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The effects of dipyridamole, a coronary and peripheral vasodilator drug, on cardiac performance were investigated in nine patients with severe chronic heart failure. Dipyridamole (30 to 80 mg IV) increased cardiac index (1.63 to 2.65 l/min/m2) and decreased systemic vascular resistance (2097 to 1124 dyn/sec/cm-5). Left ventricular filling pressure decreased (23.7 to 20.7 mm Hg) without significant changes in mean right atrial pressure or heart rate. These effects were similar to the hemodynamic responses after 100 mg hydralazine in the same patients, but they were of shorter duration (less than 90 min). In contrast, oral dipyridamole induced only modest responses in three of eight patients despite large single doses of the drug (150 to 300 mg). Dipyridamole is a rapid-acting short-lived vasodilator, which exerts predominantly arterial vasodilator actions similar to those of hydralazine. Due to inconsistent response after oral doses, however, the therapeutic application of dipyridamole in long-term management of chronic heart failure appears to be limited.

Four studies were conducted in 36 patients with severe chronic heart failure to compare the central hemodynamic effects of captopril (CPT) to other vasodilator agents. While CPT produced less marked increases in cardiac output than did hydralazine (n = 14), nitroprusside (n = 15), or prazosin (n = 7), it produced decreases in left ventricular filling pressures similar to nitroprusside and prazosin but more than hydralazine. CPT and isosorbide dinitrate (n = 11) produced similar decreases in systemic vascular resistance and left ventricular filling pressure. However, cardiac output increased less with CPT than with nitrates, because heart rate slowed during CPT therapy. In addition, mean right atrial pressure decreased less with CPT than with nitrates, because CPT had minimal effects on limb venous capacitance and pulmonary arteriolar resistance. Alterations in left ventricular pressure-volume relationships likely contributed to the marked decreases in left ventricular filling pressures seen with CPT. In conclusion, the central hemodynamic effects of CPT differ significantly from other vasodilator drugs used in the treatment of heart failure patients. These effects cannot be characterized simply in terms of "balanced" peripheral arterial and venous vasodilation; CPT exerts highly complex effects on peripheral vessels as well as having actions independent of its peripheral vasodilator effects.

The hemodynamic and clinical responses to calcium channel blockade with verapamil and nifedipine were compared with those of hydralazine in 12 patients with pulmonary hypertension secondary to obliterative pulmonary vascular disease. All three drugs produced a marked and similar decrease in pulmonary vascular resistance; however, this was accompanied by a significant increase in cardiac index with hydralazine (+0.71 liter/min per m2, p less than 0.01), no change in cardiac index with nifedipine and a significant decrease in cardiac index with verapamil (-0.25 liter/min per m2, p less than 0.05). Mean pulmonary artery pressure decreased markedly with both calcium channel blocking drugs (-16.0 mm Hg with verapamil and -14.5 mm Hg with nifedipine, both p less than 0.01), but this was associated with a concomitant increase in mean right atrial pressure (+6.2 mm Hg with verapamil and +4.4 mm Hg with nifedipine, both p less than 0.01); neither variable changed after hydralazine. Hence, right ventricular performance (as reflected by right ventricular stroke work index) deteriorated during treatment with both calcium channel blocking drugs, despite the decrease in resistance to right ventricular ejection; in contrast, right ventricular stroke work index increased after hydralazine. The unfavorable hemodynamic effects of calcium channel blockade were accompanied by severe adverse clinical events, including profound hypotension and cardiogenic shock during acute drug administration and the exacerbation of right heart failure during long-term treatment. These deleterious responses to verapamil and nifedipine are likely the result of a direct depressant effect exerted by these drugs on right ventricular function independent of their pulmonary vasodilatory actions.

We compared the short-term hemodynamic effects of isosorbide dinitrate (40 mg orally) and captopril (25 mg orally) in 18 patients with severe chronic heart failure in a randomized, crossover study conducted on consecutive days. Captopril and isosorbide dinitrate produced similar decreases in systemic vascular resistance, but whereas nitrate therapy decreased pulmonary arteriolar resistance significantly, captopril did not; the difference between the two drugs was highly significant (-25% vs -5%, p less than 0.001). Left ventricular filling pressures declined similarly with both captopril (-10.5 mm Hg) and with isosorbide dinitrate (-9.3 mm Hg), but because pulmonary arteriolar resistance fell significantly with nitrate therapy, mean right atrial pressure decreased more with isosorbide dinitrate than with captopril (-5.4 vs -2.8 mm Hg, respectively; p less than 0.001). Although systemic resistance declined similarly with both drugs, cardiac index increased more with nitrate therapy than during converting-enzyme inhibition (+0.47 vs +0.23 L/min/m2) (p less than 0.01), and therefore mean arterial pressure fell less with isosorbide dinitrate than with captopril (-10.5 mm Hg vs -16.7 mm Hg); p less than 0.05); two patients developed symptomatic hypotension with captopril, whereas none did so with the nitrate. The difference in the effects of the two drugs on cardiac index was not due to differences in their effects on heart rate, since heart rate fell similarly with both drugs, and thus both drugs produced similar increases in stroke volume index. These data indicate that, in patients with severe chronic heart failure, nitrates exert favorable dilating effects on the pulmonary circulation not shared by captopril.(ABSTRACT TRUNCATED AT 250 WORDS)

To determine the effects of vasodilator and inotropic therapy on hyponatremia in patients with severe heart failure, we measured serum sodium concentration before and after treatment with captopril (70 patients), hydralazine (42 patients), prazosin (22 patients), and amrinone (19 patients), while diuretic dosages were kept constant. Serum sodium concentration increased only in hyponatremic patients treated with captopril (131.2 +/- 0.5 to 135.9 +/- 0. 5 SE ; p less than 0.001), but not during therapy with the other agents and not in patients with normal serum sodium concentration before treatment. Serum sodium began to rise 48 hours after the initiation of captopril therapy and reached its peak after 14 to 16 days. Correction of hyponatremia was related to functional interference with the renin-angiotensin system, but not to changes in renal function, serum potassium concentration, body weight, or the magnitude of hemodynamic or clinical improvement. These findings support experimental evidence that the renin-angiotensin system is important in the pathogenesis of hyponatremia in patients with severe heart failure treated with diuretics.

Exercise capacity in patients with left heart failure is closely related to the performance of the right ventricle and the pulmonary circulation. To determine the significance of changes in pulmonary resistance during long-term vasodilator therapy, hemodynamic studies were performed before and after 1 to 3 months of treatment with captopril in 75 patients with severe chronic left heart failure. Patients were grouped according to the relative changes in pulmonary and systemic resistances during long-term therapy: patients in Group I (n = 24) showed greater decreases in pulmonary arteriolar resistance (PAR) than in systemic vascular resistance (SVR) (% delta PAR/% delta SVR greater than 1.0), whereas patients in Group II showed predominant systemic vasodilation (% delta PAR/% delta SVR less than 1.0). Despite similar changes in systemic resistance, patients in Group I showed greater increases in cardiac index, stroke volume index and left ventricular stroke work index (p less than 0.01 to 0.001) but less dramatic decreases in mean systemic arterial pressure (p less than 0.02) than did patients in Group II. Despite similar changes in left ventricular filling pressure, patients in Group I showed greater decreases in mean pulmonary artery and mean right atrial pressures (p less than 0.02 to 0.01) than did patients in Group II. Pretreatment variables in Groups I and II were similar, except that plasma renin activity was higher (8.7 +/- 2.1 versus 3.0 +/- 0.6 ng/ml per h) and serum sodium concentration was lower (133.1 +/- 0.9 versus 137.1 +/- 0.6 mEq/liter) in Group II than in Group I (both p less than 0.05). Both groups improved clinically after 1 to 3 months, but symptomatic hypotension occurred more frequently in Group II than in Group I (36 versus 8%) (p less than 0.005). These findings indicate that changes in the pulmonary circulation modulate alterations in both right and left ventricular performance during the treatment of patients with left heart failure. Hyponatremic patients are likely to experience symptomatic hypotension with captopril because they are limited in their ability to increase cardiac output as a result of an inadequate pulmonary vasodilator response to the drug.

To clarify the continuing controversy concerning the use of transdermal nitroglycerin (TDN), the shortterm hemodynamic responses to sublingual, oral and transcutaneous nitrates were evaluated and compared in 22 patients with severe chronic congestive heart failure. Sixteen patients showed favorable hemodynamic effects with TDN, but the doses needed to achieve this response varied greatly: 10 mg/24 hours in 6 patients, 20 mg/24 hours in 5 patients, 40 mg/24 hours in 3 patients and 60 mg/24 hours in 2 patients. Of the 6 remaining patients, 3 did not respond to high-dose TDN even though they showed marked effects after sublingual and oral nitrate administration; 3 others did not respond to any nitrate formulation by any route. TDN produced immediate increases in cardiac index and decreases in right and left ventricular filling pressure, mean arterial pressure and systemic vascular resistance (p less than 0.01). These effects, however, became rapidly attenuated within 3 to 6 hours; after 18 to 24 hours, only modest decreases in right and left ventricular filling pressures were observed. After removal of TDN treatment, rebound decreases in cardiac index and rebound increases in mean arterial pressure and systemic vascular resistance occurred, but right and left ventricular filling pressures returned to pretreatment values without rebound changes. Isosorbide dinitrate, 40 mg orally, produced hemodynamic effects that were greater in magnitude than effects seen after administration of TDN (p less than 0.05 to 0.01), but 4 patients in whom tolerance to TDN developed showed reversible cross tolerance to oral isosorbide dinitrate.(ABSTRACT TRUNCATED AT 250 WORDS)

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.

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.

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.

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.

Hemodynamic responses to different doses of hydralazine were evaluated in 18 patients with severe refractory resistant heart failure. There were no significant overall hemodynamic effects after 50 mg hydralazine. After 75 mg, CI increased slightly (+0.36 l/min/m2) with a 19% decrease in SVR. After 100 mg, there were substantial increases in CI (+0.60 l/min/m2) and decreases in SVR (31%) changes which were greater than those after 75 mg, but the decrease in MAP with 100 mg (-6.6 mm Hg) was of the same order as that after 75 mg (-5.0 mm Hg). LVFP and SWI improved significantly only with 100-mg doses. Seven patients in whom 100 mg hydralazine induced no hemodynamic effects all responded to single doses of 150 to 200 mg. The duration of action of hydralazine was longer (p less than 0.001) in patients with a CCr less than 35 ml/min (14.3 +/- 1.4 hr) than in patients with adequate renal function (7.9 +/- 0.5 hr). Thus, the dose and dosing interval of hydralazine needed to induce hemodynamic improvement in patients with severe heart failure are variable and require individualization.

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)

Although amrinone produces acute hemodynamic improvement in patients with severe chronic congestive heart failure (CHF), it has not produced clinical benefits in long-term controlled trials. To determined if the administration of subtherapeutic doses of amrinone may account for its lack of efficacy in these studies, the dose requirements of the drug were investigated in 30 patients with severe CHF. Doses of 100 mg of oral amrinone produced moderate increases in cardiac index (0.35 liters/min/m2) and decreases in pulmonary capillary wedge pressure (6.8 mm Hg) and systemic vascular resistance (16%) (all p less than 0.01); these effects, however, were short-lived (less than 2.5 hours). Doses of 200 mg of oral amrinone produced marked increases in cardiac index (0.56 liters/min/m2) and substantial decreases in left ventricular filling pressure (9.9 mm Hg) and systemic vascular resistance (30%) (all p less than 0.01), and these effects persisted for longer than 4 hours. Only 4 patients showed hemodynamic responses with 100 mg of the drug that were sufficiently marked and long-lasting to merit chronic therapy, whereas 28 patients had such a response with the 200-mg dose. When 200 mg of amrinone was administered orally every 8 hours, sustained hemodynamic benefits were seen for 48 hours. However, 16 of 22 patients who received 600 mg of the drug daily for more than 1 week had intolerable adverse reactions that required drug withdrawal. In conclusion, hemodynamically effective doses of amrinone (600 mg/day) cannot be tolerated for long periods by most patients with severe chronic CHF.(ABSTRACT TRUNCATED AT 250 WORDS)

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.

To compare the responses to oral inotropic and vasodilator drugs, maximally effective doses of amrinone (300 mg over 3 hours) and captopril (25 mg orally) were administered to 21 patients with severe chronic heart failure, who had not received either agent previously. Despite similar decreases in systemic vascular resistance with both drugs, amrinone produced greater increases in cardiac index (+ 0.56 vs. + 0.41/min/m2, p less than 0.05) and smaller decreases in mean arterial pressure (-11.1 vs. -15.2 mm Hg, p less than 0.05) than did captopril; three patients became symptomatically hypotensive with captopril, but none did so after amrinone. These differences were due to a significant decrease in heart rate with captopril (-6.3 beats/min, p less than 0.01), whereas heart rate increased with amrinone (+ 4.3 beats/min, p less than 0.01); the increases in stroke volume index with both drugs were similar. Despite similar decreases in left ventricular filling pressures, the decrease in mean right atrial pressure with amrinone was greater than with captopril (-5.6 vs. -3.2 mm Hg, p less than 0.01). This difference was the result of the greater decrease in pulmonary arteriolar resistance, and hence in right ventricular afterload, with amrinone than with captopril, (-33% vs. -16%, respectively), p less than 0.01. Despite these superior hemodynamic responses to amrinone, when patients received sequential long-term treatment with both drugs during the follow-up period, only 12% of patients benefitted during therapy with amrinone, whereas 64% improved clinically with captopril.(ABSTRACT TRUNCATED AT 250 WORDS)

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.

Although a variety of vasodilator drugs produce acute hemodynamic improvement in patients with severe chronic heart failure, long-term treatment with these agents may be associated with the development of drug tolerance and loss of initial beneficial effects. Five serial right heart catheterizations in a 78 year old man with severe chronic heart failure due to idiopathic cardiomyopathy documented the development of hemodynamic and clinical tolerance to oral hydralazine and oral captopril after initial responses were observed to both agents. However, sustained hemodynamic and clinical improvement by invasive testing was noted with minoxidil (20 mg orally twice daily) after 4 and 9 weeks of continuous therapy. These observations indicate that pharmacologic tolerance may occur with a variety of vasodilator drugs and may account for the failure of some patients to improve clinically with long-term therapy despite initial favorable hemodynamic effects. However, such tolerance seems to be drug-specific and, hence, its recognition in an individual patient does not prelude responsiveness to other vasodilator agents.

The hemodynamic effects of oral captopril and intravenous nitroprusside were compared in 15 patients with severe chronic congestive heart failure. At doses of both drugs titrated so as to produce similar decreases in systemic vascular resistance in each patient, nitroprusside produced substantially greater increases in cardiac index (+0.67 versus +0.31 liters/min/m2, p less than 0.01) but smaller decreases in mean arterial pressure (-18.4 versus -11.0 mm Hg, p less than 0.01) than did captopril. This finding was due to a significant decrease in heart rate with captopril (-7 beats/min, p less than 0.01) which was not seen with nitroprusside, since changes in stroke volume index with both drugs were similar. Nitroprusside produced a decrease in pulmonary arteriolar resistance quantitatively similar to the decrease in systemic vascular resistance, but the decrease in pulmonary arteriolar resistance with captopril was not significant. Despite similar decreases in systemic resistance, captopril produced a greater decrease in left ventricular filling pressure (-10.2 versus -6.9 mm Hg, p less than 0.01) but a smaller decrease in mean right atrial pressure (-3.1 versus -5.3 mm Hg, p less than 0.01) than did nitroprusside. Thus, captopril has actions independent of its systemic vasodilator effects which account for the quantitative differences observed in its hemodynamic responses compared with those of nitroprusside in patients with severe chronic heart failure. These differences support experimental evidence that angiotensin, in addition to its direct systemic arterial vasoconstrictor actions, exerts positive chronotropic effects and alters ventricular compliance but has minimal direct effects on the limb venous circulation and on the pulmonary vasculature.

We performed hemodynamic studies in 11 patients with severe chronic heart failure whose symptoms had returned to their pretreatment status after 37 +/- 15 weeks (mean +/- S.E.M.) of therapy with the vasodilator hydralazine. The cardiac index increased from 1.85 to 3.47 liters per minute per square meter of body-surface area, and systemic vascular resistance decreased from 1748 to 754 dyn . sec. cm-5 (both p less than 0.01) during initial hydralazine administration but returned to pretreatment values on repeat evaluation; withdrawal of the drug produced no hemodynamic deterioration. Responsiveness to hydralazine could not be restored by doubling the oral dose or by intravenous administration; tolerance was associated with fluid retention in five patients but was not reversed by intensive diuresis. In contrast, the responses to nitroprusside evaluated before and after the development of hydralazine tolerance were unaltered; other oral vasodilators were still effective. We conclude that drug-specific tolerance may account for the lack of clinical improvement in some patients with severe heart failure who receive long-term treatment with hydralazine.

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)

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)