| Placental insufficiency and fetal heart: Doppler ultrasonographic and biochemical markers of fetal cardiac dysfunction | ||
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In 1981, de Bold and co-workers found that granule-enriched atrial extracts contained a substance which caused natriuresis and vasodilatation (de Bold et al. 1981). Atrial natriuretic peptide molecule was purified and sequenced two years later (Flynn et al. 1983). Soon after that B- (BNP) and C-type natriuretic peptides (CNP) were found. The main source of BNP is the cardiac ventricle, although it was initially found in porcine brain (Sudoh et al. 1988). C-type natriuretic peptide was first localised in the nervous system (Sudoh et al. 1990), but later found to be produced by the endothelial cells (Suga et al. 1992). The gene of ANP is located on chromosome 1 in humans. Transcription of the ANP gene yields a messenger RNA species that encodes a 151-amino acid pre-proANP precursor containing a 25-amino acid signal sequence. This signal peptide is important for the translocation of pre-proANP from the ribosome into the sarcoplasmic reticulum. Pre-proANP is converted after cleavage of the signal peptide to a 126-amino acid proatrial natriuretic peptide, proANP1–126 which is the principal storage form of ANP. The ProANP1–126 is transported through the Golgi complex to secretory granules of atrial cardiocytes, and finally released by exocytosis to the extracellular space (Ruskoaho 1992). It is cleaved to the N-terminal fragment (proANP1–98 = NT-proANP) and the major biologically active hormone (C-terminal peptide ANP99–126), which is more commonly marked as ANP1–28 or ANP (Michener et al. 1986, Sundsfjord et al. 1988, Thibault et al. 1988). Thus NT-proANP and ANP are produced in equimolar amounts. Cleavage of ProANP1–126 into ANP and NT-proANP occurs in connection with exocytosis, presumably by the membrane-bound endonuclease Corin (Yan et al. 2000). The circulating 28-amino acid human ANP is the biologically active form (Misono et al. 1984).
The ANP gene is very actively expressed in fetal and neonatal ventricle (Sagnella 1998). Soon after birth, the ANP expression in the ventricles decreases to very low levels, but it can be re-induced by increased ventricular load. Elevation of the activity of ANP gene represents the return to fetal phenotype in response to ventricular load, together with the induction of genes of skeletal alpha actin, myosin light chain 1 and beta-tropomyosin (Nadal-Ginard & Mahdavi 1993). In addition, detectable levels of ANP messenger RNA have been found in central nervous system, lung, adrenal gland, kidney and vascular tissue. However, these levels are less than 1% of those detected in the atria, and therefore unlikely to have significant contribution to ANP plasma concentrations (Rosenzweig & Seidman 1991, Ruskoaho 1992).
The predominant signal for ANP release is atrial wall stretch or atrial distension due to volume expansion (Lang et al. 1985). Hypoxia is also a potent stimulus to ANP release (Lew & Baertschi 1989). Atrial stretch, increased heart rate, sympathetic stimulus and metabolic factors may mediate this effect (Ruskoaho 1992). Enhanced ANP release resulting from hyperosmolality with volume expansion has also been demonstrated (Arjamaa & Vuolteenaho 1985).
Endothelin-1, a potent vasoconstrictor of vascular smooth muscle, induces ANP secretion directly from the heart (Mantymaa et al. 1990). Inhibition of endothelin-1 receptors decreases the ANP release induced by the volume load (Leskinen et al. 1997). Endothelin-1 may also mediate atrial stretch-induced ANP release and effects of pressor hormones on the stress-activated release of ANP (Ruskoaho 1992). Endothelium- or endocardium-derived nitric-oxid may have an inhibitory effect on ANP secretion (Leskinen et al. 1995). In addition, cathecholamines (Ruskoaho 1992), acethylcoline (Ruskoaho et al. 1985), angiotensin, arginine vasopressin, prostaglandins (Ruskoaho 1992) and both glucocorticoids and thyroid hormones increase circulating ANP levels (Rosenzweig & Seidman 1991).
Atrial natriuretic peptide exerts its effects by binding to specific membrane-bound receptors. Three natriuretic peptide receptors have been identified. The ANPA and ANPB receptors have guanylate cyclase activity and mediate the biological effects of the natriuretic peptides. The ANPC receptor functions mainly as a clearance receptor removing ANP from the circulation. All natriuretic peptides are bound by the ANPC receptor. Atrial natriuretic peptide and BNP act through the ANPA receptor and CNP through the ANPB receptor (Yandle 1994)
The main targets of ANP are kidneys and vascular smooth muscle. It decreases blood pressure due to a direct relaxation of vascular smooth muscle. In addition, it increases salt and water excretion, enhances capillary permeability, and inhibits the release or action of several hormones, such as aldosterone, angiotensin II, endothelin, renin and vasopressin (Ruskoaho 1992). The natriuretic effect results from a direct inhibition of sodium absorption in the renal collecting duct, increased glomerular infiltration and inhibited aldosterone production and secretion (Rosenzweig & Seidman 1991). Atrial natriuretic peptide therefore counteracts the renin-angiotensin-aldosterone system. Thus, increased adult ANP levels are detected in adult congestive heart failure, chronic renal failure and in severe essential hypertension (Ruskoaho 1992, Yandle 1994).
The half-life of ANP is 2 to 5 minutes in humans and its metabolic clearance rate is about 14 to 25 ml/min/kg (Rosenzweig & Seidman 1991). The hormone is eliminated either enzymatically or through the clearance receptor. The ANPC receptor internalizes ANP and delivers it to lysosomes for degradation while the receptor itself is recycled. The most important enzyme regulating elimination of ANP is neutral endopeptidase 24.11. It is present in the glomerulus, in kidney smooth muscle cells, and at high levels in brush border membranes of the proximal tubule. It is also expressed in vascular tissue and vascular smooth muscle cells (Yandle 1994). Experimental and human studies have shown that inhibition of this enzyme potentiates the action of ANP (Kukkonen et al. 1992). Inhibitors that inhibit both angiotensin converting enzyme and neutral endopeptidase 24.11 are more potent antihypertensive agents than pure angiotensin converting enzyme- inhibitors (Backlund et al. 2001).
N-terminal peptide of proatrial natriuretic peptide (NT-proANP) is secreted in equimolar amounts with ANP (Itoh et al. 1988). Its high plasma concentration relative to ANP is probably due to its longer half-life in the circulation (Thibault et al. 1988). This is reflected in the proportionally larger increase in NT-proANP levels (15–20 fold) compared with those of ANP (4–5 fold) in subjects with congestive heart failure and chronic renal failure (Yandle 1994). Elevated circulating NT-proANP levels in cases of congestive heart failure have been suggested to demonstrate symptomless left ventricular dysfunction (Lerman et al. 1993, Kettunen et al. 1994). The NT-proANP is eliminated by the kidney. Demonstration of biological activity of NT-proANP has failed, probably due to the absence of a specific receptor for the N-terminal fragment (Ruskoaho 1992). The NT-proANP assay can be used to characterize endogenous ANP secretion (Itoh et al. 1988).
Conflicting data concerning the synthesis or storage of ANP in the placenta have been published (Inglis et al. 1993, McQueen et al. 1993). In experimental studies on rats, it has been shown that ANP does not cross the placenta (Mulay & Varma 1989). The lack of correlation between maternal and neonatal ANP concentrations supports the view that ANP does not cross the human placenta either (Shilo et al. 1989).
The fetus appears to produce its own atrial natriuretic factor (Hatjis et al. 1989). ANP has been detected as early as 16 gestational weeks in umbilical venous blood samples taken by cordocentesis (Ville et al. 1994). Fetuses with Rhesus isoimmunisation, characterized by long-term cardiac overload, showed significantly higher ANP levels compared to the controls (Kingdom et al. 1991, Ville et al. 1994, Walther et al. 2001). Fetal ANP levels correlated inversely with hematocrit, but not with gestational age. Fetal ANP levels showed a significant rise after transfusion, and this rise was related to the percentage of fetoplacental blood volume transfused. The changes in fetal ANP levels due to the volume expansion have been demonstrated as early as 21 weeks’ gestation (Panos et al. 1989). A weak, statistically non-significant, correlation was found between the change in fetal ANP levels and transient reductions in umbilical artery S/D-ratio (Kingdom et al. 1991). Increased neonatal ANP-levels as well as increased fetal umbilical venous ANP-levels have been reported in cases with growth restriction (Kingdom et al. 1992, Ville et al. 1994) and in fetuses born to patients with severe preeclampsia (Hatjis et al. 1989). In addition, studies on mice suggest that the maternal diabetes-induced increase in fetal ANP might be related to fetal myocardial hypertrophy (Mulay et al. 1995).