Effect of beta blockade (carvedilol or metoprolol) on activation of the renin-angiotensin-aldosterone system and natriuretic peptides in chronic heart failure

Beta blockers are known to suppress renin release in hypertension and in patients taking angiotensin-converting enzyme (ACE) inhibitors. This study sought to explore the effect of additional beta blockade on neurohumoral modulation in patients with severe heart failure (HF) who received ACE inhibitors. Forty-nine patients with chronic HF who received ACE inhibitors were given metoprolol 50 mg or carvedilol 25 mg twice daily after a 4-week dose titration period in addition to standard therapy in a prospective trial. Samples of plasma renin activity (PRA), aldosterone, aminoterminal B-type natriuretic peptide (N-BNP), and atrial natriuretic peptide (ANP) were taken at baseline and at 4, 12, and 52 weeks after starting therapy. Treatment with either beta blocker significantly lowered PRA at 4 weeks compared with baseline (-2.0 +/- 0.6 nmol/L/hour, p = 0.006), but at 12 weeks, PRA had reduced to -1.1 +/- 0.6 nmol/L/hour (p = 0.08), but at 52 weeks, it was not significantly different from baseline (+1.05 +/- 0.6 nmol/L/hour, p = 0.13). Aldosterone levels did not change significantly from baseline at 4 or 12 weeks, although there was a nonsignificant trend for lower levels at 52 weeks (baseline 232 +/- 154 pmol/L, 52 weeks 192 +/- 100 pmol/L, p = 0.09). There was significant reduction in N-BNP and ANP together with an improvement in symptom and left ventricular systolic function at 1-year follow-up. These results indicate that the suppressive effect of beta blockers on PRA in patients with HF taking ACE inhibitors is temporary, and that there is no significant effect on serum aldosterone levels.     

Effectiveness of furosemide in uncontrolled hypertension in the elderly: role of renin profiling

BACKGROUND: Despite many advances in the treatment of hypertension, adequate blood pressure (BP) control in elderly patients continues to be a challenge. Optimal control of BP remains elusive because of issues relating to drug dosage and proper choice of therapeutic agents, including questions regarding the role of diuretics. METHODS: We examined the effect of diuretic treatment on BP in 12 elderly hypertensive patients whose hypertension was poorly controlled on previous drug regimens. We also evaluated the relationship of systolic, diastolic, and mean arterial BP (SBP, DBP, MAP, respectively) to changes in plasma renin activity (PRA), serum aldosterone (SA), atrial natriuretic peptide (ANP), and serum chemistries both before and after adding furosemide to the prior antihypertensive agents. RESULTS: At baseline, 83% of patients had low PRA (< 1 ng/mL/h). After furosemide, in 67% of patients, decreases in SBP (166 +/- 5 to 134 +/- 5 mm Hg; P <.001), DBP (82 +/- 4 to 71 +/- 4 mm Hg; P =.004), and MAP (111 +/- 3 to 92 +/- 3 mm Hg; P <.001), were associated with increases in PRA (2.1 +/- 1.2 to 5.1 +/- 1.8 ng/mL/h; P =.01) and SA (4.8 +/- 1.0 to 9.4 +/- 1.4 ng/dL; P =.01) and with decreases in ANP (101 +/- 28 to 58 +/- 11 pg/mL; P =.01) and body weight (77.5 +/- 3.6 to 76.4 +/- 3.3 kg; P =.02), findings consistent with volume mediated/salt sensitive hypertension. In the remaining 33% of patients, BP also decreased significantly, but there was no increase in PRA (0.15 +/- 0.05 to 0.10 +/- 0 ng/mL/h) or SA (9.2 +/- 2.2 to 7.0 +/- 0.8 ng/dL) and no decrease in ANP (66 +/- 5 to 75 +/- 18 pg/mL) (P = ns for all), suggesting alternate mechanisms for their responses. CONCLUSIONS: Many of the elderly hypertensive patients in our study had decreased PRA levels and showed significant reductions in BP after furosemide administration. Despite the associated increases in PRA and SA and decreases in ANP in 67% of patients, diuretic use remains important in the control of hypertension in this population.     

Furosemide and the progression of left ventricular dysfunction in experimental heart failure

OBJECTIVES: We tested the hypothesis that furosemide accelerates the progression of left ventricular systolic dysfunction in a tachycardia-induced porcine model of heart failure. BACKGROUND: Furosemide activates the renin-angiotensin-aldosterone system in patients with congestive heart failure (CHF). Such activation may contribute to CHF progression, but prospective data are lacking. METHODS: Thirty-two Yorkshire pigs were randomized to furosemide (1 mg/kg intramuscularly daily, mean 16.1 +/- 0.9 mg) or placebo. Thereafter, a pacing model of heart failure was utilized to produce systolic dysfunction in both sets of animals (fractional shortening <0.16 by echocardiogram). The goal was to determine if furosemide would accelerate the progression of left ventricular dysfunction in the "treated" group. After sacrifice, sodium-calcium exchanger currents and their responsiveness to isoproterenol were measured during voltage clamp. All investigators were blinded to treatment assignment. RESULTS: Furosemide shortened the time to left ventricular dysfunction (35.1 +/- 5.1 days in placebo versus 21.4 +/- 3.2 days for furosemide animals; p = 0.038, log-rank test). By day 14, aldosterone levels were significantly higher in furosemide animals (43.0 +/- 11.8 ng/dl vs. 17.6 +/- 4.5 ng/dl; p < 0.05). Serum sodium was reduced (133.0 +/- 0.9 mmol/l furosemide vs. 135.7 +/- 0.8 mmol/l placebo; p < 0.05), but no difference in norepinephrine, potassium, magnesium, creatinine, or urea nitrogen was present. Basal sodium-calcium exchanger currents were significantly increased and isoproterenol responsiveness depressed by furosemide. CONCLUSIONS: Tachycardic pigs given furosemide had significant acceleration of both contractile and metabolic features of CHF, including left ventricular systolic dysfunction, elevated serum aldosterone levels, and altered calcium handling in a controlled experimental model of heart failure.     

Hormonal responses to synthetic atrial natriuretic peptide in patients on regular hemodialysis

The effects of atrial natriuretic peptide (ANP) on mean arterial blood pressure, heart rate, plasma renin activity, aldosterone, cortisol, norepinephrine, epinephrine and arginine vasopressin were studied in 6 anuric subjects receiving regular hemodialysis. An iv bolus injection of 8 nmol of ANP followed by infusion at 32 pmol.kg-1.min-1 for 1 h in the pre- and posthemodialysis period was performed. Basal plasma ANP was higher before than after hemodialysis. ANP administration produced a reduction in mean arterial blood pressure accompanied by an elevation of norepinephrine and of plasma renin activity (from 2.49 +/- 0.52 to 3.39 +/- 0.85 nmol.1-1.h-1 predialysis and from 2.78 +/- 0.71 to 3.15 +/- 0.86 nmol.l-1.h-1 postdialysis, respectively, mean +/- SEM; P less than 0.05). Plasma aldosterone and cortisol were significantly decreased. Plasma epinephrine and AVP remained unchanged. These hemodynamic and hormonal changes were similar in the pre- and the postdialysis period. These results suggest that 1) ANP causes a fall in mean arterial blood pressure, which in turn induces reflex tachycardia and activation of the sympathetic nervous system without diuresis; 2) the activated sympathetic nervous system as reflected in elevation of plasma norepinephrine may increase plasma renin activity; 3) reduced plasma aldosterone is not influenced by enhancement of the renin-angiotensin system; therefore, 4) reduction of plasma aldosterone as well as cortisol is probably due to direct action of ANP, and finally 5) AVP had no direct relation with ANP administration.     

Increase in plasma concentrations of atrial natriuretic peptide during infusion of hypertonic saline in conscious newborn calves

Plasma concentrations of atrial natriuretic peptide (ANP), plasma renin activity (PRA), plasma concentrations of aldosterone, urine flow rate and sodium and potassium excretion were studied in two groups of four conscious 3-day-old male calves, infused with hypertonic saline or vehicle. Hypertonic saline infusion (20 mmol NaCl/kg body weight) was accompanied by a progressive rise in plasma concentrations of ANP (from 16.5 +/- 0.2 pmol/l at time 0 to 29.3 +/- 3.0 pmol/l at 30 min; P less than 0.05) and by a gradual decrease in PRA (from 1.61 +/- 0.23 nmol angiotensin I/l per h at time 0 to 0.54 +/- 15 nmol angiotensin I/l per h at 90 min; P less than 0.05); there was no change in the plasma concentration of aldosterone. Within the first 2 h of the 24-h urine collection period there was a marked rise in urine flow rate and sodium excretion in treated calves when compared with control animals (66.0 +/- 8.3 vs 15.9 +/- 1.2 ml/kg body weight per 2 h (P less than 0.05) and 6.7 +/- 1.3 vs 0.4 +/- 0.02 mmol/kg body weight per 2 h (P less than 0.01) respectively). During the following 22 h, urinary water and sodium excretion remained at significantly high levels. Thus, in the conscious newborn calf, changes in plasma ANP levels and urinary water and sodium excretion during hypertonic saline infusion are compatible with the hypothesis that endogenous ANP participates, at least in part, in the immediate diuretic and natriuretic renal response induced by the sodium overload.     

The acute response of plasma norepinephrine, renin activity, and arginine vasopressin to short-term nitroprusside and nitroprusside withdrawal in patients with congestive heart failure

Activation of the sympathetic nervous system, manifested by an increase in heart rate and circulating plasma norepinephrine, can occur in normal subjects when they are given vasodilators. The extent to which this activation occurs in patients with congestive heart failure (CHF) and whether this activation could account for the hemodynamic rebound sometimes observed following abrupt withdrawal of nitroprusside in such patients are unclear. We prospectively and retrospectively studied the effects of nitroprusside on plasma norepinephrine in 38 patients with CHF to determine if acute vasodilator therapy activates this vasoconstrictor system during or following such treatment. Thirty-six of these patients also had plasma renin activity (PRA) measured and plasma arginine vasopressin was measured in 12 patients. Baseline supine plasma norepinephrine (714 +/- 72 pg/ml, +/- SEM), PRA (15 +/- 2 ng/ml/hr), and arginine vasopressin (10 +/- 1 pg/ml) were increased at least twofold in the CHF patients. Nitroprusside (96 +/- 11 micrograms/min) was infused for 63 +/- 5 minutes after achieving an optimal hemodynamic response: cardiac index increased (2.01 +/- 0.08 to 2.67 +/- 0.1 L/min/m2, p less than 0.001), pulmonary artery wedge pressure decreased (25 +/- 1 to 16 +/- 1 mm Hg, p less than 0.001), mean arterial pressure decreased (83 +/- 1 to 72 +/- 1 mm Hg, p less than 0.001), and heart rate was unchanged. Plasma norepinephrine (632 +/- 43 pg/ml), PRA (18 +/- 3 ng/ml/hr), and arginine vasopressin (11 +/- 1 pg/ml) did not change significantly for the group during peak effect of the vasodilator.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of centrally administered atrial natriuretic peptide on renal functions

In order to assess the effects of centrally administered atrial natriuretic peptide (ANP) on renal water and electrolytes handling, arterial blood pressure, plasma vasopressin, renin activity, aldosterone, and ANP concentrations, synthetic alpha-human ANP (alpha-hANP) was administered intracerebroventricularly at a dose of 2.6 pmol.kg-1.min-1 for 30 min in pentobarbital-anaesthetized dogs (N = 6). In the control study (N = 6), artificial cerebrospinal fluid was infused. Intracerebroventricular administration of alpha-hANP increased significantly urine flow from 178 +/- 37 to 303 +/- 43 microliter/min (mean +/- SEM), sodium excretion from 27.3 +/- 8.9 to 54.4 +/- 10.5, mumol/min, potassium excretion from 16.1 +/- 3.7 to 24.0 +/- 5.1 mumol/min, and osmolar and negative free water clearances, accompanied by a significant rise in renal blood flow from 77.0 +/- 14.6 to 94.9 +/- 16.9 ml/min. Whereas glomerular filtration rate fell significantly, blood pressure and heart rate did not change. Plasma ANP, aldosterone, and PRA did not change significantly during the experiment, but plasma AVP were slightly but significantly decreased from 52 +/- 11 to 34 +/- 6 nmol/l. On the other hand, these parameters showed no changes in the control study, except a significant fall in glomerular filtration rate and a significant rise in PRA. Thus, it has been confirmed that ANP centrally brings about diuresis, natriuresis, and kaliuresis via some unknown mechanisms independent of the release of these hormones.     

The renin-angiotensin system in malignant hypertension revisited: plasma renin activity, microangiopathic hemolysis, and renal failure in malignant hypertension

BACKGROUND: Malignant hypertension is a renin-dependent form of hypertension. However, the variations in renin-angiotensin system (RAS) activation in malignant hypertension are not completely understood. A proposed mechanism for ongoing RAS activation is the presence of microangiopathic hemolysis resulting in renovascular ischemia. METHODS: We prospectively examined the association between plasma renin activity (PRA), microangiopathic hemolysis, and renal dysfunction in 30 consecutive patients with malignant hypertension (n=18) and severe hypertension (n=12). The PRA and aldosterone were measured in the supine position and before initiating therapy. RESULTS: The PRA was 8.8 ng angiotensin I (AI)/mL/h (interquartile range [IQR] 4.8-20) in malignant hypertensive patients and 2.8 ng AI/mL/h (IQR 0.6-6.3) in patients with severe hypertension (P<.01). Aldosterone was 1.30+/-1.02 nmol/L in patients with malignant hypertension compared with 0.44+/-0.37 nmol/L in those with severe hypertension (P<.01). In malignant hypertension, PRA highly correlated with lactic dehydrogenase (LDH) (r=0.76, P<.001), meaning that 58% of the variations in PRA could be explained by LDH. The PRA positively correlated with serum creatinine values at presentation (r=0.50, P=.007), but adjustment for LDH abolished the effect of PRA on creatinine (P=.24). CONCLUSIONS: The PRA and aldosterone were markedly elevated in patients with malignant hypertension but not in severely hypertensive patients despite small differences in blood pressure (BP). The strong logarithmic correlation between PRA, microangiopathic markers, and renal dysfunction suggests a renin-mediated acceleration of vascular damage and renal dysfunction in patients with malignant hypertension.     

Effects of acute water load, hypertonic saline infusion, and furosemide administration on atrial natriuretic peptide and vasopressin release in humans

A new specific RIA for alpha-human atrial natriuretic hormone (alpha hANP) was used to determine whether changes in plasma volume elicited by acute water loading, hypertonic saline infusion, and furosemide administration caused changes in ANP release and resultant changes in renal and cardiovascular function in normal subjects. In addition, changes in plasma arginine vasopressin (AVP), PRA, and aldosterone concentrations were studied simultaneously. Mean plasma alpha hANP and AVP levels were 51.3 +/- 16.0 (+/- SE) and 3.1 +/- 0.6 pg/ml, respectively, in the basal state. Plasma alpha hANP rose to 77.8 +/- 27.6 in response to a 4.5% increase in plasma volume induced by water loading, increased further to 134.1 +/- 28.9 in response to a 23% volume increase induced by hypertonic saline, and fell to 70.2 +/- 15.8 pg/ml in response to a decrease in plasma volume after furosemide treatment (P less than 0.01-0.05). On the other hand, plasma AVP fell to 1.8 +/- 0.1 pg/ml after the water load, rose to 4.1 +/- 0.6 after hypertonic saline, and rose further to 5.8 +/- 0.8 pg/ml after furosemide (P less than 0.01-0.05). Water and hypertonic saline loading decreased PRA, but plasma aldosterone concentrations did not change; subsequent furosemide administration increased both (P less than 0.01-0.05). Arterial pressure and heart rate did not change significantly. Increases in urinary Na excretion and osmolar clearances were associated with a rise in plasma alpha hANP after water loading and hypertonic saline infusion (P less than 0.01-0.05), but changes in urine flow were mainly associated with alterations in AVP release. associated with alterations in AVP release.     

Relation between major indices of prognosis in patients with chronic congestive heart failure: studies of maximal exercise oxygen consumption, neurohormones and ventricular function.

Peak exercise capacity (Peak VO2), neurohormonal changes, ventricular enlargement and ejection fraction are among the most important determinants of prognosis in congestive heart failure. However, the inter-relation between these parameters is unknown. We, therefore, correlated these indices in patients with hemodynamically severe congestive heart failure (NYHA class II, pulmonary artery wedge pressure 25 +/- 2 mm Hg, cardiac index 2.5 +/- 0.2 l/min/m2, ejection fraction 43 +/- 2% and fractional shortening 19 +/- 1%). Peak VO2 measured directly during exercise by breath to breath expiratory gas analysis using a metabolic cart was 23 ml/min/kg. Plasma epinephrine (E) and norepinephrine (NE) were measured by high performance liquid chromatography (HPLC) and plasma renin activity (PRA), aldosterone (Aldo), cortisol, prolactin, growth hormone, anti-diuretic hormone (ADH) and antinatriuretic peptide (ANP) by radioimmunoassay. Ejection fraction was measured by echocardiography. There was no relation between peak VO2 and any of the neurohormones E: r = -0.43, NE: r = -0.43, ANP: r = -0.49, Cortisol: r = -0.37, ADH: r = -0.07, Aldo: r = -0.45, 2 tail critical value 0.55. PRA showed a modest correlation (r = -0.61). Similarly, there was no relation between ejection fraction or degree of ventricular enlargement and any of the other indices (r = -0.05). We conclude that although peak VO2, neurohormonal profile and ventricular function are important individual prognostic determinants, there seems to be no direct relation between them.     

Dissociation of Plasma Atrial Natriuretic Peptide Responses to Upright Posture and Furosemide Administration in Patients with Normal-, Low Renin Essential Hypertension and Primary Aldosteronism

Plasma levels of atrial natriuretic peptide (ANP) were measured in patients with normal renin essential hypertension (n = 12), low renin essential hypertension (n = 11) and primary aldosteronism due to aldosterone producing adenoma (APA, n = 8) and idiopathic hyperaldosteronism (IHA, n = 3) after overnight rest in the supine position and after 4 h upright posture and furosemide administration. Plasma renin activity (PRA) and aldosterone (Aldo) levels were also determined. Compared to normal renin essential hypertension (33.6± 2.2 pg/ml), basal plasma ANP was significantly higher in low renin essential hypertension (66.8± 6 pg/ml), IHA (54.1± 6.3 pg/ml) and APA before (62.4± 4.9 pg/ml) but not after adrenal surgery (22± 3 pg/ml). After upright posture and furosemide administration plasma ANP was decreased (p < 0.01) in patients with low renin and, less markedly, with normal renin essential hypertension, however not in IHA and APA. In about half of the patients with low renin essential hypertension, unchanged PRA after upright posture and furosemide administration was associated with increased plasma Aldo and decreased ANP levels. We conclude that (i) the relatively high basal plasma ANP levels in low renin essential hypertension, IHA and APA may reflect the presence of volume expansion in these patients; (ii) the hormonal responses to upright posture and furosemide administration in patients with normal and low renin essential hypertension may indicate a counterregulatory role of ANP during activation of the renin-angiotensin-aldosterone system; (iii) the high plasma ANP, which is unresponsive to upright posture and furosemide administration, in patients with APA and IHA may be a potentially interesting new finding whose pathophysiological significance remains to be established.     

Renal and adrenal resistance against atrial natriuretic peptide in congestive heart failure: effect of angiotensin I-converting-enzyme inhibition

We compared the natriuretic and diuretic effect of an intravenous infusion of 1-28 human atrial natriuretic peptide (hANP) (0.1 micrograms/kg/min over 30 min) in 10 patients with congestive heart failure (CHF) and in 10 control subjects of similar age and sex. In the controls, urine volume rose from 36.8 +/- 8.55 to 115.6 +/- 34.2 ml/30 min and urinary sodium excretion from 4.55 +/- 0.8 to 11.2 +/- 2.24 mEq/30 min before and during the infusion of ANP, respectively. In patients, baseline urine volume and sodium output were similar, however, rise in urine volume and urinary sodium was greatly reduced during the infusion of hANP. In patients with CHF, baseline plasma ANP levels (604.1 +/- 135.3 vs. 39.4 +/- 5.85 pg/ml; p less than 0.005) and urinary excretion of cyclic GMP (cGMP) (41.8 +/- 5.22 vs. 15.2 +/- 4.19 nmol/30 min; p less than 0.05) were significantly elevated compared to controls. The absolute and relative rise in cGMP excretion, however, was blunted in patients with CHF. In the controls, angiotensin I-converting-enzyme (ACE) inhibition by enalapril significantly reduced the urinary output of sodium and water after ANP infusion. Plasma ANP levels and urinary cGMP remained unaltered by ACE inhibition. Furthermore, treatment with enalapril resulted in a rise in renin and a drop in aldosterone levels. The reduction of plasma renin and serum aldosterone by ANP was maintained after ACE inhibition. In the patient group, administration of enalapril (3 X 2.5 mg every 6 h) reduced ACE activity in the serum from 84.7 +/- 16.9 to 2.13 +/- 0.88 U/l. Arterial blood pressure was lowered from 114.7 +/- 6.69 to 106.1 +/- 7.25 mm Hg systolic and from 76.9 +/- 3 to 69.2 +/- 3.7 mm Hg diastolic. However, natriuresis and diuresis and creatinine clearance following infusion of ANP remained unaltered.     

Effects of amlodipine on sympathetic nerve traffic and baroreflex control of circulation in heart failure

Short-acting calcium antagonists exert a sympathoexcitation that in heart failure further enhances an already elevated sympathetic activity. Whether this is also the case for long-acting formulations is not yet established, despite the prognostic importance of sympathetic activation in heart failure. It is also undetermined whether in this condition long-acting calcium antagonists favorably affect a mechanism potentially responsible for the sympathetic activation, ie, the baroreflex impairment. In 28 heart failure patients (NYHA functional class II) under conventional treatment we measured plasma norepinephrine and efferent postganglionic muscle sympathetic nerve activity (microneurography) at rest and during arterial baroreceptor stimulation and deactivation induced by stepwise intravenous infusions of phenylephrine and nitroprusside, respectively. Measurements were performed at baseline and after 8 weeks of daily oral amlodipine administration (10 mg/d, 14 patients) or before and after an 8-week period without calcium antagonist administration (14 patients). Amlodipine caused a small and insignificant blood pressure reduction. Heart rate, left ventricular ejection fraction, and plasma renin and aldosterone concentrations were not affected. This was the case also for plasma norepinephrine (from 2.43+/-0.41 to 2.50+/-0.34 nmol/L, mean+/-SEM), muscle sympathetic nerve activity (from 54.4+/-5.9 to 51.0+/-4.3 bursts/min), and arterial baroreflex responses. No change in the above-mentioned variables was seen in the control group. Thus, in mild heart failure amlodipine treatment does not adversely affect sympathetic activity and baroreflex control of the heart and sympathetic tone. This implies that in this condition long-acting calcium antagonists can be administered without untoward neurohumoral effects anytime conventional treatment needs to be complemented by drugs causing additional vasodilatation.     

Atrial natriuretic peptide in patients with acute myocardial infarction without functional heart failure.

The purpose of the present study was to measure plasma levels of atrial natriuretic peptide (ANP) in patients with acute myocardial infarction without heart failure, and also to assess the temporal sequence of changes of plasma ANP during the first hours of recovery from myocardial infarction. The study was performed in 22 patients who were admitted to the Intensive Care Unit with the diagnosis of acute myocardial ischaemia that had an evolution of less than 6 h. Blood samples were drawn on admission and at 1, 8, and 24 h, and plasma concentrations of ANP, renin, aldosterone, epinephrine, norepinephrine and vasopressin were measured. Compared with control subjects, on admission patients showed increased plasma levels of ANP, as well as increased plasma renin activity (PRA), aldosterone, norepinephrine, epinephrine, dopamine, and antidiuretic hormone (ADH). ANP, but not renin or aldosterone plasma values, decreased with time, and there was a significant correlation between ANP and time after onset of pain. No increase in plasma creatinine was observed during the hospital stay, and the patients showed a negative fluid balance. No relationship was found between the location or extension of the infarction, or morphine treatment and ANP plasma levels. The high levels of ANP seem to counteract the haemodynamic and fluid-retention effects of the vasoconstrictive factors released after myocardial infarction.     

Longstanding atrial fibrillation causes depletion of atrial natriuretic peptide in patients with advanced congestive heart failure

BACKGROUND: Congestive heart failure (CHF) is characterized by neurohormonal activation, including increased plasma concentrations of atrial natriuretic peptide (ANP) and N-terminal ANP (N-ANP). Onset of atrial fibrillation (AF) further increases these peptides, but it may be hypothesized that concentrations decrease during longstanding AF due to inherent atrial degeneration. AIM: We sought to investigate the relation between neurohormonal activation in patients with CHF and the duration of concomitant AF. METHODS: The study group comprised 60 patients (age 70 +/- 8 years) with advanced CHF due to left ventricular systolic dysfunction (left ventricular ejection fraction (LVEF) < 0.35) and chronic AF (duration 21 (1-340) months). Plasma neurohormone concentrations were measured, and multiple regression analysis was performed to identify their clinical predictors. RESULTS: Median plasma neurohormone concentrations were: ANP 113 pmol/l, N-ANP 1187 pmol/l, norepinephrine 496 pg/ml, renin 127 micro units/l, aldosterone 128 pg/ml and endothelin 8.1 pg/ml. Norepinephrine, renin, aldosterone and endothelin were not significantly related to the duration of AF. In contrast, ANP decreased along with the duration of AF (P = 0.03), while the same trend was observed for N-ANP (P = 0.10). However, for these peptides a first order interaction with LVEF was present, which was not observed in the other neurohormones. In patients with LVEF > 0.25 ANP and N-ANP increased along with the duration of AF, whereas in patients with LVEF < or = 0.25 an inverse relation between ANP (P = 0.02) and N-ANP (P = 0.04) and the duration of AF was present, longer-standing AF being associated with lower concentrations. CONCLUSION: In patients with advanced CHF with low LVEF plasma ANP and N-ANP concentrations decrease during longstanding AF. This finding agrees with the concept that longstanding AF leads to impaired ability of the atria to produce these neurohormones due to inherent degenerative changes.     

The interaction of plasma renin activity and plasma atrial natriuretic peptide in 21-hydroxylase deficiency patients

Plasma renin activity (PRA) determination is the main index used to evaluate the mineralocorticoid control in 21-hydroxylase deficiency (21-OHD). PRA values within or at the upper limit of the age-appropriate range, or values <5 or 10 ng/ml/h have been regarded as adequate control. Atrial natriuretic peptide (ANP) has opposite actions to those of angiotensin II/aldosterone, and could help to understand the hydrosaline homeostasis in 21-OHD. We studied the interaction between PRA and ANP levels in 10 controls and 26 patients with 21-OHD under corticoid treatment. Patients were divided into two groups according to PRA levels, < or > or = 5 ng/ml/h, irrespective of the clinical form of 21-OHD. Blood samples for determination of PRA and ANP levels were taken after 30 min in the sitting position (basal), after 30 min in the recumbent position and after 15 min of 20 degrees head-down tilting. ANP levels (pg/ml) in the basal, supine and after head-down tilting position were 25.9 +/- 1.6, 42.7 +/- 7.4 and 54.3 +/- 5.5 in controls; 28.5 +/- 2.1, 38.3 +/- 2.1 and 48.8 +/- 4.1 in the group with PRA levels <5 ng/ml/h, and 20.9 +/- 1.9, 26.6 +/- 2.5 and 34.6 +/- 3.1 in the group with PRA levels > or = 5 ng/ml/h, respectively. Basal and after head-down tilting ANP plasma levels were similar between the controls and the group with PRA levels <5 ng/ml/h. However, the group of patients with PRA levels > or = 5 ng/ml/h showed lower basal and stimulated ANP levels compared to the control group (p<0.05). The decreased plasma ANP levels in the basal condition and after head-down tilting indicate a chronic contraction of the extracellular volume in 21-OHD patients with increased PRA levels. Therefore, mineralocorticoid deficiency is counteracted by decreased ANP secretion in order to preserve fluid and electrolyte homeostasis.     

Atrial natriuretic peptide, renin and aldosterone in obstructive lung disease and heart failure

Elevations of atrial natriuretic peptide (ANP) in congestive heart failure (CHF) and chronic obstructive lung disease (COLD) are presumably due to atrial hypertension, while secondary hyperaldosteronism in these patients is thought to result from diminished renal perfusion. The responsiveness of the ANP and renin (PRA)-aldosterone (PA) systems to acute increases in right atrial pressure has not been studied in these patients, but in normals a reciprocal relationship between ANP with PRA and PA has been shown. The authors monitored venous pressure (VP, reflective of right atrial pressure), ANP, PRA and PA in 15 stable COLD patients, seven stable CHF patients and three normal controls at baseline and after elevation of VP by antishock trousers. Inflation of the trousers resulted in increased VP and ANP (p less than 0.05): control ANP, 84 +/- 17 to 108 +/- 23 pg/ml; COLD ANP, 176 +/- 5 to 200 +/- 7; and CHF ANP, 388 +/- 20 to 499 +/- 37. PRA and PA were not suppressed by increasing ANP levels and the delta ANP/delta VP ratio was similar among groups. No intergroup differences in resting PRA and PA were noted, but PRA was higher (p = 0.007) and PA tended to be higher (p = 0.08) in a sub-group of six edematous patients, as compared with non-edematous patients and controls. These findings: (1) confirm previously reported ANP differences between COLD and CHF; (2) indicate that the ANP system remains responsive to physiologic manipulations in COLD and CHF; and (3) demonstrate that ANP and the PRA-PA axis are not reciprocally related in either group.     

Renin and aldosterone secretion under converting enzyme inhibition

The converting enzyme inhibitor (CEI) is known to inhibit the conversion of angiotensin I to angiotensin II. In order to analyse the regulatory mechanisms involved in aldosterone secretion independent of renin-angiotensin system, one of the CEIs, SQ 14,225 was infused to the dogs in association with several pharmacological agents. To the mongrel dogs under pentobarbital anesthesia, SQ 14,225 was administered intravenously as a bolus injection (0.5 mg/kg), followed by two hour infusion (0.5 mg/kg/hr). The effects of several pharmacological agents on plasma renin activity (PRA) and aldosterone concentration (PA) were examined in the condition in which endogenous angiotensin II production was blocked by CEI. PRA was increased significantly from the basal level (6.4 +/- 1.2; mean +/- SEM) to 14.1 +/- 2.6 ng/ml/hr 60 min after the administration of SQ 14,225. PA, on the other hand, was decreased from 12.2 +/- 3.6 to 7.6 +/- 2.2 ng/dl. The CEI-induced increase in PRA was completely blocked by infusion of angiotensin II (40 ng/kg/min), physiological saline (0.25 approximately 0.44 ml/kg/min), pretreatment of propranolol (0.5 mg/kg) or norepinephrine (200 ng/kg/min). Both pindolol and indomethacin had no significant effect on the CEI-induced increase in PRA. Increase in PRA was also observed by the infusion of furosemide, prostaglandin 1 or E1. PA was increased by KCl infusion (1.0 mEq/kg/hr), but was not affected significantly by the administration of furosemide, pindolol, prostaglandin A1 or E1, during the SQ 14,225 infusion. An elevation of PRA observed under the converting enzyme inhibition, was considered to be due to decreased feedback inhibition as a result of reduction of angiotensin II formation. It was suggested from the present results, that the CEI-induced increase in PRA might be mediated by beta-receptor and baroreceptor in addition to the direct negative feedback by angiotensin II. The present data also suggested that both furosemide and prostaglandins stimulated aldosterone secretion via the renin-angiotensin system, rather than by acting directly on the adrenal cortex.     

Neurohumoral activation, regulation of sodium excretion and vasodilator treatment in heart insufficiency]

BACKGROUND: The benefits of vasodilator therapy guided by hemodynamic goals in patients with severe heart failure (HF) are well documented. Nevertheless, therapy induced arterial underfilling may activate compensatory neurohumoral mechanisms and sodium retention. OBJECTIVES: To evaluate the effect of vasodilator therapy on neurohumoral activation and sodium excretion in severe HF patients submitted to tailored therapy guided by hemodynamic parameters. METHODS: Ten male patients (aged 70.2 +/- 2.9 years) with severe HF (left ventricle ejection fraction = 15.2 +/- 1.1%) were evaluated according to hemodynamic parameters and plasma levels of brain natriuretic peptide (BNP), norepinephrine, aldosterone, plasma renin activity (PRA), sodium and creatinine and urinary levels of sodium and creatinine, prior to beginning of nitroprusside therapy, every six hours thereafter (for 24 hours) and again after five days of inhibition of angiotensin converting enzyme (ACE) with lisinopril. RESULTS: Nitroprusside therapy caused marked increase in cardiac index and substantial reduction in systemic vascular resistance index. Plasma levels of BNP failed significantly while those of PRA, aldosterone and norepinephrine markedly rose, causing substantial reduction of sodium urinary excretion. There were no changes in renal function. Following ACE inhibition by lisinopril, BNP and sodium plasma levels rose, but BNP values remained significantly lower than the initial ones. Norepinephrine and aldosterone returned to base levels and PRA rose sharply. There was an intense natriuretic response and significant elevation of urinary volume. Urinary creatinine and creatinine clearance decreased non-significantly. CONCLUSIONS: Our results show that intensive vasodilator therapy in patients with severe HF improves hemodynamic parameters and causes activation of renin-angiotensin-aldosterone and adrenergic systems, resulting in sodium retention. Nevertheless, this neurohumoral activation is reversed by ACE inhibitors, thus supporting the "wide spectrum" neurohumoral modulation role attributed to these drugs.     

Plasma adrenocorticotrophin, cortisol and aldosterone responses to ovine corticotrophin-releasing factor and vasopressin in sheep

Ovine corticotrophin-releasing factor (oCRF) (1 microgram/kg) and arginine vasopressin (AVP) (1 microgram/kg) were injected iv in sheep, both separately and in combination. Plasma levels of immunoreactive ACTH (IR-ACTH), cortisol, and aldosterone were measured for 3 h after the injections. Mean levels before injections were 8 +/- 4 pmol/l for ACTH, 7 +/- 3 nmol/l for cortisol, and 28 +/- 9 pmol/l for aldosterone. CRF caused a rapid rise in IR-ACTH and a peak level of 125 +/- 52 pmol/l was obtained 15 min after injection. Highest values for cortisol and aldosterone levels were 40 +/- 9 nmol/l and 64 +/- 13 pmol/l, respectively, 30 min after injection. AVP also increased IR-ACTH (maximum level: 202 +/- 77 pmol/l at 5 min) and aldosterone (128 +/- 36 pmol/l at 15 min), whereas the cortisol increase was lower than after CRF. Simultaneous injection of CRF and AVP produced an addition of the IR-ACTH response (295 +/- 82 pmol/l at 15 min), but the changes in cortisol levels were similar to those obtained after CRF alone and those in aldosterone levels resembled those induced by AVP alone. Plasma Na and K, osmolality, and plasma renin activity (PRA) were not modified by either CRF or AVP. It is suggested that the increase in aldosterone levels after CRF could be mediated by ACTH and that after AVP by an IR-ACTH peptide with less effect on cortisol secretion.