than 0.05). Similarly, left ventricular filling pressure increased with tocainide and encainide (+4 +/- 1 and +5 +/- 2 mm Hg, respectively; both p less than 0.05), but not with procainamide; the increase was significantly greater with tocainide and encainide than with procainamide (p less than 0.001). These deleterious hemodynamic effects were accompanied by worsening symptoms of heart failure in six patients with encainide and seven patients with tocainide but in only two patients with procainamide. Serum levels for all drugs were in the therapeutic range. In conclusion, although the three type I antiarrhythmic agents tested may all adversely affect left ventricular function in patients with heart failure, encainide and tocainide are more likely than procainamide to cause hemodynamic and clinical deterioration.

Adverse hemodynamic and clinical effects of encainide in severe chronic heart failure.

STUDY OBJECTIVE: To evaluate the hemodynamic effects of the antiarrhythmic drug, encainide, in patients with severe chronic heart failure. DESIGN: Unblinded, before-after study. SETTING: Referral center for patients with heart failure. PATIENTS: Thirty patients with severe chronic heart failure and a left ventricular ejection fraction less than 40%. INTERVENTIONS: Invasive hemodynamic measurements were done (using a balloon-tipped thermodilution catheter) before and for 3 hours after a single oral dose of 50 mg of encainide. MEASUREMENTS AND MAIN RESULTS: Ninety to one hundred and twenty minutes after its administration, encainide produced a significant deterioration in cardiac performance, as reflected by a fall in cardiac index from 2.3 to 1.8 L/min.m2 body surface (mean change 0.5 +/- 0.1; P less than 0.001), a fall in stroke work index from 26 to 18 g.m/m2 (mean change 8 +/- 2; P less than 0.001), and an increase in left ventricular filling pressure from 19 to 22 mm Hg (mean change 3 +/- 2; P less than 0.05). These deleterious hemodynamic effects were accompanied by worsening symptoms of heart failure in 8 of the 30 patients. Serum levels of encainide and its metabolites, O-desmethylencainide and 3-methoxy-O-desmethylencainide, were within the therapeutic range in most patients. CONCLUSIONS: Encainide can cause adverse hemodynamic and clinical effects in patients with severe chronic heart failure.

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.

Prognostic importance of the immediate hemodynamic response to nifedipine in patients with severe left ventricular dysfunction.

To determine the clinical significance of the occurrence of hemodynamic deterioration after the administration of calcium channel blocking drugs, nifedipine (20 mg orally) was administered to 29 patients with severe left ventricular dysfunction. Thirteen patients showed hemodynamic improvement with the drug (Group 1), as shown by a notable increase in cardiac index associated with a modest decrease in mean arterial pressure. The other 16 patients exhibited hemodynamic deterioration after nifedipine (Group 2), as reflected by a decline in right and left ventricular stroke work indexes accompanied by a marked hypotensive response. These differences were not related to differences in the peripheral vascular response to nifedipine, because both groups showed similar decreases in systemic and pulmonary vascular resistances. Groups 1 (hemodynamic improvement) and 2 (hemodynamic deterioration) were similar with respect to all demographic variables and pretreatment left ventricular performance (cardiac index, left ventricular filling pressure and systemic vascular resistance). Yet, the 1 year actuarial survival in patients in Group 1 was substantially better than that in patients in Group 2 (67 versus 23%, p = 0.009). Group 2, however, had higher values for plasma renin activity (17.7 +/- 6.0 versus 4.3 +/- 1.4 mg/ml per h, p less than 0.05), lower values for serum sodium concentration (134.6 +/- 1.2 versus 139.2 +/- 0.6 mEq/liter, p less than 0.05) and higher values for mean right atrial pressure (15.8 +/- 2.0 versus 7.9 +/- 1.4 mm Hg, p less than 0.01) than did patients in Group 1.(ABSTRACT TRUNCATED AT 250 WORDS)

Identification of hyponatremia as a risk factor for the development of functional renal insufficiency during converting enzyme inhibition in severe chronic heart failure.

To identify patients with severe chronic heart failure who are at greatest risk of developing functional renal insufficiency during converting enzyme inhibition, creatinine clearance was measured in 59 patients before and after long-term therapy with captopril (39 patients) or enalapril (20 patients), while digitalis and diuretic therapy was kept constant. Creatinine clearance increased or remained constant in 33 of the 59 patients (Group I), but declined in the remaining 26 patients (Group II). The two groups were similar with respect to the cause of heart failure, pretreatment renal function and all pretreatment hemodynamic variables. Patients in Group II, however, had lower values for serum sodium concentration (134.8 +/- 1.0 versus 137.0 +/- 0.6 mmol/liter) and higher values for plasma renin activity (10.6 +/- 3.4 versus 3.0 +/- 0.5 ng/ml per hour), received larger doses of furosemide (108 +/- 11 versus 84 +/- 6 mg/day), were more frequently diabetic (42 versus 15%) and were more frequently treated with enalapril (50 versus 21%) than were patients in Group I (all p less than 0.05). By stepwise logistic analysis, only hyponatremia (or an elevated plasma renin activity) and enalapril therapy independently predicted the decline in creatinine clearance during converting enzyme inhibition. These observations could not be explained by changes in systemic blood pressure. In patients with a normal serum sodium concentration (greater than or equal to 137 mmol/liter), creatinine clearance increased with captopril (+21%, p less than 0.05), but not with enalapril (-6%, p = NS).(ABSTRACT TRUNCATED AT 250 WORDS)

Prevention and reversal of nitrate tolerance in patients with congestive heart failure.

To evaluate possible mechanisms underlying the development of nitrate tolerance, we treated 35 patients who had severe chronic heart failure with a prolonged (48-hour) intravenous infusion of nitroglycerin (6.4 micrograms per kilogram of body weight per minute) given either continuously or intermittently (12-hour infusions separated by intervals of 12 hours). Intravenous nitroglycerin produced immediate hemodynamic benefits in all patients, but the magnitude of this improvement was greatly diminished after 48 hours of continuous therapy with the drug. This attenuation was accompanied by cross-tolerance to oral isosorbide dinitrate and by an increase in heart rate, plasma renin activity, and body weight. In contrast, intermittent therapy with intravenous nitroglycerin was not associated with a loss of hemodynamic efficacy or cross-tolerance to oral nitrates and was not accompanied by changes in neurohormonal activity or body weight. In eight patients in whom nitrate tolerance developed during continuous intravenous therapy, the administration of the sulfhydryl-containing compound N-acetylcysteine (200 mg per kilogram orally) restored the hemodynamic state toward that observed at the start of the infusion of nitroglycerin (partial reversal of tolerance). In contrast, N-acetylcysteine had little hemodynamic effect in patients who were not receiving nitroglycerin. These data support the hypothesis that neurohormonal activation and depletion of sulfhydryl groups may interact to cause the loss of hemodynamic efficacy that occurs during prolonged treatment with intravenous nitroglycerin in patients with heart failure. Evaluation of the suggested role of sulfhydryl depletion in the development of tolerance will, however, require direct studies of vascular tissue.

Influence of diabetes mellitus on changes in left ventricular performance and renal function produced by converting enzyme inhibition in patients with severe chronic heart failure.

Diabetes mellitus is frequently accompanied by specific abnormalities of the renin-angiotensin system, but it is not known whether these alterations modify the response to converting enzyme inhibition. To evaluate this possibility, 129 patients with severe chronic heart failure were treated with captopril or enalapril for one to three months, while doses of digoxin and diuretics were kept constant; 35 patients had diabetes mellitus. Prior to therapy, diabetic patients had lower plasma renin activity (3.4 +/- 0.5 versus 7.0 +/- 1.1 ng/ml/hour) than did nondiabetic control subjects (p less than 0.05); yet the initial hemodynamic response to captopril was similar in both groups. Plasma renin activity predicted the hypotensive response to the first dose of captopril in nondiabetic control subjects (r = 0.70, p less than 0.001) but not in diabetic patients (r = 0.29). During long-term treatment with captopril or enalapril, both diabetic and nondiabetic patients had similar increases in cardiac index and decreases in mean arterial pressure and systemic vascular resistance. Diabetic patients, however, showed larger reductions in left ventricular filling pressure (-13.8 versus -9.1 mm Hg, p less than 0.02) and mean right atrial pressure (-6.2 versus -3.9 mm Hg, p less than 0.05) than did nondiabetic subjects; this was accompanied by a notable decline in body weight in diabetic patients only. Renal function remained unaltered during converting enzyme inhibition in nondiabetic patients, but deteriorated significantly in diabetic patients, as reflected by a marked increase in serum creatinine concentration (1.7 +/- 0.1 to 2.1 +/- 0.1 mg/dl, p less than 0.001). In conclusion, despite lower pretreatment plasma renin activity, diabetic patients with severe chronic heart failure demonstrated improvement during long-term converting enzyme inhibition to a degree similar to (if not greater than) that seen in nondiabetic control subjects, but were more susceptible to the development of functional renal insufficiency than their nondiabetic counterparts. These differences are explicable by abnormalities of renin/aldosterone synthesis and angiotensin-mediated vasoregulation that are known to be present in the diabetic state.

Functional renal insufficiency during long-term therapy with captopril and enalapril in severe chronic heart failure.

Renal function was evaluated in 104 patients with severe chronic heart failure whom we treated with captopril or enalapril. Seventy patients showed no change or an improvement in renal function (group A), and 34 patients developed functional renal insufficiency (group B). Before converting-enzyme inhibition, group B patients received higher doses of furosemide (p less than 0.02) and had lower central venous pressures (p less than 0.05) than group A patients. After 1 to 3 months of converting-enzyme inhibition, an excessive reduction in left ventricular filling pressure (to less than 15 mm Hg) or mean arterial pressure (to less than 60 mm Hg) was noted in 28 of 34 (82%) patients in group B but in only 22 of 70 patients in group A (31%) (p less than 0.001). At the end of the study, drug-induced azotemia resolved after a reduction in the dosage of diuretics, despite unaltered treatment with captopril and enalapril. Hence, the deterioration of renal function after converting-enzyme inhibition in heart failure is not a toxic or immunologic reaction to therapy but results from specific hemodynamic events that can be ameliorated by sodium repletion.

Comparison of captopril and enalapril in patients with severe chronic heart failure.

To evaluate the concept that long duration of action is an advantageous property of angiotensin-converting enzyme inhibitors in the treatment of severe heart failure, we randomly assigned 42 patients to therapy with either a short-acting inhibitor (captopril, 150 mg daily) or a long-acting inhibitor (enalapril, 40 mg daily) for one to three months while concomitant therapy with digoxin and diuretics was kept constant. The treatment groups had similar hemodynamic and clinical characteristics at base-line evaluation and similar initial responses to converting-enzyme inhibition. During long-term therapy, captopril and enalapril produced similar decreases in systemic blood pressure, but the hypotensive effects of enalapril were more prolonged and persistent than those of captopril. Consequently, although the patients in both groups improved hemodynamically and clinically during the study, serious symptomatic hypotension (syncope and near syncope) was seen primarily among those treated with enalapril. Sustained hypotension also probably accounted for the decline in creatinine clearance (P less than 0.05) and the notable retention of potassium (P less than 0.05) observed in the patients treated with enalapril but not in those treated with captopril. We conclude that when large, fixed doses of converting-enzyme inhibitors are used in the treatment of patients with severe chronic heart failure, long-acting agents may produce prolonged hypotensive effects that may compromise cerebral and renal function, and thus they may have disadvantages in such cases, as compared with short-acting agents.

Comparative hemodynamic and clinical effects of long-term treatment with prazosin and captopril for severe chronic congestive heart failure secondary to coronary artery disease or idiopathic dilated cardiomyopathy.

Short- and long-term hemodynamic and clinical responses to sequential therapy with prazosin (15 mg/day for 3 to 12 weeks) and captopril (75 to 300 mg/day for 2 to 15 weeks) were compared in 22 patients with severe chronic congestive heart failure. First doses of prazosin produced marked increases in cardiac index and stroke volume index (p less than 0.01), but these effects were lost during long-term treatment. First doses of captopril produced only modest increases in both variables, but these persisted without attenuation during prolonged therapy. Both drugs produced immediate decreases in left ventricular filling pressure, mean arterial pressure, mean right atrial pressure and systemic vascular resistance; these changes became significantly attenuated (p less than 0.01) with prazosin but not with captopril. At the end of treatment, stroke volume index was significantly higher and right and left ventricular filling pressures were significantly lower with captopril than with prazosin (p less than 0.05 to 0.01). Only 8 of the 22 patients (36%) treated with prazosin benefited clinically, whereas 14 of 19 patients (74%) treated with captopril felt that they had improved (p less than 0.05). These differences could not have been predicted by comparing responses to first doses of the 2 drugs. These findings indicate that the choice of 1 vasodilator drug over another in patients with congestive heart failure should be based on studies that compare their long-term rather than short-term hemodynamic and clinical effects.

Systemic vasoconstrictor effects of oxygen administration in obliterative pulmonary vascular disorders.

Although oxygen is frequently administered to patients with obliterative pulmonary vascular disorders (OPVD) for diagnostic and therapeutic purposes, its hemodynamic effects in these patients have not been systematically evaluated. The response to administration of 50 to 70% oxygen was studied in 14 patients with pulmonary hypertension secondary to OPVD. Mean pulmonary artery pressure decreased (from 62 +/- 5 to 57 +/- 5 mm Hg, p less than 0.01) after oxygen inhalation secondary to a decrease in cardiac index (1.9 +/- 0.2 to 1.8 +/- 0.2 liters/min/m2, p less than 0.01), without changes in pulmonary arteriolar resistance. This decline in forward output appeared to result from a systemic vasoconstrictor effect of oxygen (change in systemic vascular resistance from 1,965 +/- 275 to 2,297 +/- 336 dynes s cm-5, p less than 0.01), which decreased heart rate (from 93 +/- 3 to 89 +/- 2 beats/min, p less than 0.01) by stimulation of baroreceptor reflexes and decreased stroke volume (from 22 +/- 3 to 21 +/- 2 ml/beat/m2, p less than 0.05) by increasing impedance to left ventricular ejection. The decrease in left-sided cardiac output likely led to a decline in venous return to the right side of the heart and, consequently, to a decrease in right atrial and pulmonary arterial pressures. Accordingly, the percent decrease in mean pulmonary artery pressure varied linearly and directly with the percent increase in systemic vascular resistance (r = 0.84), but not with changes in pulmonary arteriolar resistance (r = 0.15).(ABSTRACT TRUNCATED AT 250 WORDS)

Role of the renin-angiotensin system in the development of hemodynamic and clinical tolerance to long-term prazosin therapy in patients with severe chronic heart failure.

Right heart catheterization was performed before and during long-term therapy with prazosin in 27 patients with severe chronic heart failure who underwent serial hemodynamic studies during 3 to 12 weeks of treatment with the drug. Doses of digoxin and furosemide remained constant during the trial; in addition, 11 of the 27 patients were assigned to concomitant therapy with spironolactone, while the remaining 16 patients did not receive the aldosterone antagonist. First doses of prazosin produced marked increases in cardiac index and marked decreases in mean arterial pressure, left ventricular filling pressure and systemic vascular resistance in both groups of patients (all p less than 0.01), but these effects became rapidly attenuated (p less than 0.01) in both groups after 48 hours and remained attenuated during long-term therapy. After 3 to 12 weeks, values for cardiac index returned to pretreatment levels and did not decrease when the drug was withdrawn; values for mean arterial pressure, left ventricular filling pressure and systemic vascular resistance remained significantly decreased (although attenuated) after 3 to 12 weeks (p less than 0.01) and increased to pretreatment values when the drug was withdrawn. The magnitude and time course of these responses were not altered by concomitant therapy with spironolactone. Complete loss of hemodynamic efficacy (prazosin tolerance) was noted in 14 (58%) of the 24 patients who underwent long-term hemodynamic study and was not accompanied by long-term changes in plasma renin activity or body weight. These data indicate that prazosin produces long-term hemodynamic and clinical benefits in only 30 to 40% of patients with severe chronic heart failure and do not support a role for the renin-angiotensin system in the development of tolerance to alpha-adrenergic blockade. This low response rate explains why most randomized double-blind trials of prazosin in heart failure have not been able to demonstrate a significant difference between patients treated with placebo and those receiving active drug.

Influence of renal function on the hemodynamic and clinical responses to long-term captopril therapy in severe chronic heart failure.

To evaluate the influence of renal function on the efficacy of converting-enzyme inhibition in patients with severe chronic heart failure, we measured the long-term hemodynamic and clinical responses to captopril in 101 consecutive patients with heart failure grouped according to pretreatment serum creatinine concentration (group I, less than 1.4 mg/dL; group II, 1.4 to 2.8 mg/dL; and group III, greater than 2.8 mg/dL). After 1 to 3 months of treatment, patients with preserved renal function (group I) had greater increases in stroke volume index and greater decreases in left ventricular filling pressure and systemic vascular resistance than did patients with renal impairment (groups II and III) (p less than 0.05). Clinical improvement paralleled these hemodynamic benefits; only 2 of 12 patients with severe renal insufficiency (group III) improved clinically compared with 29 of 40 patients with preserved renal function (group I) and 29 of 49 patients with mild-to-moderate renal impairment (group II), (p less than 0.005). Therapy-limiting rash and dysgeusia occurred most frequently in patients with renal impairment. Our findings support an important role for the kidneys in mediating the beneficial actions of captopril in patients with severe congestive heart failure.