Atrial natriuretic peptide in hypoxia

A growing number of mammalian genes whose expression is inducible by hypoxia have been identified. Among them, atrial natriuretic peptide (ANP) synthesis and secretion is increased during hypoxic exposure and plays an important role in the normal adaptation to hypoxia and in the pathogenesis of cardiopulmonary diseases, including chronic hypoxia-induced pulmonary hypertension and vascular remodeling, and right ventricular hypertrophy and right heart failure. This review discusses the roles of ANP and its receptors in hypoxia-induced pulmonary hypertension. We and other investigators have demonstrated that ANP gene expression is enhanced by exposure to hypoxia and that the ANP so generated protects against the development of hypoxic pulmonary hypertension. Results also show that hypoxia directly stimulates ANP gene expression and ANP release in cardiac myocytes in vitro. Several cis-responsive elements of the ANP promoter are involved in the response to changes in oxygen tension. Further, the ANP clearance receptor NPR-C, but not the biological active NPR-A and NPR-B receptors, is downregulated in hypoxia adapted lung. Hypoxia-sensitive tyrosine kinase receptor-associated growth factors, including fibroblast growth factor (FGF) and platelet derived growth factor (PDGF)-BB, but not hypoxia per se, inhibit NPR-C gene expression in pulmonary arterial smooth muscle cells in vitro. The reductions in NPR-C in the hypoxic lung retard the clearance of ANP and allow more ANP to bind to biological active NPR-A and NPR-B in the pulmonary circulation, relaxing preconstricted pulmonary vessels, reducing pulmonary arterial pressure, and attenuating the development of hypoxia-induced pulmonary hypertension and vascular remodeling.     

Atrial natriuretic peptide in acute hypoxia-induced pulmonary hypertension in rats.

To test the hypothesis that exogenous atrial natriuretic peptide (ANP) prevents the acute pulmonary pressor response to hypoxia, ANP (20-micrograms/kg bolus followed by 1-microgram.kg-1.min-1 infusion) or vehicle was administered intravenously to conscious rats beginning 3 min before exposure to hypoxia or room air for 90 min. Exogenous ANP abolished the acute pulmonary pressor response to hypoxia in association with marked and parallel increases in plasma ANP and guanosine 5'-cyclic monophosphate (cGMP) and with a significant increase in lung cGMP content. To examine whether endogenous ANP modulates the acute pulmonary pressor response to hypoxia, rats were pretreated with a monoclonal antibody (Ab) to ANP and exposed to hypoxia. Mean pulmonary arterial pressure (MPAP) in the Ab-treated rats was not different from control over the first 6 h of hypoxic exposure. Thereafter, the Ab-treated group had significantly higher MPAP than control. Our data suggest that 1) exogenous ANP blocks the pulmonary pressor response to acute hypoxia via stimulation of cGMP accumulation in the pulmonary vasculature, and 2) endogenous ANP may modulate the subacute, but not acute, phase of hypoxic pulmonary hypertension.     

Atrial natriuretic peptide induces natriuretic peptide receptor-cGMP-dependent protein kinase interaction

Circulating natriuretic peptides such as atrial natriuretic peptide (ANP) counterbalance the effects of hypertension and inhibit cardiac hypertrophy by activating cGMP-dependent protein kinase (PKG). Natriuretic peptide binding to type I receptors (NPRA and NPRB) activates their intrinsic guanylyl cyclase activity, resulting in a rapid increase in cytosolic cGMP that subsequently activates PKG. Phosphorylation of the receptor by an unknown serine/threonine kinase is required before ligand binding can activate the cyclase. While searching for downstream PKG partners using a yeast two-hybrid screen of a human heart cDNA library, we unexpectedly found an upstream association with NPRA. PKG is a serine/threonine kinase capable of phosphorylating NPRA in vitro; however, regulation of NPRA by PKG has not been previously reported. Here we show that PKG is recruited to the plasma membrane following ANP treatment, an effect that can be blocked by pharmacological inhibition of PKG activation. Furthermore, PKG participates in a ligand-dependent gain-of-function loop that significantly increases the intrinsic cyclase activity of the receptor. PKG translocation is ANP-dependent but not nitric oxide-dependent. Our results suggest that anchoring of PKG to NPRA is a key event after ligand binding that determines distal effects. As such, the NPRA-PKG association may represent a novel mechanism for compartmentation of cGMP-mediated signaling and regulation of receptor sensitivity.     

Atrial natriuretic peptide in the sheep

To study atrial natriuretic peptide (ANP) physiology in the chronically catheterized pregnant sheep model we developed a heterologous radioimmunoassay for ovine ANP using an antiserum raised against 1-28 human ANP. This antiserum (Tor I) is specific for the aminoterminus of the human ANP molecule and shows little cross reaction with any carboxyterminus ANP fragments. Ovine ANP immunoreactivity was characterized using this antiserum and a commercially available carboxyterminus ANP antiserum obtained from Peninsula Laboratories. Each antiserum detected 2 peaks of immunoreactivity in ovine atrial extracts chromatographed on a Biogel P-10 column. The minor peak migrated at a position close to 125I-human ANP whereas the major peak represented a larger molecular weight species of ANP. Examination of gel filtration eluates of ovine plasma extracts showed one immunoreactive ANP peak using the Tor I assay system and 2 peaks with the Peninsula Laboratories assay. Plasma immunoreactive ANP levels were determined in 9 sheep using both radioimmunoassay systems. Mean (+/- SEM) levels were similar using the Peninsula Laboratories and the Tor I assay systems (57 +/- 8 pg/ml versus 43 +/- 4 pg/ml, P greater than 0.05). Using the Tor I antiserum, fetal plasma immunoreactive ANP levels were found to be significantly higher than maternal levels (188 +/- 17 versus 48 +/- 8 pg/ml, P less than 0.01) whereas pregnant and nonpregnant adult sheep had similar plasma immunoreactive ANP levels (48 +/- 8 versus 43 +/- 4 pg/ml, P greater than 0.05). Disappearance curves of synthetic human ANP from the plasma of maternal and fetal sheep were assessed using both immunoassay systems and found to be similar.     

Atrial natriuretic peptide, B-type natriuretic peptide, and serum collagen markers after acute myocardial infarction.

Experimental data suggest that atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP) act locally as antifibrotic factors in heart. We investigated the interrelationships of natriuretic peptides and collagen markers in 93 patients receiving thrombolytic treatment for their first acute myocardial infarction (AMI). Collagen formation following AMI, evaluated as serum levels of amino terminal propeptide of type III procollagen, correlated with NH(2)-terminal proANP (r = 0.45, P < 0.001), BNP (r = 0.55, P < 0.001) and NH(2)-terminal proBNP (r = 0.50, P < 0.01) on day 4 after thrombolysis. Levels of intact amino terminal propeptide of type I procollagen decreased by 34% (P < 0.001), and levels of carboxy terminal cross-linked telopeptide of type I collagen (ICTP) increased by 65% (P < 0.001). ICTP levels correlated with NH(2)-terminal proBNP (r = 0.25, P < 0.05) and BNP (r = 0.28, P < 0.05) on day 4. Our results suggest that ANP and BNP may act as regulators of collagen scar formation and left ventricular remodeling after AMI in humans. Furthermore, degradation of type I collagen is increased after AMI and may be regulated by BNP.     

Atrial natriuretic peptide levels and plasma volume contraction in acute alveolar hypoxia

Albert, T. S. E., V. L. Tucker, and E. M. Renkin.Atrial natriuretic peptide levels and plasma volume contraction in acute alveolar hypoxia. J. Appl.Physiol. 82(1): 102-110, 1997.Arterial oxygentensions (Pa_O2), atrial natriureticpeptide (ANP) concentrations, and circulating plasma volumes (PV) weremeasured in anesthetized rats ventilated with room air or 15, 10, or8% O₂(n = 5-7). After 10 min ofventilation, Pa_O2 values were 80 ± 3, 46 ± 1, 32 ± 1, and 35 ± 1 Torrand plasma immunoreactive ANP (irANP) levels were 211 ± 29, 229 ± 28, 911 ± 205, and 4,374 ± 961 pg/ml, respectively. AtPa_O2 40 Torr, irANP responses weremore closely related to inspiredO₂(P = 0.014) than toPa_O2 (P = 0.168). PV was 36.3 ± 0.5 µl/g in controls but 8.5 and9.9% lower (P  0.05) for10 and 8% O₂, respectively.Proportional increases in hematocrit were observed in animals withreduced PV; however, plasma protein concentrations were not differentfrom control. Between 10 and 50 min of hypoxia, small increases (+40%)in irANP occurred in 15% O₂;however, there was no further change in PV, hematocrit, plasma protein,or irANP levels in the lower O₂groups. Urine output tended to fall during hypoxia but was notsignificantly different among groups. These findings are compatiblewith a role for ANP in mediating PV contraction during acute alveolarhypoxia.

     

Atrial natriuretic peptide in infants and children

Atrial natriuretic peptide (ANP) was measured in the plasma of 192 normal infants and children aged 1 day to 18 years. Plasma ANP was high during postnatal adaptation, particularly in premature infants. In 96 infants and children aged 4 months to 18 years, plasma ANP was similar to values obtained in 7 healthy adult volunteers (23.9 +/- 11.9 vs. 25.7 +/- 4.6 fmol/ml). There was no significant relationship between ANP and age. ANP is elevated about twofold in full-term neonates being 3-4 days of age, and returned to normal thereafter. It is concluded that ANP is raised during the postnatal adaptation. This hormone is possibly involved in the postnatal volume contraction and may antagonize vasoconstrictor hormones that are elevated during the postnatal period.     

Atrial natriuretic peptide concentrations in pre-eclampsia.

The concentration of plasma immunoreactive atrial natriuretic peptide is positively associated with right atrial and pulmonary capillary wedge pressure, suggesting that blood volume and hence atrial pressure govern its release. Expansion of plasma volume is a central physiological adjustment in normal pregnancy. Conversely, pregnancies complicated by pre-eclampsia are associated with a reduction in plasma volume and central venous pressure. A study was therefore undertaken to test the hypothesis that plasma atrial natriuretic peptide concentrations are low in pre-eclampsia owing to deficient secretion. Concentrations of the peptide were measured by a specific radioimmunoassay. The mean plasma immunoreactive atrial natriuretic peptide concentration in healthy pregnant women (n = 22; third trimester) was higher (56 (1 SD 29) ng/l) than in 25 young, non-pregnant controls (37 (19) ng/l). Concentrations in patients suffering from mild pre-eclampsia (n = 9) were higher (127 (60) ng/l) than in normal pregnant women, and in patients with severe pre-eclampsia (n = 6) concentrations were higher still (392 (225) ng/l). Despite failure of plasma volume expansion and low central venous and pulmonary capillary wedge pressures in pre-eclampsia this condition is associated with greatly increased plasma concentrations of plasma immunoreactive atrial natriuretic peptide, which increase still further with the severity of the disease. These findings are clear evidence that atrial pressure may not be the principal determinant of the release of the natriuretic peptide in pre-eclampsia.     

Cerebral blood flow in acute mountain sickness

Changes in cerebral blood flow (CBF) were measured using the radioactive xenon technique and were related to the development of acute mountain sickness (AMS). In 12 subjects, ascending from 150 to 3,475 m, CBF was 24% increased at 24 h [45.1 to 55.9 initial slope index (ISI) units] and 4% increased at 6 days (47.1 ISI units). Four subjects had similar increases of CBF when ascending to 3,200 m 3 mo later, indicating the reproducibility of the measurements. In nine subjects, ascending from 3,200 to 4,785-5,430 m, CBF increased to 76.4 ISI units, 53% above estimated sea-level values. CBF and increases in CBF were similar in subjects with or without AMS. In six subjects, CBF was measured before and after therapeutic intervention. At 2 h CBF increased 22% (71.3 to 87.3 ISI units) above pretreatment values in three subjects given 1.5 g acetazolamide, while three subjects given placebo showed no change. Symptoms remained unaltered in all subjects during the 2 h of the study. Overall, the results indicated that increases in CBF were similar in subjects with or without AMS while acetazolamide-provoked increases of CBF in AMS subjects caused no acute change in symptoms. Alterations in CBF cannot be directly implicated in the pathogenesis of AMS.     

Atrial natriuretic peptide and vasopressin in human plasma

Using a specific radioimmunoassay for atrial natriuretic peptide (ANP), plasma immunoreactive ANP was measured in 17 normal subjects and 83 patients with various diseases. Plasma ANP concentration in normal subjects was 14.1 +/- 1.7 pg/ml (mean +/- S.E.). Relatively high plasma ANP concentrations were detected in patients with diabetes mellitus, hyperthyroidism, atrial fibrillation and liver cirrhosis. Plasma ANP concentrations in the patients correlated positively with mean arterial blood pressure and plasma AVP concentrations. Plasma ANP concentrations in the patients also had positive correlations with left atrial dimension and left ventricular diastolic dimension determined by echocardiography. Another positive correlation was observed in the patients between plasma AVP concentrations and mean arterial blood pressure. These results suggest that ANP is a volume regulatory hormone but also that ANP may be involved in the blood pressure regulating system.