Baroreceptor-mediated release of vasopressin in patients with chronic congestive heart failure and defective sympathetic responsiveness.

In patients with congestive heart failure (CHF), overactivity of the sympathetic nervous system may be accompanied by an impairment of the baroreflex control mechanism. To evaluate the reflex responses of the sympathetic nervous system, the renin-angiotensin system and vasopressin release to baroreceptor unloading, 38 patients with left ventricular dysfunction were studied. Hemodynamic data, and plasma norepinephrine, renin activity and vasopressin concentrations were measured before and 60 minutes after administration of high-dose hydralazine (0.4 mg/kg intravenously). On the basis of blood pressure response to vasodilator administration, patients were divided arbitrarily into those with a decrease in mean arterial blood pressure greater than or equal to 15 mm Hg (group A; n = 12) and those with a decrease less than 15 mm Hg (group B; n = 26) compared with control values. In response to hydralazine, heart rate decreased in group A from 100 to 92 beats/min (p less than 0.001) and increased in group B from 90 to 96 beats/min (p less than 0.05). In group A, hemodynamic changes induced by hydralazine were accompanied by a decrease in plasma norepinephrine from 822 to 518 pg/ml (p less than 0.01) and an increase in plasma vasopressin from 8.4 to 45.2 pg/ml (p less than 0.001). In group B, plasma norepinephrine and vasopressin did not change significantly (407 vs 447, and 8.4 vs 8.3 pg/ml, respectively). Plasma renin activity remained unchanged in group A and increased in group B (p less than 0.001). The data show that baroreceptor-mediated release of vasopressin is not impaired in patients with CHF and a defective sympathetic reflex control mechanism.(ABSTRACT TRUNCATED AT 250 WORDS)     

Acute hemodynamic and hormonal effects of CI-930, a new phosphodiesterase inhibitor, in severe congestive heart failure

The phosphodiesterase inhibitor CI-930 hydrochloride exerts a positive inotropic and vasodilator effect in experimental animals. The acute hemodynamic and hormonal effects of intravenous CI-930 were studied in 9 patients with severe congestive heart failure. At 60 minutes of drug infusion, there was an increase in cardiac index (2.7 +/- 0.9 vs 2.0 +/- 0.7 liters/min/m2, p less than 0.01) and positive dP/dt (1,390 +/- 470 vs 1,100 +/- 300 mm Hg/s, p less than 0.02). Additionally, there were decreases in mean systemic arterial (78 +/- 16 vs 86 +/- 15 mm Hg, p less than 0.01), mean right atrial (5 +/- 3 vs 9 +/- 4 mm Hg, p less than 0.02), mean pulmonary arterial (27 +/- 11 vs 37 +/- 9 mm Hg, p less than 0.01) and LV end-diastolic (19 +/- 8 vs 28 +/- 6 mm Hg, p less than 0.01) pressures. Heart rate did not change (97 +/- 17 vs 97 +/- 22 beats/min). The inotropic response correlated significantly (r = 0.70, p less than 0.05) with the dose of CI-930. Plasma renin activity did not change significantly (from 16 +/- 9 to 23 +/- 15 ng/ml/hour), nor did plasma norepinephrine or arginine vasopressin levels. The plasma atrial natriuretic peptide level decreased (from 153 +/- 97 to 83 +/- 35 pg/ml, p less than 0.02). These findings suggest that intravenous CI-930 hydrochloride is a useful therapeutic agent in congestive heart failure and that its use does not appear to further activate potentially deleterious hormonal systems.     

Vasopressin, renin and norepinephrine levels before and after captopril administration in patients with congestive heart failure due to idiopathic dilated cardiomyopathy

The effects of 4 weeks of captopril treatment were studied in 10 patients with chronic congestive heart failure (CHF). Acute administration of 50 mg of captopril resulted in an increase in cardiac index and significant decreases in arterial pressure, peripheral vascular resistance and pulmonary capillary wedge pressure. Before treatment, all patients had elevated vasopressin levels (17 +/- 4 pg/ml) relative to decreased plasma osmolality (274 +/- 15 mOsm/kg H2O), and these values were not initially affected by captopril administration (22 +/- 7 pg/ml). However, the relation between arginine vasopressin and plasma osmolality was restored to normal by long-term therapy with captopril (50 mg 3 times daily) (3.0 +/- 1.3 pg/ml; 283 +/- 166 mOsm/kg H2O), which also resulted in sustained improvement of cardiac function. Long-term captopril therapy increased plasma renin concentration from already elevated levels (11 +/- 4 to 32 +/- 8 ng AI/ml X hour) and decreased plasma norepinephrine from 1,054 +/- 244 to 488 +/- 101 pg/ml. Thus, nonosmolar stimulation of vasopressin secretion in CHF can be restored to normal by chronic converting enzyme blockade. The acute vasodilator effects of converting enzyme blockade are not mediated by a reduction of possible vasoconstrictor effects of vasopressin.     

Differential long-term intrarenal and neurohormonal effects of captopril and prazosin in patients with chronic congestive heart failure: importance of initial plasma renin activity

Fifty patients with congestive heart failure received, by infusion, 15 ml/kg body weight water load, and systemic hemodynamic, renal function, and neurohumoral parameters values were measured before, 2 days, and 1 month after randomly allocating patients to prazosin or captopril therapy. Both prazosin and captopril caused similar and persistent hemodynamic changes, but important differences existed between their renal and neurohumoral effects. After 1 month of continuous therapy, captopril increased creatinine clearance from 71 to 84 ml/min/1.73(2) (p less than .05), increased the water load excreted in 5 hr from 50% to 71% (p less than .005), and increased 5 hr sodium excreted from 6.8 to 14.7 meq (p less than .005), Captopril also caused a decrease in plasma norepinephrine from 568 to 448 pg/ml (p less than .005), in plasma epinephrine from 94 to 73 pg/ml (p less than .05), and in plasma aldosterone from 57 to 28 ng/dl (p less than .005), without changing plasma vasopressin. These beneficial effects were greater after 1 month of therapy than after 2 days. The only beneficial effect of prazosin was to increase water excretion from 49% to 59% (p less than .05). The long-term response to captopril was similar in patients with higher (greater than 2.5 ng/ml/hr) and lower renin levels. However, in patients with lower renin levels, prazosin decreased pulmonary capillary wedge pressure (24.8 to 21.8 mm Hg, p less than .05), decreased plasma arginine vasopressin (1.16 to 0.75 pg/ml, p less than .05), increased water excretion (62% to 85%, p less than .005), and decreased plasma epinephrine (81 to 46 pg/ml, p less than .05), while in patients with higher renin levels none of these beneficial effects were noted. We conclude that captopril produces long-term beneficial renal and neurohumoral effects that prazosin does not despite similar hemodynamic changes with the two drugs, that these effects are at least partially dependent on the initial neurohumoral and hemodynamic status of the patient, and that through hemodynamic improvement vasodilators may chronically interrupt vasopressin overstimulation.     

Hemodynamic effects of infused arginine vasopressin in congestive heart failure

The hemodynamic effects of exogenously administered arginine vasopressin were assessed in 11 patients with chronic congestive heart failure. Infusion rates of 0.1 to 0.8 pmol/kg per min increased plasma arginine vasopressin from 6.5 +/- 2.7 (SD) pg/ml at control to 63 +/- 39 pg/ml at the highest infusion rate. There were progressive decreases in cardiac output and stroke volume, with increases in systemic vascular resistance and pulmonary capillary wedge pressure, but only minimal changes in heart rate and blood pressure. Changes in cardiac output, stroke volume and systemic resistance were evident from the first infusion rate, which increased plasma arginine vasopressin from 6.5 +/- 2.7 to 9.9 +/- 4.6 pg/ml. A paired analysis of baseline hemodynamic data with those measured during infusions producing an arginine vasopressin level averaging 15 +/- 2.6 pg/ml yielded the following changes: cardiac output decreased from 4.6 +/- 1.2 to 4.2 +/- 0.96 liters/min (p less than 0.01), stroke volume decreased from 60 +/- 19 to 54 +/- 16 ml (p less than 0.005) and systemic vascular resistance increased from 1,329 +/- 396 to 1,443 +/- 395 dynes X s X cm-5 (p = 0.01). Thus, small increases in circulating arginine vasopressin cause modest but significant adverse circulatory effects in patients with congestive heart failure. A fall in cardiac output, probably as a result of increased afterload, is seen at levels of arginine vasopressin within the basal range found in congestive heart failure. These data demonstrate that circulating arginine vasopressin in physiologic concentrations is capable of influencing hemodynamics in patients with congestive heart failure and suggest that therapy for this condition directed at inhibition of the vascular effect of arginine vasopressin may be potentially useful.     

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.     

MDL 17,043 therapy in severe congestive heart failure: characterization of the early and late hemodynamic, pharmacokinetic, hormonal and clinical response

MDL 17,043, an agent with both inotropic and vasodilator properties, was evaluated in the treatment of chronic severe heart failure. The early and late hemodynamic, hormonal, pharmacokinetic and clinical responses to oral MDL 17,043 were studied in 20 patients. MDL 17,043 acutely increased cardiac output from 3.6 +/- 0.9 to 4.6 +/- 1.0 liters/min (+28%, p less than 0.001) and decreased mean pulmonary artery wedge pressure from 24 +/- 8 to 13 +/- 8 mm Hg (-46%, p less than 0.001), mean right atrial pressure from 10 +/- 5 to 4 +/- 4 mm Hg (-60%, p less than 0.001) and mean arterial pressure from 78 +/- 9 to 70 +/- 11 mm Hg (-10%, p less than 0.001). Hemodynamic improvement was sustained for 8 hours. Plasma renin activity tended to increase (0.10 less than p greater than 0.05), plasma norepinephrine tended to decrease (0.10 less than p greater than 0.05) and arginine vasopressin did not show any directional change. Elimination half-life for MDL 17,043 was approximately 20 hours. Hemodynamic responsiveness was maintained in six patients undergoing restudy at 4 weeks. Initial subjective improvement in the 20 patients occurred in 90%, was present at 4 weeks in 50% and continued longer than 3 months in 25%. Side effects occurred in 75% and required cessation of treatment in 10%. Thirteen (93%) of 14 patients on long-term therapy died (median time after start of MDL 17,043 therapy 39 days). Deaths were sudden in 69%. It is concluded that oral MDL 17,043 produces early and late hemodynamic improvement in patients with severe heart failure.(ABSTRACT TRUNCATED AT 250 WORDS)     

Dissociation of sympathetic responses to baroreceptor loading and unloading in compensated congestive heart failure secondary to ischemic or nonischemic dilated cardiomyopathy.

This study tested the hypothesis that abnormalities of baroreceptor-mediated suppression of sympathetic activity may persist in chronic congestive heart failure (CHF) despite pharmacologic treatment and clinical stability. Plasma norepinephrine and norepinephrine kinetics (using 3HNE infusions) were measured during head-up and head-down tilt in 8 patients with chronic CHF and 6 normal control subjects. In response to upright tilt, normal subjects increased plasma norepinephrine (270 +/- 45 to 413 +/- 60 pg/ml, p less than 0.001) and norepinephrine spillover (540 +/- 103 to 781 +/- 124 ng/min, p less than 0.001). Patients also increased plasma norepinephrine (436 +/- 105 to 600 +/- 112 pg/ml, p less than 0.05) and norepinephrine spillover (802 +/- 180 to 1,037 +/- 370 ng/min). During head-down tilt, plasma norepinephrine decreased in normal subjects (from 413 +/- 60 to 256 +/- 26 pg/ml, p less than 0.001). The decrease was due entirely to a decrease in norepinephrine spillover (781 +/- 124 to 466 +/- 40 ng/min, p less than 0.001). In contrast, there was no significant change in norepinephrine spillover (1,037 +/- 370 to 949 +/- 338 ng/min) during head-down tilt in patients with CHF. These data suggest that suppression of sympathetic activity during baroreceptor loading may be defective in CHF despite relative preservation or correction of the response to baroreceptor unloading.     

Contribution of vasopressin to vasoconstriction in patients with congestive heart failure: comparison with the renin-angiotensin system and the sympathetic nervous system

Ten patients with advanced congestive heart failure were treated with an arginine vasopressin V1 antagonist during hemodynamic monitoring to determine the contribution of vasopressin to vasoconstriction in this disorder. The vasopressin antagonist caused a decrease in systemic vascular resistance in the three patients whose plasma vasopressin was greater than 4.0 pg/ml (average for the group was 2.4 +/- 0.6). Plasma vasopressin concentration correlated with the percent decrease of systemic vascular resistance (r = 0.70, p less than 0.025), serum sodium (r = 0.72, p less than 0.02) and serum creatinine (r = 0.85, p less than 0.005). To compare the relative roles of vasopressin, the renin-angiotensin system and the sympathetic nervous system, these patients also received captopril and phentolamine. Captopril decreased systemic vascular resistance by 20% (p less than 0.05), mostly in patients with high plasma renin activity. Levels of plasma renin activity ranged between 1 and 46 ng/ml per h (average 14.7 +/- 5.7) and correlated with serum sodium (r = 0.77, p less than 0.025), serum creatinine (r = 0.73, p less than 0.025) and right atrial pressure (r = 0.67, p less than 0.05). Phentolamine decreased systemic vascular resistance in all patients (average 34%, p less than 0.01), but the decrease did not correlate with the pretreatment norepinephrine concentration. Norepinephrine levels were elevated in all patients (694 +/- 110 pg/ml) and correlated with baseline stroke volume index (r = 0.75, p less than 0.025) and plasma renin activity (r = 0.67, p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)     

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.     

Neurohumoral and hemodynamic effects of lower body negative pressure in patients with congestive heart failure

Baroreflex modulation of forearm vascular resistance (FVR) has been reported to be abnormal in patients with congestive heart failure (CHF). However, the neurohumoral mechanisms for this impairment are not defined. We assessed the responses of arterial pressure, FVR, plasma norepinephrine, and plasma renin activity to lower body negative pressure in 29 patients with compensated CHF (New York Heart Association class III and IV) and in 11 normal age-matched control subjects. Baseline mean arterial pressure (83 +/- 2 vs 84 +/- 2 mm Hg) and mean arterial pressure during LBNP (-10, -20, and -40 mm Hg) were not significantly different in the two groups. Basal FVR (43.7 +/- 4 vs 27 +/- 2 units), plasma norepinephrine (605 +/- 81 vs 155 +/- 8 pg/ml), and plasma renin activity (8.3 +/- 1.7 vs 1.2 +/- 0.2 ng/ml/hr) were significantly (p less than 0.01) higher in patients with CHF. The relative increases in FVR responses during LBNP of -10, -20, and -40 mm Hg (10 +/- 4% vs 70 +/- 12%, 17 +/- 6% vs 106 +/- 21%, and 24 +/- 9% vs 152 +/- 28%) were markedly attenuated in patients with CHF compared to control subjects. Plasma norepinephrine and plasma renin activity responses during LBNP were also attenuated in patients with heart failure. Our results suggest that baroreflex control of FVR and plasma norepinephrine and plasma renin activity is impaired in CHF because of the inability of the cardiopulmonary baroreceptors to alter sympathetic outflow.     

Impaired response of plasma vasopressin to orthostatic stress in patients with congestive heart failure

Arginine vasopressin, a potent vasoconstrictor and regulator of body water, is frequently increased in the plasma of patients with congestive heart failure. Other neurohumoral control networks, such as the sympathetic nervous system and the renin-angiotensin system, also demonstrate increased activity in congestive heart failure, but fail to respond normally to physiologic stress, such as orthostatic tilt. To assess the response of plasma vasopressin to orthostasis in heart failure, vasopressin was measured before and at 10 and 45 minutes during passive upright tilt in 15 patients with congestive heart failure and their response was compared with that in 9 normal control subjects. Arginine vasopressin was measured by radioimmunoassay. In the normal subjects, plasma arginine vasopressin was 5.3 +/- 2.3 pg/ml at control, was unchanged at 10 minutes, but significantly increased to 7.0 +/- 2.5 pg/ml at 45 minutes (p less than 0.05). In contrast, patients with congestive heart failure showed no significant changes in arginine vasopressin levels from the control levels of 11.6 +/- 5.5 pg/ml. Both plasma norepinephrine and renin activity increased in the normal subjects, but failed to increase from higher baselines in patients with congestive heart failure. Thus, plasma arginine vasopressin, like plasma norepinephrine and renin activity, does not increase in response to upright tilt in patients with congestive heart failure. The explanation is not evident but could involve either abnormalities in reflex control of plasma vasopressin in congestive heart failure or in clearance of the hormone during orthostasis.     

Failure of plasma norepinephrine to consistently reflect sympathetic activity in humans

To determine whether venous plasma norepinephrine concentrations consistently reflect changes in sympathetic nervous activity, the influence of mental arithmetic, static handgrip, and submaximal bicycle exercise on intra-arterial blood pressure, heart rate, and plasma norepinephrine was studied in 51 subjects with untreated essential hypertension (mean age, 46 years; range, 16-69 years). At rest, plasma norepinephrine was unrelated to age or blood pressure. Mental arithmetic increased mean arterial pressure from 108 +/- 18 to 127 +/- 18 mm Hg (mean +/- S.D.; p less than 0.001) and heart rate from 69 +/- 7 to 93 +/- 13 beats/min (p less than 0.001) but not plasma norepinephrine (547 +/- 297 to 518 +/- 250 pg/ml). Isometric exercise raised mean arterial pressure from 115 +/- 18 to 148 +/- 21 mm Hg (p less than 0.001) and heart rate from 76 +/- 9 to 95 +/- 13 beats/min (p less than 0.001) but not plasma norepinephrine (683 +/- 253 to 741 +/- 253 pg/ml). Bicycle exercise increased mean arterial pressure from 114 +/- 20 to 146 +/- 26 mm Hg (p less than 0.001), heart rate from 77 +/- 9 to 128 +/- 19 beats/min (p less than 0.001), and plasma norepinephrine from 645 +/- 228 to 1151 +/- 462 pg/ml (p less than 0.001). Both the maximum mean arterial pressure and the peak heart rate attained during bicycle exercise were related to the exercise plasma norepinephrine level (r = 0.33, p less than 0.02 and r = 0.28, p less than 0.03, respectively). Increases in plasma norepinephrine with exercise were not greater in older or more hypertensive subjects.(ABSTRACT TRUNCATED AT 250 WORDS)     

The neurohumoral and hemodynamic response to orthostatic tilt in patients with congestive heart failure

Thirty-five patients with varying degrees of congestive heart failure were subjected to 60 degrees upright tilt. Eight of the patients with normal resting hemodynamics had elevated resting plasma norepinephrine levels (PNE) (p less than 0.001), but their response to upright tilt was similar to that in normal subjects: All had increases in heart rate, plasma norepinephrine (from 263 +/- 32 to 483 +/- 78 pg/mg, p less than 0.02) and plasma renin activity (from 4.8 +/- 0.9 to 13.7 +/- 7.6 ng/ml/hour, p less than 0.05). In 27 patients with high resting pulmonary wedge pressure and low cardiac index, resting PNE was higher (668 +/- 71 ng/ml), but PNE, plasma renin activity and heart rate did not increase significantly during tilt despite a fall in pulmonary capillary wedge pressure and cardiac index. In 18 of these patients, PNE rose during tilt, whereas in nine it did not change or fell; the resting hemodynamics and the hemodynamic response to tilt were not significantly different in these two groups. These data suggest that an abnormality of mechanoreceptor or baroreceptor function is common in patients with CHF. This abnormality corresponds in part to the severity of the resting hemodynamic abnormality, but among patients with severe CHF, the reflex neurohumoral abnormality may provide independent information about the severity of the disease.     

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.     

Hemodynamic, renal, and hormonal responses to brain natriuretic peptide infusion in patients with congestive heart failure

BACKGROUND. This study was designed to examine the hemodynamic, renal, and hormonal effects of brain natriuretic peptide (BNP) infusion in patients with congestive heart failure (CHF) and in control subjects. METHODS AND RESULTS. We infused synthetic human BNP at a rate of 0.1 micrograms/kg/min. BNP infusion decreased pulmonary capillary wedge pressure (control, from 5 +/- 1 to 2 +/- 1 mm Hg, p less than 0.01; CHF, from 21 +/- 3 to 14 +/- 4 mm Hg, p less than 0.05) and systemic vascular resistance (control, from 1,264 +/- 75 to 934 +/- 52 dyne.sec.cm-5; CHF, from 2,485 +/- 379 to 1,771 +/- 195 dyne.sec.cm-5; p less than 0.01, respectively) and increased stroke volume index (control, from 49.9 +/- 2.7 to 51.5 +/- 2.3 ml/m2, p = NS; CHF, from 25.6 +/- 3.8 to 32.0 +/- 3.9 ml/m2, p less than 0.01). BNP infusion significantly increased urine volume (control, from 2.3 +/- 0.7 to 7.5 +/- 1.9 ml/min; CHF, from 0.8 +/- 0.2 to 5.3 +/- 1.0 ml/min; p less than 0.01, respectively), excretion of sodium (control, from 79.2 +/- 21.6 to 332.8 +/- 70.9 microEq/min; CHF, from 77.4 +/- 20.8 to 753.5 +/- 108.0 microEq/min; p less than 0.01, respectively), and excretion of chloride (control, from 72.5 +/- 18.4 to 256.0 +/- 43.3 microEq/min; CHF, from 74.0 +/- 19.6 to 708.8 +/- 103.3 microEq/min; p less than 0.01, respectively). Urinary excretion of sodium and of chloride in response to BNP infusion was higher in patients with CHF than in control subjects (p less than 0.01, respectively). BNP infusion increased the levels of plasma atrial natriuretic peptide (control, from 65 +/- 11 to 84 +/- 14 pg/ml; CHF, from 262 +/- 65 to 301 +/- 62 pg/ml; p less than 0.05, respectively) and decreased plasma aldosterone concentrations in both groups (control, from 43.3 +/- 12.1 to 27.3 +/- 7.1 pg/ml; CHF, from 91.1 +/- 34.3 to 66.3 +/- 27.2 pg/ml; p less than 0.05, respectively). CONCLUSIONS. We conclude that BNP infusion improves left ventricular function in patients with CHF by vasodilation and prominent natriuretic action.     

Elevation of plasma neuropeptide Y levels in congestive heart failure

PURPOSE: Our objectives were to assess whether plasma neuropeptide Y (NPY) levels are elevated in patients with congestive heart failure (CHF) and whether or not NPY levels can serve as a reliable indicator of sympathetic activity in CHF. PATIENTS AND METHODS: Plasma levels of the sympathetic neurotransmitters norepinephrine and epinephrine and of the sympathetic co-transmitter NPY were measured in 17 patients with CHF and 14 healthy control subjects at rest and after maximal exercise. RESULTS: Under resting conditions, plasma NPY and norepinephrine levels were elevated in patients with CHF compared with control subjects (551 +/- 48 pg/ml versus 311 +/- 22 pg/ml, p less than or equal to 0.001 for NPY, and 306 +/- 73 pg/ml versus 124 +/- 22 pg/ml, p less than or equal to 0.02 for norepinephrine). Plasma NPY correlated better with plasma norepinephrine than with epinephrine, indicating its origin from sympathetic nerve terminals. Acute stimulation of sympathetic activity by dynamic exercise increased plasma norepinephrine levels in control subjects and patients with CHF, but did not significantly alter the mean plasma NPY value in the latter group. CONCLUSION: NPY may play a role in the pathophysiology of CHF.     

Efficacy of captopril in low-renin congestive heart failure: importance of sustained reactive hyperreninemia in distinguishing responders from nonresponders

To determine the efficacy of converting-enzyme inhibition in patients with low-renin congestive heart failure (CHF), the long-term hemodynamic and clinical responses to captopril were evaluated in 26 consecutive patients with severe, chronic CHF whose pretreatment plasma renin activity (PRA) was less than 2 ng/ml/hour. After 2 to 8 weeks of continuous treatment with captopril, 14 patients (54%) showed long-term hemodynamic benefits, of whom 13 (50%) improved clinically by at least 1 New York Heart Association functional class. To distinguish responders from nonresponders, patients were grouped based on the presence or absence of sustained reactive hyperreninemia (PRA during chronic therapy greater than 4 ng/ml/hour). After 2 to 8 weeks of therapy with captopril, 14 patients had sustained reactive hyperreninemia. Their cardiac index increased by 0.33 liters/min/m2 (p less than 0.01), left ventricular filling pressure decreased by 12.6 mm Hg (p less than 0.001), mean right atrial pressure decreased by 4.9 mm Hg (p less than 0.001) and systemic vascular resistance decreased by 529 dyne s cm-5 (p less than 0.001). Twelve of these 14 patients improved clinically. Twelve other patients had no reactive increase in PRA, and these patients showed no significant improvement in any hemodynamic variable after 2 to 8 weeks of treatment with captopril; only 1 of the 12 patients improved clinically (p less than 0.001 between groups). The 2 groups were otherwise similar with regard to pretreatment demographic, hemodynamic and hormonal variables.(ABSTRACT TRUNCATED AT 250 WORDS)     

Acute hemodynamic effect of a vascular antagonist of vasopressin in patients with congestive heart failure

To assess the role of arginine vasopressin (AVP) in congestive heart failure (CHF), 10 patients with CHF refractory to conventional treatment were studied before and 60 minutes after intravenous administration of 5 micrograms/kg of d(CH2)5Tyr(Me)AVP, a specific antagonist of AVP at the vascular receptor level. Heart rate, systemic arterial pressure, pulmonary arterial pressure, pulmonary capillary wedge pressure, cardiac index by thermodilution and cutaneous blood flow by laser-Doppler technique were measured. In 9 patients with no significant hemodynamic and cutaneous blood flow response to the AVP antagonist, baseline values (mean +/- standard deviation) were: heart rate, 77 +/- 14 beats/min; systemic arterial pressure, 120/79 +/- 18/8 mm Hg; pulmonary arterial pressure, 42/21 +/- 12/8 mm Hg; pulmonary capillary wedge pressure, 19 +/- 7 mm Hg; cardiac index, 2.2 +/- 0.6 liters/min/m2; plasma AVP, 2.3 +/- 0.8 pg/ml; and plasma osmolality, 284 +/- 14 mosm/kg H2O. The tenth patient had the most severe CHF. His plasma AVP level was 55 pg/ml and plasma osmolality was 290 mosm/kg. He responded to the AVP antagonist with a decrease in systemic arterial pressure from 115/61 to 79/41 mm Hg, in pulmonary arterial pressure from 58/31 to 33/13 mm Hg and in pulmonary capillary wedge pressure from 28 to 15 mm Hg. Simultaneously, cardiac index increased from 1.1 to 2.2 liters/min/m2 and heart rate from 113 to 120 beats/min; cutaneous blood flow increased 5-fold.(ABSTRACT TRUNCATED AT 250 WORDS)     

Arginine vasopressin and the renal response to water loading in congestive heart failure

Previous studies have shown on the basis of isolated comparisons that plasma arginine vasopressin (AVP) levels are inappropriately increased for a given serum osmolality in patients with CHF. To explore further the osmoregulation of AVP in this condition, the response of plasma AVP to a 15- to 20-ml/kg oral water load was compared in 26 patients with CHF and 14 normal subjects. In the normal subjects, serum osmolality decreased from 289 +/- 5.0 to 282 +/- 5.0 mOsm/kg (p less than 0.001) and AVP from 3.6 +/- 1.1 to 2.1 +/- 0.78 pg/ml (p less than 0.001). In the patients with CHF, osmolality decreased from 289 +/- 7.0 to to 281 +/- 7.0 mOsm/kg and AVP from 7.1 +/- 3.6 to 5.8 +/- 3.4 pg/ml (p less than 0.001). As a percentage of the control value, the decrease in AVP was much greater in the normal group, 41 +/- 15% vs 18 +/- 10% (p less than 0.001). Urinary osmolality levels were measured before and after water loading in 11 patients and in 7 normal subjects. Normal subjects diluted from 812 +/- 130 to 133 +/- 26 mOsm/kg (p less than 0.001) and CHF patients from 599 +/- 218 to 253 +/- 170 mOsm/kg, a statistically significant (p less than 0.01) but smaller (p less than 0.05) level of suppression. There were, however, 2 distinct groups within the CHF population: one in which urine osmolality was appropriately decreased (from 594 +/- 269 to 144 +/- 37 mOsm/kg, p less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)