Plasma Atrial Natriuretic Factor Levels Research Articles

Non-Invasive Ultrasound Modulation of Solitary Tract Nucleus Exerts a Sustainable Antihypertensive Effect in Spontaneously Hypertensive Rats.

We applied the method of non-invasive ultrasound (US) neuromodulation to regulate blood pressure (BP) by stimulating the solitary tract nucleus (NTS) of spontaneously hypertensive rats (SHRs). The rats were exposed to US stimulation for 20 mins every day for two months. Morphology and function of the hypertensive target organs (heart and kidney) were then examined by echocardiography and immunohistochemical staining. C-fos immunofluorescence assays were used to evaluate neuronal activity in the US stimulated areas and to explore related neural pathways. Moreover, the effects of US stimulation on biochemical indicators angiotensinII (ANGII), aldosterone (Aldo), endothelin-1 (ET-1), atrial natriuretic factor (ANF), cortisol (Cor) in SHRs were detected. In addition, HE, TUNEL, and Nissl staining were performed to evaluate the safety of long-term transcranial US stimulation. After two months of US stimulation, systolic blood pressure (SBP) decreased from 170 ± 1.1 mmHg to 158 ± 1.8 mmHg, p < 0.01. What's more, US stimulation effectively inhibited the pathological process of target organs from both morphological and functional levels. With US stimulation, neuronal activities were also significantly enhanced in the NTS, ventrolateral periaqueductal gray (vlPAG), and the caudal ventrolateral medulla (CVLM) region. And US stimulation did not cause brain tissue damage. Meanwhile, the plasma levels of ANF, ANGII, Aldo, and Cor content were inhibited. US stimulation of the NTS could significantly lower BP in SHRs. Non-invasive transcranial US stimulation acting on the NTS might be a potential therapeutic intervention due to its efficacy and safety.

Uncoordinated regulation of atrial natriuretic factor and brain natriuretic peptide in lipopolysaccharide-treated Rats

We investigated the expression and secretion of the natriuretic peptides (NPs) ANF and BNP in lipopolysaccharide (LPS)-induced sepsis and its association with cytokines and other biologically active substances. LPS treatment increased plasma levels of ANF and BNP. The latter increase was larger than the increase in plasma ANF. LPS also increased cardiac content and gene expression of BNP but not of ANF. LPS treatment significantly increased gene expression cytokines, chemokines and proteases, which significantly correlated with BNP gene expression. SB203580, a p38 MAP kinase inhibitor, inhibited the elevation of BNP in plasma. The present work suggests that during inflammation, BNP gene expression and secretion is uniquely related to changes in gene expression in the absence of hemodynamic changes and hence differentiates ANF and BNP as biomarkers of cardiac disease.

Role of potassium channels in stretch-promoted atrial natriuretic factor secretion

The cardiac polypeptide hormone atrial natriuretic factor (ANF) plays important roles in the regulation of blood volume and pressure. Few specific details are known about basal or stretch-promoted ANF secretion. Here, we investigated the involvement of K + channels in ANF secretion based on investigations of their nature as revealed by oligonucleotide microarray analysis and on protein-protein interactions evidenced by a yeast two-hybrid approach using a heterotrimeric Gαo-1 G protein subunit, which is particularly abundant in the atrium. Based on these data, we investigated the effect of drugs known to pharmacologically affect the function of specific K + channels on ANF secretion from the isolated rat atrium. These included adenosine triphosphate-sensitive K + channels, TWIK-related K + channel 1 (TREK-1), and the Ca +2-activated intermediate conductance K + channel (SK4). The sulfonylurea ligands tolbutamide and repaglinide, but not glibenclamide, increased stretch-promoted ANF secretion. The channel openers diazoxide, pinacidil, and cromakalim all decreased this type of stimulated ANF secretion. TRAM 34, a specific SK4 inhibitor, and oleylamine, a nonspecific TREK-1 inhibitor, significantly decreased or increased respectively, both basal and stretch-stimulated ANF secretion. Inhibition of Gi/o by pretreatment with Pertussis toxin often significantly affected the effect of these treatments. We concluded that the atria express K + channels that are related to Gi/o protein signaling and that significantly affect the endocrine function of the heart. These findings are significant for the development of therapeutic drugs with properties related to the manipulation of ANF plasma levels.

Modification of atrial natriuretic factor by the AV transmission time in pacemaker patients

The possible relationship of variations in the programmed a-v interval on the peripheral-venous plasma level of the atrial natriuretic factor (ANF) was investigated in nine patients with dual-chamber pacemakers (DDD). During atrial and ventricular stimulation at 82 beats/min the pacemakers of the resting patients were programmed to give successive a-v intervals of 200, 175, 150, 125, 100, 50 and 15 ms. Blood samples were obtained from a peripheral arm vein ten minutes after each change of programme. ANF was extracted from each sample and determined by radioimmunoassay. Both the absolutely and relatively lowest plasma ANF level was obtained at an a-v interval of 175 ms. Lengthening the interval to 200 ms or shortening it to 150 ms or less increased the level. It is possible that both "too long" and "too short" a-v intervals produce an increase in atrial pressure and stretch, to which ANF reacts highly sensitively with an increase in peripheral-venous plasma levels of ANF.

Neuroendocrine Profiling of Humans Receiving Cardiac Allografts

Several studies have investigated changes in circulating hormones and markers of cardiac status after heart transplantation in humans. As a result, plasma levels of various hormones and autocoids have been associated with cardiac allograft rejection status. However, no clear associations can be defined given the highly contradictory nature of the available literature. In this study of 69 consecutive heart transplant patients followed for >2 years we examine the relationship between neurohumors potentially related to allograft rejection and endomyocardial biopsy grade of rejection (according to the ISHLT) and hemodynamic status. Markers assessed include brain natriuretic peptide (BNP), amino-terminal pro-BNP (N-BNP), atrial natriuretic factor (ANF), adrenomedullin, interleukin-1beta, interleukin-6, tumor necrosis factor-alpha, troponin C and C-reactive protein. The highest plasma levels for most neurohumors were found shortly after surgery and showed a trend towards normalization with time. BNP and N-BNP were the only significantly elevated plasma analytes for patients with Grade 3 rejection as compared with other ISHLT grades. ANF plasma levels correlated with BNP and N-BNP in Grades 0 to 2, but not in Grade 3, suggesting that in this rejection grade the usual coordinated changes observed in BNP and ANF secretion no longer exist. Cardiac filling pressures were correlated with plasma BNP, N-BNP and ANF levels only for Grades 0 and 1. The timing of blood sampling after transplantation influences the level of the neurohumors measured, which may help explain the conflicting literature reports on the association between neurohumor levels and rejection grade. The significant increase in circulating levels of BNP and N-BNP observed in most cases of Grade 3 rejection occurred with no apparent relationship to post-transplantation time, which suggests a specific influence of acute rejection on BNP gene expression.

Oligopeptidase B from Trypanosoma evansi: A PARASITE PEPTIDASE THAT INACTIVATES ATRIAL NATRIURETIC FACTOR IN THE BLOODSTREAM OF INFECTED HOSTS

Serine oligopeptidases of trypanosomatids are emerging as important virulence factors and therapeutic targets in trypanosome infections. We report here the isolation and characterization of oligopeptidase B (OpdB) and its corresponding gene from Trypanosoma evansi, a pathogen of significant veterinary importance. The T. evansi opdB gene was present as a single copy per haploid genome containing an open reading frame of 2148 bp encoding a protein of 80.664 kDa. Purified OpdB hydrolyzed substrates with basic residues in P1 (k(cat)/K(m) for carbobenzyloxy-L-arginyl-L-arginyl-7-amido-4-methylcoumarin, 337 s(-1) x microm(-1)) and exhibited potent arginyl carboxypeptidase activity (k(cat)/K(m) for Val-Lys-Arg Arg-OH, 231 s(-1) x mM(-1)). While not secreted, T. evansi released OpdB into the plasma of infected hosts where it retained catalytic activity. Plasma OpdB levels correlated with blood parasitemia. In vitro, OpdB cleaved the peptide hormone atrial natriuretic factor (ANF) at four sites: Arg3 Arg4, Arg4 Ser5, Arg11 Ile12, and Arg27 Tyr28, thereby abrogating smooth muscle relaxant and prohypotensive properties of ANF. Circulating plasma ANF levels in T. evansi-infected rats were depressed from 130 to 8 pg x ml(-1), and plasma ANF levels inversely correlated with plasma OpdB activity. The in vitro half-life of ANF in rat plasma was reduced 300-fold in plasma from T. evansi-infected rodents, which contains high levels of OpdB activity. Addition of OpdB inhibitors to cell-free plasma from infected rodents significantly abrogated this ANF hydrolysis. Furthermore the in vivo ANF half-life was reduced 5-fold in T. evansi-infected rats. Thus, we propose a role for OpdB in peptide hormone dysregulation in trypanosomiasis, specifically in generating the depressed plasma levels of ANF in mammals infected with T. evansi.

Natriuretic peptides as prognostic and diagnostic markers in Chagas' disease

Atrial natriuretic factor (ANF) is a hormone secreted predominantly from atrial myocardium in response to changes in wall tension. Chagas' disease is caused by the parasite Trypanosom cruzi (T. cruzi), the heart being one of the most affected organs, resulting in myocarditis and chronic cardiomyopathy. The inflammatory response of the myocardium may be the result of factors such as ischemia, direct parasite invasion, and autoimmune mechanisms. In this review, we discuss the current knowledge about ANF in Chagas' disease and describe our findings in studying: (1) the development of chagasic cardiomyophathy in T. cruzi-infected rats and its relationship with plasma ANF levels; (2) the evolution of plasma ANF in chagasic patients in different stages (asymptomatic, with conduction defects and with chronic heart failure [CHF]); and (3) the possible usefulness of plasma ANF as a prognostic factor of development of myocardial compromise and survival. In rats, the elevated ANF levels found could mirror the inflammatory response of myocardial cells to acute T. cruzi infection and of progressive failure of cardiac function in the chronic infection. In patients, plasma ANF could be a sensitive marker capable of detecting gradual impairments in cardiac function and poor survival in CHF patients and of myocardiopathy development in the asymptomatic state.

Attenuated ANF Response to Exercise in Athletes with Exercise-Induced Hypoxemia

Some highly trained endurance athletes develop an exercise-induced hypoxemia (EIH) at least partially due to a hemodynamic factor with a potential stress failure on pulmonary capillaries. Atrial natriuretic factor (ANF) is a pulmonary vasodilatator and its release during exercise could be reduced with endurance training. We hypothesized that athletes exhibiting EIH, who have a greater training volume than non-EIH athletes, have a reduced ANF release during exercise explaining the pathophysiology of EIH. Ten highly trained EIH-athletes (HT-EIH), ten without EIH (HT-nEIH), and nine untrained (UT) males performed incremental exercise to exhaustion. No between group differences occurred in resting ANF plasma levels. In contrast to HT-nEIH and UT (p < 0.05), HT-EIH showed a smaller increase in ANF concentration between rest and maximal exercise (HT-EIH: 8.12 +/- 0.69 vs. 14.1 +/- 1.86 pmol x l (-1); HT-nEIH: 10.46 +/- 1 vs. 18.7 +/- 1.8 pmol x l (-1); UT: 6.23 +/- 0.95 vs. 20.38 +/- 2.79 pmol x l (-1)). During the recovery, ANF levels decreased significantly in HT-nEIH and UT groups (p < 0.05). Electrolyte values increased in all groups during exercise but were higher in both trained groups. In conclusion, this study suggested that ANF response to exercise may be important for exercise-induced hypoxemia.

Echocardiographic features of Radiation-Associated valvular disease

1. Gandhi SK, Powers JC, Nomier AM, Fowle K, Kitzman DW, Rankin KM, Little WC. The pathogenesis of acute pulmonary edema associated with hypertension. N Engl J Med 2001;344:17–22. 2. Fontana F, Bernardi P, Pich EM, Capelli M, Bortoluzzi L, Spampinato S, Canossa M. Relationship between plasma atrial natriuretic factor and opioid peptide levels in healthy subjects and in patients with acute congestive heart failure. Eur Heart J 1993;14:219–225. 3. Pohar B, Horvat M. Influence of hemodynamic changes on neuroendocrine response in acute heart failure. Int J Cardiol 1997;60:263–271. 4. Geppert A, Zorn G, Heinz G, Huber K, Siostrzonek P. Soluble selctins in the pulmonary and systemic circulation in acute cardiogenic and non-cardiogenic pulmonary failure. Intensive Care Med 2001;27:521–527. 5. Sato Y, Takaysu Y, Kataoka K, Yamada T, Taniguchi R, Sasayama S, Matsumori A. Serial circulating concentrations of C-reactive protein, interleukin (IL)-4 and IL-6 in patients with acute left heart decompensation. Clin Cardiol 1999;22:811–813. 6. Cotter G, Moshkovitz Y, Kaluski E, Nobikov Y, Scneeweiss A, Krakover R, Vered Z. The role of cardiac power and systemic vascular resistence in the pathophysiology and diagnosis of patients with acute congestive heart failure. Eur J Heart Fail 2003; in press. 7. Cotter G, Moshkovitz Y, Milovanov O, Salah A, Blatt A, Krakover R, Vered Z, Kaluski E. Acute congestive heart failure: a novel approach to its pathogenesis and treatment (review). Eur J Heart Failure 2002;4:227–234. 8. Orus J, Roig E, Villa FP, Pare C, Azqueta M, Fiella X, Heras M, Sanz G. Prognostic value of serum cytokines in patients with congestive heart failure. J Heart Lung Transplant 2000;19:419–425. 9. Rauchhaus M, Doehner W, Francis DP, Davos C, Kemp M, Liebenthal C, Niebauer J, Hooper J, Volk HD, Coats AJS, Anker SD. Plasma cytokines parameters and mortality in patients with chronic heart failure. Circulation 2000;102:3060–3067. 10. Maeda K, Tsutamoto T, Wada A, Mabuchi N, Hayashi M, Tsutsui T, Ohnishi M, Sawaki M, Fujii M, Matsumoto T, Kinoshita M. High levels of plasma brain natriuretic peptide and interleukin-6 after optimized treatment for heart failure are independent risk factors for morbidity and mortality in patients with congestive heart failure. J Am Coll Cardiol 2000;36:1587–1593. 11. Tsutamoto T, Hisanaga T, Wada A, Maeda K, Ohnishi M, Fukai D, Mabuchi N, Sawaki M, Kinoshita M. Interleukine-6 spillover in the peripheral circulation increases with the severity of heart failure, and the high plasma level of interleukine-6 an important prognostic predictor in patient with congestive heart failure. J Am Coll Cardiol 1998;31:391–398.

Behavior of atrial natriuretic factor in an experimental model of Trypanosoma cruzi infection in rats.

Enhanced atrial natriuretic factor (ANF) production by the heart is related to hemodynamic overload, cardiac growth, and hypertrophy. The heart is one of the most affected organs during Trypanosoma cruzi infection. We tested the hypothesis that myocarditis produced by parasite infection alters the natriuretic peptide system by investigating the behavior of plasma ANF during the acute and chronic stages of T. cruzi infection in rats. Sprague-Dawley rats were infected with T. cruzi clone Sylvio-X10/7. Cardiac morphology showed damage to myocardial cells and lymphocyte infiltration in the acute phase; and fibrosis and cell atrophy in the chronic period. Plasma ANF levels (radioimmunoassay) were significantly higher in acute (348 +/- 40 vs. 195 +/- 36 pg/ml, P < 0.05, n = 17) and chronic T. cruzi myocarditis (545 +/- 81 vs. 229 +/- 38 pg/ml, P < 0.001, n = 11) than in their respective controls (n = 10 and 14). Rats in the chronic phase also showed higher levels than rats in the acute phase (P < 0.01). The damage of myocardial cells produced by the parasite and the subsequent inflammatory response could be responsible for the elevation of plasma ANF during the acute period of T. cruzi infection. The highest plasma ANF levels found in chronically infected rats could be derived from the progressive failure of cardiac function.

Modulation of cardiac natriuretic peptide gene expression following endothelin type A receptor blockade in renovascular hypertension.

Increased expression of the cardiac natriuretic peptides (NP), atrial natriuretic factor (ANF) and brain natriuretic peptide (BNP) is observed during chronic hemodynamic overload. The mechanisms underlying this process are not fully understood. In vitro, endothelin 1 (ET-1) is a powerful stimulator of cardiac NP and, therefore, has been assumed to be one possible mediator of increased NP gene expression following chronic pressure or volume overload. In the present work we investigated the possible role of ET-1 in mediating the observed upregulation of cardiac NP in two kidney-one clip (2K-1C) Goldblatt hypertensive rats treated for 6 weeks with the ET-1 type A (ET(A)) receptor subtype receptor antagonist ABT-627. 2K-1C hypertension was induced in male Sprague-Dawley rats weighing 100-125 g by placing a silver clip (internal diameter 0.25 mm) around the left renal artery through a flank incision. The right kidney was left undisturbed. Sham operated rats underwent the same experimental procedures but no clip was placed on the left renal artery. ABT-627 was administered (10 mg/kg per day) in the drinking water for 6 weeks. In hypertensive rats, ABT-627 prevented a further rise in blood pressure beginning at 3 weeks after clipping and reduced the ventricular hypertrophy observed at the end of the experiment. ET(A) blockade prevented enhanced NP gene expression in the right ventricle and partially prevented it in the left ventricle. No modifications in atrial NP gene expression were observed in either control or 2K-1C animals. ET(A) blockade decreased BNP circulating levels but did not affect ANF plasma levels in clipped rats. ABT-627 increased alpha-myosin heavy chain gene expression and decreased the abundance of the beta isoform transcript. The results obtained in the present investigation show the participation of ET-1 in the increased expression of ventricular NP in 2K-1C renovascular hypertension and an apparent lack of effect of ET(A) blockade on atrial NP gene expression in both control and hypertensive animals thus showing that in vivo, atrial and ventricular NP gene expression are differentially regulated.

Hormonal response to dobutamine cardiac stress testing in a conscious canine model of early left ventricular dysfunction induced by chronic rate overload

The aims of this study were to investigate (1) hormonal activation before and during dobutamine cardiac stress testing (DST) in a canine model of early left ventricular dysfunction (ELVD) induced by rapid right ventricular pacing (RRVP) and (2) the relationship between this hormonal profile and carnitine concentrations. Before the pacing period, the 6 dogs were assigned to 2 groups according their baseline total plasma carnitine concentration. A DST was performed on each dog before activation of the pacemaker and every 3 to 4 days during development of 3 progressive stages of ELVD (stages 1, 2 and 3). Plasma atrial natriuretic factor (ANF), angiotensin II (ANG II) and endothelin-1 (ET-1) levels were measured at the start and at the end of each DST. Effects of ELVD, DST and plasma carnitine concentration on these measurements were tested. The RRVP induced a significant increase of ANF and ANG II and a non significant trend toward increase of ET-1 in all dogs. Before the pacing period, ANF remained constant during the DST in dogs with normal total plasma carnitine concentration, while it significantly decreased in dogs with low total plasma carnitine concentration. Dobutamine stress testing induced a significant decrease in ANF in all dogs in ELVD. Dobutamine infusion induced a significant increase in ANG II in all dogs before as well as during the pacing period while ET-1 was unchanged. These results suggest that investigation of the hormonal profile before and after a dobutamine challenge might provide important diagnostic information in dogs with asymptomatic or mildly symptomatic cardiac dysfunction of different origins.

Mechanisms of hypertension in patients with chronic obstructive pulmonary disease and acute respiratory failure

PURPOSE: To investigate the effects of hypoxemia, hypercapnia, and cardiovascular hormones (norepinephrine, endothelin-1, and atrial natriuretic factor) on blood pressure during acute respiratory failure. PATIENTS AND METHODS: Patients with chronic obstructive pulmonary disease and acute respiratory failure were divided into four groups of 10 patients each: hypoxemia-normocapnia, hypoxemia-hypercapnia, hypoxemia-hypocapnia, and normoxemia-hypercapnia. Plasma norepinephrine levels were determined by high-performance liquid chromatography with electrochemical detection. Plasma endothelin-1 and atrial natriuretic factor levels were radioimmunoassayed after chromatographic preextraction. RESULTS: Systolic blood pressure and cardiovascular hormone levels were greater in patients with hypercapnia (whether or not they also had hypoxemia) than in those with normocapnia and hypoxemia. For example, in patients with hypercapnia and normoxemia, the mean (± SD) systolic blood pressure was 183 ± 31 mm Hg and the mean norepinephrine level was 494 ± 107 pg/mL, as compared with 150 ± 6 mm Hg and 243 ± 58 pg/mL in those with normocapnia and hypoxemia (both P <0.05). Similar results were seen for endothelin-1 and atrial natriuretic factor levels, and for the comparisons of hypoxemic patients who were hypercapnic with those who were normocapnic. CONCLUSIONS: These results suggest that blood carbon dioxide levels, rather than oxygen levels, are responsible for hypertension during acute respiratory failure, perhaps as a result of enhanced sympatho-adrenergic activity.

Effect of nitric oxide synthase inhibition on cardiovascular and hormonal regulation during pregnancy in the rat

Recent studies have shown that nitric oxide (NO) biosynthesis increases in pregnancy and that inhibition of nitric oxide synthase (NOS) induces some pathological processes characteristic of preeclampsia. The current project sought to study the effect of the NOS inhibitor Nomega-nitro-L-arginine methyl ester (L-NAME, 10 microg x min(-1), sc for 7 days) on plasma volume, plasma atrial natriuretic factor (ANF), plasma endothelin-1 (ET), and plasma renin activity (PRA) during gestation in conscious rats. NOS inhibition caused mean arterial pressure to increase in both virgin and 21-day pregnant rats. Plasma volume fell in the pregnant rats [L-NAME, 4.5 +/- 0.3 mL x 100 g(-1) body wt. (n = 7) vs. D-NAME, 6.8 +/- 0.2 mL x 100 g(-1) body wt. (n = 10); P < 0.05] but not in the virgin rats [L-NAME, 4.3 +/- 0.1 mL x 100 g(-1) body wt. (n = 6) vs. D-NAME, 4.8 +/- 0.2 mL x 100 g(-1) body wt. (n = 8)]. There was no effect of NOS inhibition on plasma ANF levels or PRA in either the virgin or pregnant rats. However, L-NAME did decrease plasma ET levels in the pregnant rats [L-NAME, 19.6 +/- 1.6 pg x mL(-1) (n = 8) vs. D-NAME, 11.6 +/- 2.5 pg x mL(-1) (n = 9); P < 0.05]. Our results confirm that NO is involved in cardiovascular homeostasis in pregnancy; NOS inhibition selectively reduces plasma volume in pregnant rats, thus mimicking a major pathophysiological perturbation of preeclampsia. However, it does not induce the hormonal changes characteristic of preeclampsia, namely the decrease in PRA and increase in plasma ET and ANF levels.

Effect of nitric oxide synthase inhibition on cardiovascular and hormonal regulation during pregnancy in the rat

Recent studies have shown that nitric oxide (NO) biosynthesis increases in pregnancy and that inhibition of nitric oxide synthase (NOS) induces some pathological processes characteristic of preeclampsia. The current project sought to study the effect of the NOS inhibitor Nomega-nitro-L-arginine methyl ester (L-NAME, 10 microg x min(-1), sc for 7 days) on plasma volume, plasma atrial natriuretic factor (ANF), plasma endothelin-1 (ET), and plasma renin activity (PRA) during gestation in conscious rats. NOS inhibition caused mean arterial pressure to increase in both virgin and 21-day pregnant rats. Plasma volume fell in the pregnant rats [L-NAME, 4.5 +/- 0.3 mL x 100 g(-1) body wt. (n = 7) vs. D-NAME, 6.8 +/- 0.2 mL x 100 g(-1) body wt. (n = 10); P < 0.05] but not in the virgin rats [L-NAME, 4.3 +/- 0.1 mL x 100 g(-1) body wt. (n = 6) vs. D-NAME, 4.8 +/- 0.2 mL x 100 g(-1) body wt. (n = 8)]. There was no effect of NOS inhibition on plasma ANF levels or PRA in either the virgin or pregnant rats. However, L-NAME did decrease plasma ET levels in the pregnant rats [L-NAME, 19.6 +/- 1.6 pg x mL(-1) (n = 8) vs. D-NAME, 11.6 +/- 2.5 pg x mL(-1) (n = 9); P < 0.05]. Our results confirm that NO is involved in cardiovascular homeostasis in pregnancy; NOS inhibition selectively reduces plasma volume in pregnant rats, thus mimicking a major pathophysiological perturbation of preeclampsia. However, it does not induce the hormonal changes characteristic of preeclampsia, namely the decrease in PRA and increase in plasma ET and ANF levels.

Alveolar epithelial fluid clearance persists in the presence of moderate left atrial hypertension in sheep.

The effect of moderate left atrial (LA) hypertension on alveolar liquid clearance (ALC) was investigated in anesthetized, ventilated sheep, surgically prepared to measure lung lymph flow as well as hemodynamics. To simulate alveolar edema, 3-4 ml/kg of isosmolar 5% albumin in Ringer lactate were instilled into each lower lobe, and ALC was measured. After 4 h of LA hypertension (24 cmH2O), ALC was similar to that in control sheep (31 +/- 3% with LA hypertension vs. 34 +/- 10% with normal LA pressure). Because plasma epinephrine levels were moderately elevated in the presence of LA hypertension, ALC was then studied in the presence of LA hypertension following bilateral adrenalectomy. Without endogenous release of epinephrine, ALC was significantly reduced compared with normal LA pressure (20 +/- 7% compared with 34 +/- 10%, P < 0.05). Thus endogenous catecholamines caused a submaximal stimulation of ALC in the presence of LA hypertension. Exogenous administration of aerosolized beta2-agonist therapy with salmeterol increased ALC in the presence of normal LA pressure but had no stimulatory effect in the presence of moderate LA hypertension. Therefore, we tested the hypothesis that endogenous release of atrial natriuretic factor (ANF) may downregulate alveolar epithelial Na+ and fluid transport in the presence of LA hypertension. There was a modest twofold increase in plasma ANF levels after LA hypertension. Additional in vitro studies demonstrated that, in the presence of beta2-agonist stimulation, ANF decreased Na+ pump activity (Na+-K+-ATPase) in isolated rat alveolar epithelial type II cells. ANF may downregulate vectorial Na+ and fluid transport stimulated by endogenous or exogenous beta-adrenergic agonist stimulation in the presence of LA hypertension. In summary, ALC continues even in the presence of moderate LA hypertension. Aerosolized beta2-adrenergic agonist therapy significantly increased ALC, but only when LA pressure was normal.

Increased Plasma Atrial Natriuretic Factor in Catecholamine-Producing Tumor Patients

The aim of this study was to evaluate plasma levels of ANF in patients with catecholamine-secreting tumors with and without hypertension and to relate ANF secretion to levels of plasma and urinary catecholamines and blood pressure. Twenty-one pheochromocytoma (15 with sustained, 6 with paroxysmal hypertension), 6 neuroblastoma (1 hypertensive) patients and 28 aged-matched controls were studied in basal conditions. Plasma and urinary norepinephrine (NE),epinephrine (E), dopamine (DA) and DOPA were determined by HPLC-ED and plasma ANF by RIA. Both neuroblastoma and pheochromocytoma patients had significantly higher plasma ANF levels than controls. Neuroblastomas showed higher ANF concentration than pheochromocytomas. No differences were found in plasma ANF between hypertensive and normotensive patients. Pheochromocytomas with ANF levels within the normal range had plasma and urinary NE and urinary DA and DOPA levels significantly higher than patients with

Atrial natriuretic factor and brain natriuretic peptide gene expression in the spontaneous hypertensive rat during postnatal development

The increase in natriuretic peptides (NP), atrial natriuretic factor (ANF), and brain natriuretic peptide (BNP) production and release by cardiocytes that occurs in hypertension has been considered to be a compensatory mechanism against ventricular overload. Studies on NP production in the spontaneously hypertensive rat (SHR), an experimental model of human hypertension, have produced controversial results and were carried out when hypertension was already established (> 17 weeks). At this time, age-related physiologic and molecular changes in cardiac muscle are difficult to separate from those related to hypertension, ie, increased ANF production and plasma levels. In addition, most of the studies used male rats because the rate of increase in arterial blood pressure—as well as the level to which it rises—is greater in males than in females. Studies of a similar nature using female SHR are not available. The aim of this work was to determine 1) whether ANF and BNP production and secretion increase with the development of hypertension in genetically hypertensive rats; 2) whether a sexual dimorphism in ANF and BNP production and secretion is present in the genetically hypertensive rat during the development of hypertension; and 3) whether the demand for ANF and BNP is the same from each chamber of the heart under these experimental conditions. Age-matched male and female SHR, Wistar-Kyoto (WKY), and Sprague Dawley (SD) rats at 2, 4, and 8 weeks of age were used. The normotensive SD were included to provide a wider basis for baseline findings, as WKY rats are not always a suitable control for SHR due to genetic variations. Natriuretic peptide plasma levels and tissue content were measured by radioimmunoassay. ANF, BNP, as well as α- and β-myosin heavy chain (MHC) mRNA were estimated by Northern blot analysis. Blood pressure (BP) of more than 150 mm Hg was found only in 8-week-old male SHR. Plasma immunoreactive (ir)ANF and irBNP increased significantly at puberty (8 weeks) in both male and female SHR. The earliest molecular change encountered during the development of hypertension was a significant increase in BNP mRNA in the right and left atria from both male and female 8-week-old SHR. In the ventricles from both male and female SHR, there was no increase in the ratio of left ventricular wet weight/body weight, no increase in ventricular ANF mRNA transcripts, and no myosin heavy chain isoform switch (a protein marker of hypertrophy). irBNP ventricular concentration, however, increased significantly in both male and female SHR, but only in female SHR was there a concomitant increase in BNP mRNA. These results suggest that 1) ANF and BNP production are not coordinated in all cardiac compartments during the development of hypertension; 2) upregulation of BNP in the atria from male and female SHR is the earliest event detected at 8 weeks; 3) the prehypertensive stage, in the genetically hypertensive female rats, is associated with an increase in ventricular irBNP concentration and BNP mRNA; 4) there is a dissociation between BP and plasma levels of NP; and 5) as well, there is a dissociation between NP gene expression and MHC isoform switch. The regulation of NP is not coordinated in either gender during the development of hypertension. The activation of the BNP gene in female SHR suggests that BNP might play an important role at the onset of hypertension.

Effects of ANF infusion on the renal responses to lower-body negative pressure in humans.

To investigate the role of atrial natriuretic factor (ANF) in renal responses to a decrease in central blood volume, we examined the effects of ANF infusion on renal function and hormones during prolonged lower-body negative pressure (LBNP). Ten healthy volunteers participated in two experimental sequences, each comprising a 120-min baseline period followed by the application of -20 mm Hg LBNP for 90 min. During one of the two sequences, ANF was infused throughout LBNP application at the constant rate of 2.5 ng/kg/min. Glomerular filtration rate (GFR) and effective renal plasma flow (ERPF) were measured by using inulin and p-aminohippuric acid clearance techniques. LBNP induced a significant decrease in ERPF (534 +/- 28 to 457 +/- 26 ml/min; p < 0.05), GFR (120 +/- 2.5 to 112 +/- 2.5 ml/min; p < or = 0.01), in urine excretion (12 +/- 0.9 to 5.6 +/- 0.5 ml/min; p < 0.001), in sodium excretion (0.36 +/- 0.03 to 0.30 +/- 0.02 mmol/min; p < 0.05), and in plasma ANF (19 +/- 3 to 11 +/- 2 pg/ml; p = 0.001) concomitant with an increase in plasma renin activity (PRA; 0.48 +/- 0.09 to 0.87 +/- 0.16 ng/ml/h; p = 0.01) and of forearm vascular resistance (FVR; p < 0.05). The combination of ANF infusion with LBNP led to a slight increase in plasma ANF from baseline (from 20 +/- 2 to 28 +/- 3 pg/ml; p < 0.05). Compared with values obtained during LBNP with saline vehicle infusion, values obtained during LBNP with ANF infusion were similar for ERPF (463 +/- 23 vs. 457 +/- 26 ml/min), for GFR (111 +/- 2 vs. 112 +/- 2 ml/min), and for urine excretion (7 +/- 0.6 vs. 5.6 +/- 0.5 ml/min; p = 0.07), but greater for fractional excretion of sodium (2.38 +/- 0.25% vs. 1.91 +/- 0.11%; p < 0.05) and FVR (p < 0.05), and smaller for PRA (0.49 +/- 0.1 vs. 0.87 +/- 0.16 ng/ml/h; p < 0.01). These data show that ANF infusion attenuates the antinatriuretic effect of low-level LBNP and its PRA-increasing effects without altering renal hemodynamic responses to LBNP, although there is a decrease in the LBNP-induced forearm vasoconstriction. These results were obtained with plasma ANF levels slightly higher than those in baseline. They support the hypothesis that a decrease in ANF secretion might contribute to the antinatriuretic effect of LBNP.

Plasma atrial natriuretic factor levels in the inferior petrosal sinus blood of patients with Cushing's disease before and after corticotropin-releasing hormone administration.

Atrial natriuretic factor (ANF) was suggested to be involved as neurohormone in the modulation of hypothalamus-pituitary-adrenal axis in humans. However, this role is still controversial and widely discussed. In order to evaluate whether ANF is secreted in the hypothalamus-pituitary system in humans, plasma ANF concentrations were assayed in samples collected in the inferior petrosal sinus (IPS) blood of patients subjected to IPS sampling for diagnostic purposes or neurosurgical indications. In this retrospective study were included 22 patients: 10 with Cushing's disease (CD) and 12 patients with GH or PRL-secreting pituitary adenoma, used as control group. In the patients with CD, plasma ANF concentration was also assayed after CRH test (hCRH 100 micrograms as i.v. bolus with blood samples after 5, 10 and 15 min). Both in patients with CD and in patients with GH- or PRL-secreting pituitary adenoma, no significant difference was found in plasma ANF levels between IPS ipsilateral (13.0 +/- 1.5 and 12.2 +/- 1.2 pmol/l) or controlateral (13.0 +/- 1.6 and 12.2 +/- 1.4 pmol/l) to the adenoma and peripheral blood (14.2 +/- 2.0 and 13.7 +/- 1.5 pmol/l, respectively). Similarly, no difference was found between the IPS ipsilateral and controlateral to the adenoma in both groups of patients. In patients with CD, CRH administration induced a significant increase of ACTH levels (periphery: 34.9 +/- 6.2 vs 11.5 +/- 2.3 pmol/l, p < 0.05) but it did not induce any significant change of plasma ANF levels (14.0 +/- 2.0 vs 13.4 +/- 1.4 pmol/l in the ipsilateral IPS and 13.4 +/- 1.6 vs 13.4 +/- 1.5 pmol/l in the ipsilateral IPS and 13.4 +/- 1.6 vs 13.4 +/- 1.5 pmol/l in the contralateral IPS). In conclusion, the lack of ANF concentration gradient between IPS and peripheral blood, the lack of any difference in ANF concentrations between patients with CD and acromegalics or hyperprolactinemics and the absence of ANF response to CRH administration do not support the hypothesis of a role for ANF as neurohormone involved in the hypothalamus-pituitary control and particularly in the hypothalamus-pituitary-adrenal axis modulation in humans.