Hemodynamic effects of atrial natriuretic hormone

The atrial natriuretic hormone (ANH) alters cardiovascular function independent of changes in body fluid volume. Most investigators agree that ANH decreases mean arterial pressure (MAP). However, although some investigators have observed a decrease in total peripheral resistance in association with the decrease in MAP, a more frequent observation has been decreased cardiac output (CO). The mechanism whereby ANH decreases CO is unknown, but does not appear to be the result of direct myocardial depression, reductions in intravascular or cardiopulmonary volumes, or venodilation. Alterations in skeletal muscle and splanchnic blood flow have been reported by some but not all investigators. Although increases in renal blood flow have been reported, they are transitory and have not been consistently observed by all researchers. The cardiovascular effects of ANH appear to be influenced not only by the dose, but also by the cardiovascular control mechanisms that operate at the time of ANH administration. Non-renin-dependent hypertensive models exhibit a decrease in MAP associated with decreased CO, whereas in renin-dependent animals this hypotension is associated with a decrease in total peripheral resistance.     

Effects of intranasal administration of atrial natriuretic hormone on spontaneously hypertensive rats

The effects of the intranasal administration of synthetic alpha-human atrial natriuretic polypeptide (alpha-hANP) were investigated in 14 anesthetized spontaneously hypertensive rats (SHR; Okamoto-Aoki strain). They were given intranasally synthetic alpha-hANP in distilled water at doses of 10 micrograms/kg, 50 micrograms/kg and 100 micrograms/kg. Intranasal application of 200 microliter of distilled water as a control was also performed in 3 anesthetized SHR. Sixteen anesthetized SHR were examined for the effects of intravenous administration of alpha-hANP at doses of 4 micrograms/kg, 10 micrograms/kg, 20 micrograms/kg and 40 micrograms/kg. Urinary volume and the urinary excretion of sodium increased 2- to 3-fold during the 50 minutes following intranasal administration of a single dose of 50 micrograms/kg or 100 micrograms/kg, although neither the urinary volume nor the urinary excretion of sodium increased after intranasal administration of 10 micrograms/kg of alpha-hANP or 200 microliter of distilled water. There were no significant changes in arterial pressure or heart rate after the intranasal administration of synthetic alpha-hANP or distilled water. In contrast, arterial pressure was decreased and urinary volume and urinary excretion of sodium were increased, in a dose dependent manner, within 5 minutes after intravenous bolus-injection of alpha-hANP and returned to their baseline levels within 20 minutes. These results indicate that intranasal administration of synthetic alpha-hANP exerts its diuretic effect without concomitant changes in arterial pressure or heart rate in SHR.     

Increased secretion of brain natriuretic peptide and atrial natriuretic peptide, but not sufficient to induce natriuresis in rats with nephrotic syndrome.

The levels of immunoreactive brain natriuretic peptide (ir-BNP) and immunoreactive atrial natriuretic peptide (ir-ANP) were evaluated by radioimmunoassay in both the atrium, ventricle and plasma of adriamycin-induced nephrotic rats and control rats. There was no difference in right and left atrial concentrations of ir-BNP, however, a higher right atrial concentration of ir-ANP was observed in nephrotic rats than in controls (p less than 0.01). The ventricular ir-BNP and ir-ANP were increased in nephrotic rats compared to controls (BNP: p less than 0.001, ANP: p less than 0.001). Cardiac BNPs were composed of pro-BNP (gamma-BNP) and its C-terminal 45-amino-acid peptide (BNP-45). The ratio of BNP-45/gamma-BNP in nephrotic rats was higher than that of controls in both atria and in the ventricle. Plasma ir-BNP and ir-ANP were significantly higher in nephrotic rats than in controls (BNP: p less than 0.001, ANP: p less than 0.001), and each level was negatively correlated with urinary sodium excretion in nephrotic rats (BNP: r = -0.84, p less than 0.001, ANP: r = -0.88, p less than 0.001). These results suggest that production and secretion of both BNP and ANP are concomitantly stimulated by a decreased renal ability to eliminate sodium and water, but this secretion is insufficient to induce effective natriuresis in nephrotic rats.     

Secretory form of atrial natriuretic polypeptide as cardiac hormone in humans and rats

To elucidate the secretory form of atrial natriuretic polypeptide from the atrium, the molecular form of atrial natriuretic polypeptide in the perfusate from the isolated beating rat heart and in plasma taken at the coronary sinus of 10 patients during cardiac catheterization has been investigated using high performance gel permeation chromatography and reverse phase high performance liquid chromatography coupled with radioimmunoassay for atrial natriuretic polypeptide. Atrial natriuretic polypeptide in the perfusate from the rat heart showed a single peak eluting at the position of a low molecular weight form of atrial natriuretic polypeptide, without any detectable amounts of atrial natriuretic polypeptide with high molecular weights. The major component of atrial natriuretic polypeptide in the rat heart perfusate co-migrated with rat alpha-atrial natriuretic polypeptide in reverse phase high performance liquid chromatography. In 9 out of 10 patients atrial natriuretic polypeptide in plasma taken at the coronary sinus revealed a single peak of atrial natriuretic polypeptide emerging at the position of human alpha-atrial natriuretic polypeptide in gel filtration. Only one plasma sample had a small quantity of high molecular weight forms with the predominant low molecular weight form of atrial natriuretic polypeptide. The major component of atrial natriuretic polypeptide in the plasma extract from the coronary sinus was identified with human alpha-atrial natriuretic polypeptide. These results indicate that alpha-ANP, a 28-amino acid polypeptide, is secreted as a cardiac hormone into the coronary blood stream from the atrium.     

The role of atrial natriuretic peptide in the immune system

Atrial natriuretic peptide (ANP) is a hormone predominately produced by the heart atria which regulates the water and salt balance as well as blood pressure homeostasis. Being expressed in various parts of the immune system a link of the peptide to the immune system has been proposed. In fact, this review focus on effects of ANP in the immune system and reports about the role of the peptide in innate immune functions as well as in the adaptive immune response.     

The role of nitric oxide in saline-induced natriuresis and diuresis in rats.

This study was designed to determine to what extent nitric oxide (NO) mediates the natriuretic and diuretic responses to acute isotonic saline (0.9 gram % NaCl) volume expansion (SVE, 0.5 ml min-1 kg-1). Studies were performed on 49 pentobarbital anesthetized (65 mg/kg) female Sprague-Dawley rats with or without a NO synthase inhibitor, Nomega-nitro-L-arginine (LNA). Group 1 received saline at 27 microliter/min for 1 hr (baseline) and then SVE for 1 hr; Groups 2-4 received LNA at 10, 150, and 200 microgram kg-1 min-1, respectively, for 1 hr followed by LNA + SVE. To determine to what extent inhibition of NOS would reverse an ongoing SVE-induced natriuresis and diuresis, Group 5 was saline-volume-expanded for hours 1 and 2 whereas Group 6 was administered SVE during the first hour and then SVE + 150 microgram kg -1 min-1 LNA during the second hour. SVE caused a significant (P < 0.05) increase in the glomerular filtration rate (GFR) of Group 1 and the LNA-treated rats (Groups 2-4). This SVE-induced increase in the GFR occurred despite the fact that baseline GFR was significantly lower in the two groups of rats that were infused with the highest doses of LNA (Groups 3-4). SVE was also associated with similar increases in urine flow rate, sodium and potassium excretion, and total osmolar excretion in Groups 1-4. On the other hand, mean arterial pressure (MAP) was significantly higher in Group 2 during SVE + LNA and during the baseline as well as during the SVE periods in Groups 3-4; MAP was also significantly elevated in Group 6 during SVE + LNA. Thus, despite the fact that MAP was higher in LNA-treated rats, sodium and urine flow rates were the same as in Group 1 (i.e., there was no evidence of a pressure natriuresis or diuresis in these animals). Along these lines, there was a small but significant positive linear correlation coefficient (r = 0.41, P = 0.05) between sodium excretion values and corresponding MAP values in SVE control rats but not in Groups 3-4 during SVE (r = 0.28, P = 0.26). The current data demonstrate that 1) NO does not mediate SVE-induced hyperfiltration in the rat, 2) NO also does not mediate SVE-induced natriuresis or diuresis, and 3), consistent with other reports, NO appears to mediate pressure natriuresis and diuresis.     

Cellular mechanism of release of atrial natriuretic factor

Tissue extracts of rat heart atria contain a family of peptides with natriuretic and vasorelaxant properties. We have shown previously that this “atrial natriuretic factor” may be released in vitro from incubated atria by muscarinic cholinergic stimulation. Experiments reported here demonstrate that incubation with adrenalin or arginine vasopressin, but not with deamino-8-D-arginine vasopressin, also results in liberation of atrial natriuretic factor. Since the effective agonists have in common activation of the cellular polyphosphoinositide system with consequent production of inositol triphosphate, we suggest that inositol triphosphate is the second messenger of stimulus-secretion coupling in atrial cells.     

Effect of vasoactive substances on natriuresis induced by atrial natriuretic peptide in isolated perfused rat kidneys

We studied the interaction between synthetic atrial natriuretic peptide (ANP) and various vasoactive substances, which included isoproterenol (ISO), aminophylline (AMI), and dibutyryl cyclic AMP (dBcAMP) as vasodilators, and angiotensin II (AII) and norepinephrine (NE) as vasoconstrictors, and prazosin as an alpha-blocker in isolated perfused rat kidneys (IPK). When 10(-9) mol of ANP was administered in 75 ml of a perfusate, the renal vascular resistance (RVR) was transiently decreased for 5 min, and increased thereafter. Simultaneously, ANP increased the glomerular filtration rate (GFR), urine flow (UV), absolute Na excretion (UNaV) and absolute K excretion (UKV). All of the above mentioned effects of ANP were significantly inhibited by administering ISO, AMI or dBcAMP. On the other hand, the administration of AII and NE significantly enhanced the increases in UV and UNaV and the fractional excretion of Na induced by ANP, although AII and NE had no influence on the changes in RVR and GFR induced by ANP. Prazosin did not modify the renal effects of ANP. These results suggest that the natriuretic effect of ANP is inhibited by agents that increase cyclic AMP in vascular smooth muscle cells. It is also suggested that the natriuretic effects of ANP can be explained by an increase in GFR and changes in intrarenal hemodynamics, rather than by the direct effect of ANP on renal tubules.     

Placental barrier to atrial natriuretic peptide in rats

Transplacental passage of 125I-labelled synthetic rat atrial natriuretic peptide (ANP) was investigated in 20-day pregnant rats under pentobarbitone anesthesia. Although significant quantities of radioactivity were detected in the fetal plasma after maternal injections and in the maternal plasma after fetal injections of 125I-labelled synthetic ANP, no fraction of the placentally transferred radioactivity was due to intact ANP. Despite a rapid maternal and fetal metabolism of ANP, both maternal and fetal plasma radioactivity remained relatively stable for at least 3 h and less than 10% of the injected radioactivity was excreted in the maternal urine during a 90-min period. It is concluded that ANP is not transported in either direction across the placenta in rats.     

Regulation of adrenal atrial natriuretic hormone receptor subtypes.

Regulation of atrial natriuretic hormone (ANH) receptor binding and aldosterone suppression was studied in isolated adrenal glomerulosa cells from rats fed a high-salt (HS) or low-salt (LS) diet for 3 days. In plasma of HS rats, aldosterone levels were 5 times lower and immunoreactive ANH two times higher than in LS rats. Competitive binding studies showed the same affinity for human atrial natriuretic hormone (hANH) in both pools of cells, but receptor density was 50% higher on LS cells. A linear ANH analog that binds to non-guanylate-cyclase-coupled receptors did not show increased binding to LS cells. Cyclic GMP production in response to hANH was identical in both groups. The aldosterone-inhibitory effect of hANH on both groups of basal and angiotensin II-stimulated cells was also identical. Thus a short-term high-salt diet causes decreased density of ANH receptors in glomerulosa cells without changing biological activity of ANH. These results suggest that dietary salt content changes the number of ANH receptors and that non-guanylate-cyclase-coupled receptors contain at least two classes of receptors.     

The role of atrial natriuretic factor in dehydration and schedule-induced drinking behaviour

Dehydration-induced drinking (DID) has been defined as a type of homeostatic behaviour controlled by factors related to water balance, whereas schedule-induced polydipsia (SIP) is considered to be a type of nonhomeostatic drinking subsequent to a general increase in motor excitability. In this study, we have attempted to assess the role of atrial natriuretic factor (ANF) in both models to elucidate the mechanisms controlling water intake. Intracerebroventricular injection of ANF (2-8 nmol) caused a dose related suppression of water intake in both DID and SIP, but intravenous injection with a higher dose of ANF (8 nmol) produced a significant suppression of water intake only in DID. Before drinking started, tissue ANF levels increased in atria in both models and decreased in hypothalamus in DID but not in SIP. After 1 hour of drinking, ANF levels decreased in atria in both models and increased in hypothalamus in SIP but not in DID. These results suggest that DID and SIP are different in their thirst regulation, and that the notion that peripheral ANF serves as a humoral factor sending signals to central in the fluid homeostatic control mechanism is questionable.     

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.     

Concentration(s) of atrial natriuretic hormone in the plasma of rats with streptozotocin-induced diabetes mellitus

Blood was withdrawn from rats injected 1, 3, 6 and 12 weeks previously with the diabetogenic agent streptozotocin (55 mg/kg, I.V.) or saline. Analysis of plasma showed that while the streptozotocin-treated animals displayed significantly (p less than 0.05) diminished triiodothyronine levels and significantly (p less than 0.05) elevated osmolalities at all time points after injection, immunoreactive-ANF levels were unchanged. Thus, there would appear to be no direct relationship between plasma atrial natriuretic factor levels and plasma triiodothyronine levels or plasma osmolalities in the diabetic rat.     

Analysis of muscle protein expression in polyethylene glycol-induced chicken: rat myoblast heterokaryons

Heterokaryons derived from polyethylene glycol-mediated fusion of myoblasts at different stages of development were used to investigate the transition of cells in the skeletal muscle lineage from the determined to the differentiated state. Heterokaryons were analyzed by immunofluorescence, using rabbit antibodies against the skeletal muscle isoforms of chicken creatine kinase and myosin, and a mouse monoclonal antibody that cross-reacts with chicken and rat skeletal muscle myosin. When cytochalasin B-treated rat L8(E63) myocytes (Konieczny S.F., J. McKay, and J. R. Coleman, 1982, Dev. Biol., 91:11-26) served as the differentiated parental component and chicken limb myoblasts from stage 23-26 or 10-12-d embryos were used as the determined, undifferentiated parental cell, heterokaryons exhibited a progressive extinction of rat skeletal muscle myosin during a 4-6-d culture period, and no precocious expression of chicken differentiated gene products was detected. In the reciprocal experiment, 85-97% of rat myoblast X chicken myocyte heterokaryons ceased expression of chicken skeletal muscle myosin and the M subunit of chicken creatine kinase within 7 d of culture. Extinction was not observed in heterokaryons produced by fusion of differentiated chicken and differentiated rat myocytes and thus is not due to species incompatibility or to the polyethylene glycol treatment itself. The results suggest that, when confronted in a common cytoplasm, the regulatory factors that maintain myoblasts in a proliferating, undifferentiated state are dominant over those that govern expression of differentiated gene products.     

Water on hydrophobic surfaces: mechanistic modeling of polyethylene glycol-induced protein precipitation

Bioprocess and Biosystems Engineering - For the purification of biopharmaceutical proteins, liquid chromatography is still the gold standard. Especially with increasing product titers, drawbacks...     

Attenuated diuretic and natriuretic effects of atrial natriuretic peptide in rats with heart failure

Plasma levels of atrial natriuretic peptide (ANP) and renal responses to ANP were examined in rats with chronic cardiac failure produced by coronary artery ligation and in sham-operated controls. Plasma ANP levels were elevated in the rats with severe cardiac failure as compared with the controls (P less than 0.001). ANP injections at the doses of 1, 5, 25 and 50 micrograms/kg increased water and sodium excretion significantly at all but the lowest dose in the controls; only the two largest doses caused clear diuresis and natriuresis in the heart failure group. The diuretic and natriuretic effects of ANP were significantly weaker at the doses of 5 and 25 micrograms/kg in the rats with heart failure as compared with the controls. We conclude, that natriuretic and diuretic effects of ANP are attenuated in this chronic heart failure mode.     

Interaction of lead acetate with atrial natriuretic factor in rats

Lead exposure alters cardiovascular function and has been implicated in the etiology of hypertension. Therefore it was of interest to study the short term effect of lead treatment on atrial natriuretic factor (ANF), a hormone which produces vascular smooth muscle relaxation and natriuresis. Male Sprague Dawley rats were randomly divided into 5 groups containing 4 animals each and injected intraperitoneally with normal saline (control), 0.01, 0.1, 0.5 or 1.0 mg/kg of body weight with lead acetate solution twice a day for 7 days, and then maintained for a period of 30 days. During this period water consumption and urine volume were measured daily. At the end of the 30 day period, immunoreactive levels of ANF in hypothalamus, atria and plasma were measured by radioimmunoassay. Lead treatment did not alter water consumption, but significantly decreased urine output. At all doses, lead produced a decrease in hypothalamic content of ANF and slightly increased atrial levels. The content of ANF in plasma was decreased. The changes in ANF content indicate that lead interacts with the hormonal regulation of the cardiovascular system and these observations may relate to the cardiovascular toxicity of this heavy metal.     

Natriuretic effect of atrial natriuretic peptide in diabetes insipidus rats

Washout of the solute concentration gradient in the renal medullary interstitium has been suggested to play a role in mediating the natriuretic response to atrial natriuretic peptide (ANP). The purpose of this study was to determine the effects of ANP 8-33 on sodium excretion in Brattleboro diabetes insipidus (DI) rats, in which medullary tonicity is known to be decreased as compared to Long-Evans (LE) control rats. Basal urine osmolality (Uosm) was significantly lower in DI rats as compared to LE rats (123 +/- 6 vs 673 +/- 38 mOsm/kg). Infusion of ANP 8-33 at a rate of 4 micrograms/kg/hr for 60 min resulted in a significantly greater increase in UnaV (delta 6.1 +/- 1.2 vs delta 2.9 +/- 0.7 microEq/min) and urine flow (delta 40 +/- 12 vs delta 8 +/- 7 microliter/min) in the LE rats than in the DI rats. The greater natriuresis occurred in the LE rats despite no significant change in Uosm. Fractional lithium reabsorption (an indicator of proximal sodium reabsorption) decreased similarly in both groups. Infusion of ANP had no effect on mean arterial pressure in LE and DI groups. In summary, infusion of ANP in the DI rat resulted in a significant natriuresis, albeit less than in LE rats. The natriuresis in the LE rats occurred despite no significant change in Uosm. These data suggest that mechanisms other than medullary washout are responsible for the natriuretic effects of ANP.