Mechanisms involved in the response to prolonged infusion of atrial natriuretic factor in patients with chronic heart failure.

We examined the mechanisms involved in the cardiovascular and renal response to prolonged infusion of atrial natriuretic factor (ANF) in patients with chronic heart failure. ANF infusion was titrated to produce a 30% decrease in pulmonary capillary wedge pressure or a 20% increase in cardiac output, and this dose (average, 75 +/- 4 ng/kg/min) was then administered for 20 hours. The short-term response to ANF included significant reductions in central filling pressures, increases in cardiac output, modest increases in diuresis and glomerular filtration rates, significant reduction in plasma aldosterone levels, and a 3.6-fold increase in plasma cyclic GMP levels. During prolonged infusion, plasma cGMP levels and cardiac output gradually returned to baseline. Similarly, the initially increased diuretic effects were completely abolished during prolonged ANF infusion, although plasma alpha-hANF levels remained consistently elevated above baseline values (control, 198 +/- 38; titration, 2,760 +/- 596; 20 hours, 3,499 +/- 659 pg/ml). Four hours after beginning the ANF infusion, marked increases in hematocrit levels were noted (42.5 +/- 1.0% versus 45.3 +/- 1.4%, control and infusion, respectively, p less than 0.05); during this time, no change in total plasma protein concentration occurred, indicating extravascular shift of fluid and plasma proteins. No evidence was noted for activation of vasoconstrictor hormones during prolonged ANF infusion, although mean arterial pressure was significantly reduced throughout the infusion period. Plasma pro-ANF (31-67) levels, determined as a marker for endogenous ANF secretion, were significantly suppressed as were the reductions of central filling pressures. After ANF discontinuation, heart rate and pulmonary capillary wedge pressure increased significantly above baseline values without evidence for sympathetic stimulation. We conclude that 1) prolonged infusion of ANF causes only transient increases in plasma cGMP levels but a sustained reduction of the cardiac release of ANF and that 2) the beneficial hemodynamic effects of ANF, that is, unloading of the ventricles, may be associated with or, in part, may be secondary to a shift of plasma constituents into the extravascular space. The latter may limit the therapeutic potential of ANF for long-term treatment.     

Impaired response of atrial natriuretic factor to blood volume expansion in acute right ventricular infarction.

To assess the role of atrial natriuretic factor (ANF) in right ventricular (RV) infarction, 30 patients with inferior wall acute myocardial infarction (15 with RV involvement) and normal left heart filling pressures were studied 39 +/- 12 hours after the onset of symptoms. Serial measurements of cardiac output, right atrial, pulmonary artery and pulmonary wedge pressures, as well as plasma ANF, plasma renin activity, plasma aldosterone and vasopressin were obtained before and 30 minutes after acute volume expansion to raise wedge pressure greater than or equal to 20 mm Hg. Baseline mean right atrial pressure and plasma ANF levels were greater in patients with than without RV infarction (8 +/- 3 vs 5 +/- 2 mm Hg; p less than 0.0001, and 4.6 +/- 2.9 vs 2.7 +/- 1.5 fmol/ml; p less than 0.05, respectively). There were no differences in other baseline hemodynamic or humoral parameters between both groups. After volume expansion, pulmonary wedge pressure was similar in both groups, but right atrial pressure increased to higher levels in patients with RV infarction (19 +/- 2 vs 14 +/- 2 mm Hg; p less than 0.0001). Despite this greater stimulus for ANF secretion, the increase in plasma ANF was less pronounced in patients with RV infarction (63 +/- 81 vs 455 +/- 417%; p less than 0.002), especially among those with paroxysmal supraventricular tachyarrhythmias. Thus, despite higher baseline plasma levels of ANF, response to volume loading is markedly attenuated in patients with RV infarction complicating an inferior wall acute myocardial infarction.     

Converting enzyme inhibition prevents the effects of atrial natriuretic factor on baroreflex responses in humans

The aim of this study was to assess the influence of atrial natriuretic factor (ANF) on arterial baroreflex chronotropic responses and to investigate whether this effect of ANF is affected by angiotensin converting enzyme inhibition (CEI). For this purpose, in 13 normal volunteers, the reflex chronotropic responses to arterial baroreceptor stimulation (phenylephrine, 25-100 micrograms i.v.) or deactivation (nitroglycerin, 25-100 micrograms i.v.) were evaluated in control conditions and during the steady-state phase of a sustained infusion of ANF (50 ng/kg/min) or placebo, before and during prolonged treatment with the converting enzyme inhibitor enalapril (20 mg p.o. for 5 days). ANF infusion, which raised plasma ANF levels from 48 +/- 19 to 1,765 +/- 203 pg/ml, was associated with a slight decrease in systemic blood pressure and no change in heart rate. In addition, it caused a significant increase of the regression slope obtained with phenylephrine (from 11.3 +/- 2 to 18.5 +/- 2 msec/mm Hg) and a significant reduction of slope of the nitroglycerin-produced regression line (from 9.3 +/- 1 to 5.6 +/- 0.6 msec/mm Hg). After sustained CEI, which raised plasma renin activity from 1.4 +/- 0.4 to 19.9 +/- 5 ng/ml/hr, ANF infusion induced an increase in plasma ANF levels and a reduction in blood pressure comparable to those observed in control conditions. During CEI, however, ANF infusion had no significant effect on the chronotropic baroreflex responses produced by phenylephrine or nitroglycerin. Chronotropic and pressor responses to cold exposure were unchanged after CEI and during ANF.(ABSTRACT TRUNCATED AT 250 WORDS)     

Exercise-induced secretion of atrial natriuretic factor and its relation to hemodynamic and sympathetic stimulation in untreated essential hypertension.

This study evaluates the release of atrial natriuretic factor (ANF) during maximal exercise in 7 patients with untreated moderate to severe hypertension with invasive monitoring of hemodynamic characteristics in relation to sympathetic activity. Peripheral venous ANF (fmol/ml) was determined at rest and maximal exercise producing a respiratory exchange ratio of 1.14 +/- 0.10. In 5 of 7 patients, simultaneous right ventricular and peripheral venous ANF samples could be obtained to assess exercise myocardial secretion of ANF. With exercise, mean blood pressure increased from 150 +/- 26 to 192 +/- 29 mm Hg (p less than 0.001), pulmonary wedge pressure increased from 7 +/- 3 to 18 +/- 10 mm Hg (p less than 0.05) and ANF increased from 11.7 +/- 8.2 to 25.7 +/- 15.9 (p less than 0.02). This ANF response correlated weakly with pulmonary wedge pressure (r = 0.497, p = not significant), since patients without an increase in pulmonary wedge pressure had no increase in ANF. However, changes in pulmonary wedge pressure and plasma norepinephrine during exercise were inversely correlated (r = -0.811, p less than 0.02), with the greatest increase in norepinephrine occurring with a minimal increase in pulmonary wedge pressure. Similarly, ANF and plasma norepinephrine were inversely correlated during exercise (r = -0.869, p less than 0.05). A significant increase in right ventricular ANF indicated myocardial secretion. Plasma ANF therefore increased because of active myocardial production during exercise in patients with moderate to severe hypertension. These findings further suggest a directionally opposing relation between ANF release resulting from increased atrial tension and sympathetic nervous system influence on cardiac performance during exercise.     

Effect of vasopressors on atrial natriuretic factor and hemodynamic function in humans

To assess the effects of vasopressors on plasma levels of immunoreactive atrial natriuretic factor (ANF), 13 normal men were studied on two occasions. On the experimental day, subjects received sequential 15-minute intravenous infusions of angiotensin II in doses of 4, 8, and 16 pmol/kg/min. Following a 30-minute recovery period, subjects received sequential 15-minute infusions of phenylephrine in doses of 0.4 and 0.8 micrograms/kg/min. Right atrial pressure, mean pulmonary capillary wedge pressure, pulmonary artery pressure, mean systemic arterial pressure, and plasma levels of renin activity, aldosterone, angiotensin II, and immunoreactive ANF were obtained sequentially throughout the protocol. During the control day, vehicle was infused and plasma samples were obtained for hormone measurements. Infusion of angiotensin II and phenylephrine increased mean systemic arterial pressure in a stepwise fashion. Both right atrial pressure and pulmonary capillary wedge pressure increased significantly during both doses of phenylephrine, but only the highest dose of angiotensin II significantly increased atrial pressures. Plasma levels of immunoreactive ANF increased parallel with the changes in right atrial pressure and pulmonary capillary wedge pressure, with significant increases occurring only at the highest dose of both pressors. Angiotensin II and aldosterone levels increased and renin activity decreased during infusion of angiotensin II. There were no significant changes in plasma levels of immunoreactive ANF during the control day. These studies demonstrate that infusion of vasopressors increases plasma levels of ANF, but only when the vasopressor effect is associated with significant increases in right atrial and pulmonary capillary wedge pressures. Atrial stretch is the most likely mediator of the increase in plasma levels of immunoreactive ANF during vasoconstriction.     

Early tolerance to hemodynamic effects of high dose transdermal nitroglycerin in responders with severe chronic heart failure

Transdermal systems for delivery of nitroglycerin have been shown to provide sustained blood levels of the drug for at least 24 hours. Investigations of hemodynamic effects of transdermal nitroglycerin in patients with heart failure have demonstrated a transient reduction in pressure lasting less than the expected 24 hours. These findings could be due to the development of circulatory tolerance to the vasodilatory effects of nitroglycerin or to insufficient drug dosing. In the present study, we compared the hemodynamic effects of the first and the second doses of high dose (120 mg) transdermal nitroglycerin given 24 hours apart in 11 responders (greater than or equal to 20% reduction in mean pulmonary artery wedge pressure lasting greater than or equal to 2 hours). Initiation of nitroglycerin therapy resulted in a significant reduction in mean right atrial pressure lasting for 14 hours and in a reduction in mean pulmonary artery and mean pulmonary artery wedge pressures lasting 24 hours. After administration of the second dose, mean right atrial pressure at 2 hours (9 +/- 5 versus 7 +/- 4 mm Hg), 4 hours (8 +/- 5 versus 6 +/- 4 mm Hg) and 8 hours (8 +/- 5 versus 6 +/- 3 mm Hg) was higher than after the first dose (p less than 0.05). Both mean pulmonary artery and mean pulmonary artery wedge pressures were significantly higher after the second nitroglycerin dose.(ABSTRACT TRUNCATED AT 250 WORDS)     

Sustained saline-induced secretion of atrial natriuretic hormone is not maintained by atrial stretch

To determine the relationship between changes in right and left atrial pressures and changes in plasma levels of immunoreactive atrial natriuretic hormone (ANH), 11 normal men were studied during rapid infusion of 1 L 150 mmol/L NaCl. Right atrial pressure, pulmonary capillary wedge pressure, and peripheral plasma ANH levels were measured serially for 30 min in 6 men and for 90 min in 5 men. There were significant increases in right atrial pressure at 15 and 30 min [4.8 +/- 0.4 (+/- SE) vs. 8.9 +/- 0.3 and 6.5 +/- 0.4 mm Hg; P less than 0.001] and in pulmonary capillary wedge pressure at the same time intervals [8.5 +/- 0.6 vs. 13.6 +/- 0.8 (P less than 0.001) and 10.6 +/- 0.6 mm Hg (P less than 0.01)]. Plasma ANH increased significantly at 30 min (11.5 +/- 2.4 vs. 20.6 +/- 3.0 pmol/L; P less than 0.001). Regression analysis revealed no correlation between the increase in plasma ANH at 30 min and the increase in either right atrial or pulmonary capillary wedge pressure at 15 min (r = 0.46; P = 0.16 for right atrial pressure; r = 0.02; P = 0.96 for pulmonary capillary wedge pressure). In the 5 men studied for 90 min, right atrial and pulmonary capillary wedge pressures returned to basal values by 45 min. In contrast, plasma ANH levels remained significantly elevated at all sampling times from 30-90 min (P less than 0.001); the peak value occurred at 75 min. We conclude that ANH secretion persists after saline infusion and that the cause of this prolonged secretion is not atrial stretch.     

Atrial natriuretic peptide in severe heart failure: response to controlled changes in atrial pressures during intravenous nitroglycerin therapy.

Atrial natriuretic peptide (ANP) levels were measured in 17 patients with severe congestive heart failure (New York Heart Association functional class IV), and the response of the peptide was studied during changes in cardiac filling pressures induced by a 24-hour infusion of nitroglycerin. In the control state plasma ANP levels (687 +/- 551 pg/ml) were 10-fold normal. During the administration of nitroglycerin, natriuretic peptide levels decreased (p less than 0.005) with changes matching very closely the decreases in pulmonary arterial wedge and right atrial pressures, a 1% mean decrease in the peptide level for every 1.5 to 2% mean change in atrial filling pressures. In patients with hemodynamic tolerance to constant-dose nitroglycerin infusion, the resulting increase in atrial pressures was accompanied by an appropriate secondary increase in the plasma ANP level. During the 24-hour study period there was a direct linear relationship between both wedge (r = 0.93, p = 0.007) and right atrial (r = 0.93, p = 0.008) pressures and the plasma ANP level, with a zero-pressure ANP intercept near normal (69 pg/ml for wedge, 174 pg/ml for right atrial pressure). The findings were no different in a subgroup of five patients receiving simultaneous treatment with captopril, except that plasma renin activity was higher and the aldosterone level lower than in the control group by a factor of approximately 2.5. The close relationship and tracking of atrial pressure and natriuretic peptide curves suggested that the sensitivity of the atrial stretch response to changes in atrial filling pressures was maintained in severe congestive heart failure.     

Influence of dilated cardiomyopathy, myocarditis and cardiac transplantation on the relation between plasma atrial natriuretic factor and atrial pressures.

To determine whether dilated cardiomyopathy, myocarditis or cardiac transplantation affect the relation between plasma immunoreactive atrial natriuretic factor (ANF) and cardiac filling pressures, right atrial plasma ANF concentration, pulmonary arterial wedge pressure and right atrial pressure were measured in patients with dilated cardiomyopathy (n = 48), dilated cardiomyopathy secondary to myocarditis (n = 20) and prior cardiac transplantation (n = 34). ANF level significantly correlated with both pulmonary arterial wedge and right atrial pressures in patients with dilated cardiomyopathy; however, the presence or absence of myocarditis did not significantly alter these relations (p = 0.88 and p = 0.33 for interaction terms, respectively). For the combined group the ANF-pulmonary arterial wedge pressure relation had a slope of 8.1 pg/ml/mm Hg (95% confidence interval (CI), 5.4 to 10.8; p = 0.0001) and the ANF-right atrial pressure relation a slope of 13.6 pg/ml/mm Hg (CI, 8.5 to 18.7; p = 0.0001). Receiver operator curve analysis identified an optimal dividing point of ANF 150 pg/ml with 100% (CI, 72 to 100%) of patients with right atrial pressure greater than or equal to 8 mm Hg having ANF greater than or equal to 150 pg/ml, but only 56% (CI, 42 to 69%) with pressure less than 8 mm Hg having ANF less than 150 pg/ml. Unlike the patients with cardiomyopathy (with or without myocarditis), cardiac transplant recipients displayed no correlation between ANF level and either pulmonary arterial wedge pressure (p = 0.50) or right atrial pressure (p = 0.29) despite similarly elevated ANF concentrations (mean +/- standard deviation 168 (83) pg/ml in transplant patients versus 185 (114) pg/ml in cardiomyopathy patients). It is concluded that left and right intracardiac pressures are important determinants of circulating ANF level unaffected by inflammation in patients with cardiomyopathy.(ABSTRACT TRUNCATED AT 250 WORDS)     

Pulmonary arterial pressure and plasma concentration of atrial natriuretic factor (ANF) in patients with heart disease

To study the factors controlling the release of atrial natriuretic factor (ANF), we analyzed the peripheral plasma ANF concentration in 34 patients with heart disease who underwent cardiac catheterization. A significant positive correlation between plasma ANF concentration and pulmonary arterial pressure (systolic, r = 0.87; diastolic, r = 0.75; mean, r = 0.85; each p less than 0.001) was found in all the patients examined. There were significant positive correlations between plasma ANF concentration and systolic right ventricular pressure (r = 0.86, p less than 0.001), pulmonary capillary wedge pressure (r = 0.50, p less than 0.01) and mean right atrial pressure (r = 0.39, p less than 0.05). A weak but significant negative correlation was found between plasma ANF concentration and stroke volume index (r = -0.43, p less than 0.05). The correlation coefficient between plasma ANF concentration and mean pulmonary arterial pressure was significantly stronger than those between plasma ANF concentration and pulmonary capillary wedge pressure, and between plasma ANF concentration and mean right atrial pressure (p less than 0.05 and p less than 0.01, respectively). In 10 patients with mitral valvular disease, significant correlations with plasma ANF concentration were also found for pulmonary arterial pressure (systolic, r = 0.80; diastolic, r = 0.82; mean, r = 0.82; each p less than 0.01). These findings suggest that pulmonary arterial pressure may play an important role in the mechanism of release of ANF from atrial cardiocytes.     

Baseline and post-atrial pacing release of atrial natriuretic factor in mitral stenosis

To investigate the release of atrial natriuretic factor (ANF) in mitral stenosis and the influence of the increase on the frequency of atrial contraction or atrial distention on ANF secretion, we studied 10 patients with symptoms of congestive heart failure (New York Heart Association classes II and III) in sinus rhythm, who were undergoing cardiac catheterization as part of an evaluation workup for mitral stenosis. Echocardiographic tracings, repeat determinations of mean pulmonary artery wedge pressure (MPAWP) and mean right atrial pressure, and blood sampling from the pulmonary artery for measurements of ANF were performed at baseline, during atrial pacing (pacing rate of 125 beats/min for 5 minutes), and 5 minutes after the pacing protocol was completed. Baseline ANF levels were closely related to right atrial pressure (r = 0.89; p less than 0.001) and increased markedly after atrial pacing from 205.6 +/- 39.8 (SEM) to 343.9 +/- 57.9 (SEM) pg/ml. A similar pacing-induced increase was shown for MPAWP and left atrial size. Our data indicate that pacing-induced increases in atrial distention and intracavitary pressure further stimulate release of ANF. However, an independent effect of frequency of atrial pacing on plasma ANF in humans could not be identified.     

Atrial natriuretic factor, cardiac volumes and filling pressures during exercise in congestive heart failure.

To study the mechanism of atrial natriuretic factor (ANF) release in heart failure, we measured plasma ANF concentrations, cardiac volumes and filling pressures at rest and during three graded exercise levels (E1, E2, E3) in six male patients with congestive heart failure (CHF) and compared them with 13 normal male subjects. At rest, ANF concentrations were sixfold higher in patients with CHF than in normal subjects (at rest: 53 +/- 12 vs 8 +/- 1 pmol.l-1; P less than 0.02). End-systolic ventricular volumes were increased threefold in patients with CHF (P less than 0.02) despite normal mean central venous pressure, pulmonary artery pressure (PAP) and pulmonary wedge pressure (PWP). A positive correlation was found between end-systolic ventricular volumes and plasma ANF (r = 0.93, P less than 0.001). During exercise, ANF rose by 120% over basal values both in patients with CHF and in normal subjects (P less than 0.01). Volumes higher than normal in patients with CHF increased further at E2 (P less than 0.05) in contrast to a decrease of systolic volumes recorded in normal subjects (P less than 0.05). Filling pressures rising abnormally in patients with CHF correlated with plasma ANF during exercise (r = 0.53, P less than 0.02 for PAP; r = 0.51, P less than 0.05 for PWP). In conclusion, our data suggest that ANF release in CHF is regulated at rest by cardiac volumes when filling pressures are still normal. During exercise, ANF release is not impaired in CHF with normal rest filling pressures and is regulated during exercise by left filling pressures.     

Failure of atrial natriuretic factor to increase with volume expansion in acute and chronic congestive heart failure in the dog

It remains unclear whether the levels of atrial natriuretic factor (ANF) observed in chronic CHF are appropriate for the magnitude of elevations in atrial pressures. Specifically, it is not known whether acute increases in atrial pressure in CHF can result in further significant increases in circulating ANF. The present study was designed to test the hypothesis that in chronic CHF there is an attenuated relation between circulating ANF and atrial pressure such that the heart is unable to respond to further increases in atrial pressure with appropriate increases in ANF. Cardiovascular hemodynamics and plasma levels of ANF were measured at baseline and after rapid right ventricular pacing (RRVP) to produce acute (n = 10, 25 minutes RRVP) and chronic (n = 7, 14-16 days RRVP) CHF. Acute saline volume expansion was then performed in each group to determine the response of circulating ANF to acute increases in atrial pressure in both acute and chronic CHF. In chronic CHF, right atrial pressure was much higher than in acute CHF (8.5 +/- 0.9 vs. 3.4 +/- 1.3 mm Hg, p less than 0.05); however, circulating ANF was not greater in chronic as compared with acute CHF (385 +/- 73 vs. 500 +/- 89 pg/ml), which is consistent with an attenuated release of ANF in chronic CHF. In response to volume expansion, right atrial pressure increased in both acute (3.4 +/- 1.3 to 12.1 +/- 7 mm Hg) and chronic (8.5 +/- .9 to 13.3 +/- 1.0 mm Hg) CHF.(ABSTRACT TRUNCATED AT 250 WORDS)     

Clinical application of atrial natriuretic polypeptide in patients with congestive heart failure: beneficial effects on left ventricular function

Synthetic alpha-human atrial natriuretic polypeptide was infused in patients with congestive heart failure (CHF) (New York Heart Association class III or IV) and in those without CHF. The infusion of atrial natriuretic polypeptide (ANP) at a rate of 0.1 microgram/kg/min significantly decreased pulmonary capillary wedge pressure and increased stroke volume index in all of the patients with CHF, whereas it decreased pulmonary capillary wedge pressure but caused no significant change in stroke volume index in the patients without CHF. Concomitant significant reductions in total systemic resistance were observed in both groups of patients. The ANP infusion significantly increased the urine volume, the excretion of sodium, and endogenous creatinine clearance in the patients without CHF. In the patients with CHF, it also showed a tendency to increase all these variables, but the urine volume did not correlate with the reduction in pulmonary capillary wedge pressure. The ANP infusion also decreased plasma aldosterone concentrations in these patients, although no significant difference was observed in the decrement of the plasma aldosterone concentration in the patients with and those without CHF. These findings indicate that the ANP infusion improves left ventricular function in patients with CHF, and suggest that this improvement results mainly from the vasodilating activity of ANP.     

Low-dose infusion of atrial natriuretic factor in mild essential hypertension

Intra-arterial blood pressure, cardiac output, heart rate, right heart indexes, urinary electrolytes, and urinary volume were monitored in eight patients with untreated (WHO Class I) essential hypertension. The patients were given synthetic atrial natriuretic factor (ANF) (99-126 alpha-hANP) at 1 and 2 pmol/kg/min in series (phases 1 and 2, 2 hours each dose) or vehicle (hemaccel) in random order on two separate occasions while on their usual diet. Arterial plasma ANF levels increased significantly from basal and time-matched placebo values from 25 +/- 2 and 28 +/- 3 pmol/l to 50 +/- 4 and 83 +/- 9 pmol/l at the end of phases 1 and 2, respectively (p less than 0.001). After 30 minutes during phase 2, systolic blood pressure decreased significantly by 20 +/- 4 mm Hg (p less than 0.001) from basal and time-matched placebo values and remained significantly reduced (-17 +/- 4 mm Hg, p less than 0.001) by the end of the recovery period (2 hours after infusions were completed). Pulmonary systolic blood pressure decreased by 5 +/- 1 mm Hg (phase 2, p less than 0.05). Cardiac output decreased by 0.5 +/- 0.1 l/min below baseline at the end of phase 2 of ANF infusion, whereas it increased significantly (p less than 0.02) by 0.6 +/- 0.1 l/min during vehicle infusion. Systemic diastolic, pulmonary diastolic, right atrial, and wedge pressures were not significantly changed during ANF or vehicle infusions, nor were pulmonary vascular resistance or heart rate altered. Systemic vascular resistance did not change significantly during both infusions, whereas during recovery, systemic vascular resistance decreased significantly after ANF infusion was discontinued (p less than 0.05). Microhematocrit levels increased dose dependently during ANF. The maximum increase was observed at the end of phase 2 (+4.7 +/- 1.7%), whereas the microhematocrit level decreased to -2.4 +/- 0.6% with vehicle (p less than 0.001) at the end of phase 2. Urinary sodium excretion increased significantly (p less than 0.02) by the end of phase 2 under ANF infusion (+38 +/- 15%), whereas it decreased (-10 +/- 6%) under placebo infusion by the end of phase 2. Urinary magnesium excretion was significantly increased during ANF infusion from phase 1 (p less than 0.02), whereas urinary potassium levels, calcium levels, creatinine levels, volume, and glomerular filtration rate did not differ significantly between the two infusions. Plasma renin, angiotensin II, aldosterone, and catecholamine concentrations did not change significantly during ANF or vehicle infusions.(ABSTRACT TRUNCATED AT 400 WORDS)     

Comparative evaluation of isosorbide-5-mononitrate and nitroglycerin in chronic congestive heart failure

The hemodynamic effects of isosorbide-5-mononitrate (IS-5-MN) and nitroglycerin were compared in 10 patients with chronic congestive heart failure (CHF). Both drugs were given intravenously, at an infusion rate individually titrated to achieve a maximal increase in cardiac output and a maximal decrease in pulmonary capillary wedge pressure. Both drugs produced the typical hemodynamic responses to nitrates, the most prominent of which were decreases in pulmonary capillary wedge, pulmonary arterial and right atrial pressures, and an increase in cardiac output. Several differences in the response to these 2 drugs were observed. Pulmonary capillary wedge pressure was reduced from 31.5 +/- 3.0 to 19.6 +/- 5.0 mm Hg with nitroglycerin and to 15.0 +/- 3.12 mm Hg with IS-5-MN. Both the absolute and the percent decrease with IS-5-MN were significantly greater (p less than 0.05) than those observed with nitroglycerin. Mean systemic arterial pressure was reduced from 89.2 +/- 11.3 to 79.8 +/- 10.8 with IS-5-MN (difference not significant) and to 67.5 +/- 7.7 mm Hg with nitroglycerin (p less than 0.01). The difference, both in absolute and percent reductions, was statistically significant. Thus, in patients with chronic CHF, IS-5-MN produced a greater decrease in pulmonary capillary wedge pressure (the major beneficial effect of nitrates in this condition) and a smaller decrease in systemic arterial pressure (the potentially deleterious effects of nitrates). These findings indicate a potential advantage of IS-5-MN over nitroglycerin in patients with CHF, particularly in those with CHF of ischemic etiology.     

Atrial natriuretic factor during exercise in patients with congestive heart failure

In order to evaluate the potential relationship between atrial pressure development and release of atrial natriuretic factor (ANF), 33 patients with congestive heart failure were investigated with right-sided heart catheterization during supine graded bicycle exercise. Resting plasma ANF levels were higher in patients with heart failure as compared with normal controls, 75.1 +/- 45.6 pmol/l vs 12.3 +/- 6.2 pmol/l (mean +/- SD, N = 33 and N = 42, respectively) and correlated with right atrial, pulmonary arterial and pulmonary capillary wedge pressures. During exercise, central pressures rose steeply with a simultaneous increase in plasma ANF in all patients. Plasma ANF levels correlated with heart rate at a workload of 25 w, to pulmonary arterial and pulmonary capillary wedge pressure at 50 w, and to pulmonary capillary wedge pressure at 75 w. The increments in ANF levels between the different workloads during exercise did not correlate with the corresponding increments in pressure values. In congestive heart failure, the capability of ANF secretion in consequence to pressure stimuli is preserved, and left atrial pressure seems to be the major stimulus for ANF release during exercise.     

Rapidly developing tolerance to transdermal nitroglycerin in congestive heart failure

We have reported early attenuation of hemodynamic effects of transdermal nitroglycerin in patients with heart failure. We now report nitroglycerin plasma levels in those same patients. We administered transdermal nitroglycerin, 60 mg/24 h, to eight patients or placebo to seven patients in a double-blind fashion, and monitored pulmonary wedge pressure and nitroglycerin plasma levels for 24 hours. After placebo administration, nitroglycerin plasma levels and pulmonary wedge pressure remained unchanged. During transdermal nitroglycerin administration, the plasma nitroglycerin level rose from 0.04 +/- 0.12 ng/mL at baseline to near peak levels at 2 hours (7.43 +/- 7.21 ng/mL). Between 2 and 24 hours, levels fluctuated at a steady state. Pulmonary wedge pressure fell from 22 +/- 7 mm Hg at control to a nadir of 14 +/- 5 mm Hg at 4 hours (p less than 0.01). Despite persistently high plasma nitroglycerin levels, by 18 hours pulmonary wedge pressure was no longer significantly reduced (20 +/- 9 mm Hg). These results indicate that rapid development of tolerance is the cause of attenuated hemodynamic efficacy of transdermal nitroglycerin.     

Atrial natriuretic peptides in the diagnosis and treatment of congestive heart failure

Atrial natriuretic peptides (ANPs) consist of a family of peptides (atrial natriuretic factor [ANF], long acting natriuretic peptide, vessel dilator, kaliuretic peptide, urodilatin, brain natriuretic peptide [BNP], and C type natriuretic peptide [CNP]) which are synthesized within the heart, except for urodilatin. Of these natriuretic peptides, the vessel dilator radioimmunoassay (RIA) of a single plasma sample is the most sensitive and specific in the diagnosis of early (i.e., NYHA class I) congestive heart failure (CHF). Vessel dilator is beneficial in the treatment of CHF, enhancing of urine flow two- to 13-fold and sodium excretion three- to four-fold for 3 hours after stopping its infusion. This 37 amino acid peptide hormone simultaneously decreases systemic vascular resistance 24%, pulmonary vascular resistance 25%, pulmonary capillary wedge pressure 33%, and central venous pressure 27% while increasing cardiac output 34%, cardiac index 35%, and stroke volume index 24% in individuals with CHF. (c)1999 by CHF, Inc.     

Pulmonary extraction and left atrial secretion of atrial natriuretic factor during cardiopulmonary bypass surgery.

We have investigated the role of the lungs in the extraction of atrial natriuretic factor (ANF) by measuring plasma levels in samples taken from the central circulation in 12 patients (mean age 59 years; range 43 to 68) undergoing cardiac surgery. We also investigated the effects of cardiopulmonary bypass on ANF levels. ANF levels (mean +/- SD) were lower in pulmonary venous samples (41 +/- 20 pg/ml) than in pulmonary arterial samples (54 +/- 18 pg/ml; p less than 0.001), demonstrating 24% extraction of ANF by the lungs. Both left atrial (47 +/- 23 pg/ml) and systemic arterial levels (52 +/- 22 pg/ml) were higher than pulmonary venous levels (both p less than 0.05), indicating secretion of ANF into the left side of the heart. During cardiopulmonary bypass, plasma ANF concentration fell from 68 +/- 23 pg/ml before aortic cross-clamping to 35 +/- 13 pg/ml 10 minutes after and 28 +/- 9 40 minutes after the application of clamps (both p less than 0.001). A rebound rise to 122 +/- 33 pg/ml followed the release of the clamp (p less than 0.001). This study demonstrates that ANF is extracted by the lungs and secreted directly into the left side of the heart. The considerable fall in plasma levels that was observed during aortic cross-clamping might contribute to the neurohumoral activation and increased peripheral resistance observed after prolonged cardiopulmonary bypass and to the risk of renal ischemic injury.