Natriuretic peptides in the lung modulated by pneumonectomy

BACKGROUND: Natriuretic peptides are vasodilator hormones involved in the regulation of blood pressure and volume homeostasis. However, the mechanism of these peptides after pneumonectomy remains obscure. METHODS: We investigated changes in the pulmonary arterial pressure and the localization and changes in the atrial (A-type) natriuretic peptide (ANP) and the C-type natriuretic peptide (CNP) in the lung, using immunohistochemistry and radioimmunoassay (RIA) in anesthetized dogs. Furthermore, we examined guanosine 3', 5'-monophosphate (cGMP) levels in plasma and in the contralateral lung. RESULTS: Pulmonary arterial pressure was significantly increased after pneumonectomy. The immunoreactivities of both ANP and CNP were detected in the endothelium of the pulmonary artery. In the contralateral lung, the concentrations of ANP and CNP were both significantly increased. In plasma, only ANP levels were significantly increased. In contrast, the plasma and lung cGMP levels were significantly reduced after pneumonectomy. CONCLUSIONS: We postulate that the processes from secretion in the vascular endothelial cells to the action via ANP and CNP receptors are effected in the contralateral lung tissue at the acute stage of pneumonectomy.     

Neutral endopeptidase inhibition potentiates the effects of natriuretic peptides in renin transgenic rats

The influence of neutral endopeptidase (NEP) inhibition with (S)-thiorphan on the hormonal, renal, and blood-pressure-lowering effects of an infusion of atrial (ANP), brain (BNP), and C-type natriuretic peptide (CNP) was evaluated in hypertensive transgenic rats (TGR) harboring an additional mouse renin gene (TGR(m(Ren2)27)). These TGR possess an activated natriuretic peptide system as compared with Sprague-Dawley rats (SDR), used in this study as control. (S)-Thiorphan significantly decreased blood pressure in anesthetized TGR but not in anesthetized SDR during the 60-min infusion period. Exogenously administered ANP decreased blood pressure in SDR with no significant effects in TGR after 60 min. In contrast, BNP infusion significantly decreased blood pressure in TGR, while changes in SDR were not significant. The blood pressure was further decreased after combined infusion of ANP and BNP with (S)-thiorphan in TGR. No effect on blood pressure was registered during infusion of CNP in either experimental group. The plasma levels of ANP, BNP, and cGMP were higher in TGR than in SDR, whereas plasma renin activity was lower. Co-administration of ANP, BNP, or CNP with the NEP inhibitor (S)-thiorphan potentiated the plasma ANP, BNP, and cGMP. Infusion of ANP alone did not affect BNP plasma levels of TGR and vice versa. In contrast, CNP infusion increased ANP plasma levels in both TGR and SDR. Renal excretion of sodium and cGMP increased after infusion of (S)-thiorphan and ANP or BNP in both TGR and SDR. The combination of ANP and (S)-thiorphan had a slightly greater effect on urinary excretion of sodium and cGMP in TGR than either compound alone, but the effects were more pronounced in SDR than in TGR. Finally, infusion of CNP alone and in combination with (S)-thiorphan influenced the excretion of sodium and cyclic GMP only slightly. These results indicate that inhibition of neutral endopeptidase by (S)-thiorphan potentiates the hemodynamic and renal effects of natriuretic peptides ANP and BNP, and to some extent those of CNP, in hypertensive TGR and normotensive SDR. In contrast to ANP and BNP, infusion of CNP had no effect on the blood pressure in anesthetized TGR or SDR. Inhibition of NEP therefore seems to be a promising way to potentiate endogenous levels of natriuretic peptides, which may be of therapeutic benefit in cardiovascular diseases such as hypertension or heart failure.     

Type B and type C natriuretic peptide receptors modulate intraocular pressure in the rabbit eye

We investigated (1) the in vivo functional significance of the type B (ANP(B)) and type C (ANP(C)) natriuretic peptide receptors in the rabbit eye by evaluating the effect of intracameral administration of C-type natriuretic peptide (CNP) and C-ANP-(4-23) on intraocular pressure, and (2) the action of CNP on guanylate cyclase activity in the rabbit ciliary process membranes. Atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) were also studied for comparison. We demonstrated that the natriuretic peptides decrease intraocular pressure and stimulate guanylate cyclase activity, CNP being the most potent. The duration of the effect of C-ANP-(4-23) on intraocular pressure reduction was almost 9-fold that of the BNP and 20-fold that of ANP and CNP effect. This ligand increased threefold the immunoreactive natriuretic peptides levels in aqueous humour. Our data demonstrate the presence of functional ANP(A) and ANP(B) receptors in the rabbit eye and that the ANP(C) receptor modulates the concentration of the natriuretic peptides in the aqueous humour.     

A case of pulmonary arteriovenous fistulas (PAVF) treated with detachable balloon embolotherapy

Previous studies of the effects of C-type natriuretic peptides (CNP) in intact mammals have demonstrated limited hypotensive responses, in contrast to other natriuretic peptides. Our previous studies, on isolated vascular smooth muscle (VSM) from various fish species, utilizing either mammalian or non-homologous fish atrial natriuretic peptides (ANP), have demonstrated vasodilation with a relatively high sensitivity (EC50 approximately 5 nM). The recent sequencing of a C-type natriuretic peptide from the heart of the dogfish shark, Squalus acanthias, has enabled us to compare the efficacy of this peptide on aortic VSM from that species with two other CNPs (from killifish and pig), as well as rat ANP. The EC50 of dilation for sCNP, as well as kCNP and pCNP, was 0.5 nM, over 15 times lower than the EC50 of the response to rANP. These data suggest that CNP is released from the dogfish shark heart and is a circulating hormone with potent vasodilatory effects, in sharp contrast to the apparent role of CNP predominantly as a brain neuropeptide in mammals.     

Regulation of guanosine 3':5'-cyclic monophosphate in ovine tracheal epithelial cells

1. Guanosine 3':5'-cyclic monophosphate (cyclic GMP) is an important second messenger mediating the effects of nitric oxide (NO) and natriuretic peptides. Cyclic GMP pathways regulate several aspects of lung pathophysiology in a number of airway cells. The regulation of this system has not been extensively studied in pulmonary epithelial tissue. 2. We have studied the production of cyclic GMP by suspensions of ovine tracheal epithelial cells in response to activators of soluble guanylyl cyclase (sodium nitroprusside (SNP) and S-nitroso-N-acetyl-penicillamine (SNAP) and particulate guanylyl cyclase (atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), C-type natriuretic peptide (CNP) and E. coli heat stable enterotoxin (STa)). 3. Both 10(-7)-10(-3) M and 10(-7)-10(-3) M SNAP generated a concentration-dependent marked elevation in cyclic GMP production when incubated with 10(-3) M 3-isobutyl-l -methylxanthine (IBMX) (both greater than 25 x baseline values with highest drug concentration). 4. The increase in production of cyclic GMP in response to 10(-6) M SNP and 10(-5) M SNAP was markedly inhibited by both 5 x 10(-5) M haemoglobin (102% and 92% inhibition) and 5 x 10(-5) M methylene blue (82% and 84% inhibition). 5. The increase in cyclic GMP in response to 10(-3) M SNP was measured following co-incubation with the phosphodiesterase inhibitors 10(-7)-10(-3) M IBMX, 10(-7)-10(-4) M milrinone and 10(-7)-10(-4) M SKF 96231. Only 10(-4)-10(-3) M IBMX significantly increased cyclic GMP levels. 6. Cyclic GMP production was also significantly elevated from baseline by 10(-5) M ANP, 10(-5) M BNP, 10(-5) M CNP and 200 iu ml-3 of E. coli STa toxin in the presence of 10(-3) M IBMX. Increases with these natriuretic peptides and STa toxin were smaller in magnitude (2-4 fold) than those seen with SNP and SNAP. CNP was the most potent of the natriuretic peptides studied suggesting type B membrane bound guanylate cyclase is the predominant form expressed. 7. These results suggest that ovine tracheal epithelial cells contain active guanylyl cyclases. The more marked response to SNP and SNAP than to natriuretic peptides suggests that soluble guanylyl cyclase predominates.     

Mechanisms of natriuretic-peptide-induced growth inhibition of vascular smooth muscle cells

OBJECTIVE: While natriuretic peptides can inhibit growth of vascular muscle cells (VSMC), controversy exists as to whether this effect is mediated via the guanylate cyclase-coupled receptors, NPR-A and NPR-B, or the clearance receptor, NPR-C. The original aim of this study was to examine the mechanism by which the NPR-C receptor regulates growth. METHODS: Rat VSMC were characterized with regard to natriuretic peptide receptor expression by RT/PCR and radioligand binding studies. The effect on growth following addition of the peptides and the ligands for NPR-C was measured by [3H]thymidine incorporation. Cyclic guanosine monophosphate (cGMP) levels were determined by radioimmunoassay and mitogen activating protein kinase activity was based on the phosphorylation of myelin basic protein. RESULTS: In rat VSMC, passages 4-12, both atrial natriuretic peptide (ANP) and C-type natriuretic peptide (CNP) dose-dependently inhibited serum and PDGF-induced VSMC growth. In contrast, NPR-C specific ligands alone had no effect on cell growth but enhanced growth inhibition when co-administered with ANP and CNP. ANP and CNP also decreased PDGF-BB-stimulated MAP kinase activity. Once again, NPR-C specific ligands alone had no effect but enhanced the effects of ANP. Furthermore, a cGMP specific phosphodiesterase inhibitor dose-dependently inhibited VSMC growth and markedly enhanced natriuretic-peptide-induced inhibition at low peptide concentrations. To examine a potential mechanism for the controversy concerning the NPR-C, we investigated the autocrine expression of ANP and CNP by VSMC and found that mRNA encoding both peptides could be detected by RT/PCR. CONCLUSION: Our findings indicate that the guanyl-cyclase-linked receptors mediate the antiproliferative actions of the natriuretic peptides on vascular smooth muscle cell growth. Moreover, we hypothesize that the apparent inhibition of growth by NPR-C specific ligands reported by others may be due to stabilization of natriuretic peptides produced by the cultured VSMC and subsequent action of these peptides at guanyl-cyclase-linked receptors.     

Induction of necrosis by zinc in prostate carcinoma cells and identification of proteins increased in association with this induction

Endothelin-1 (ET-1) is a cardiovascular peptide that binds to two distinct receptors, ET(A) and ET(B), resulting in systemic and regional vasoconstriction, alteration in sodium excretion, mitogenesis, and release of other vasoactive peptides such as atrial natriuretic peptide (ANP). A role for ET-1 has been proposed in congestive heart failure (CHF) based on the increase in circulating ET-1 in this cardiovascular disease state. The present study determined the cardiorenal and endocrine responses to chronic selective oral ETA antagonism in experimental CHF. Two groups of conscious dogs underwent 21 days of pacing-induced CHF. These groups included a control untreated group (n = 6) and a group that received an orally active ET(A) receptor antagonist (A-127722, Abbott Pharmaceuticals, 5 mg/kg PO bid, n = 6). Each group was studied at baseline before the onset of CHF and after 14 and 21 days of CHF. Compared with the CHF control group, the ET(A) receptor antagonism group at 14 days of CHF showed lower mean arterial pressure and systemic vascular resistance. Similarly, ET(A) receptor antagonism markedly attenuated the increase in circulating ANP despite similar atrial pressures. At 21 days of CHF, ET(A) receptor antagonism lowered pulmonary artery pressure, pulmonary vascular resistance, and systemic vascular resistance in association with a higher cardiac output. Plasma ANP remained suppressed. Despite the lower mean arterial pressure and circulating ANP in the ET(A) receptor antagonist group, the absolute decrease in sodium excretion from baseline was less compared with the untreated CHF control group. The present investigation supports the conclusion that endogenous ET-1 participates in the systemic and pulmonary vasoconstriction, the elevation of ANP, and the sodium retention that characterize this model of experimental CHF, suggesting a potential therapeutic role for ET(A) receptor antagonism in CHF.     

Mechanism of adsorption of human albumin to titanium in vitro

1. This study explored the hypothesis that atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), and C-natriuretic peptide (CNP) have differing antiproliferative and antihypertrophic effects on pulmonary artery (PA) and thoracic aorta (TA) smooth-muscle cells (SMCs). 2. Cultured cells were exposed to 5% fetal calf serum (FCS) and angiotensin II (A-II) to induce DNA and protein synthesis, respectively. 3. ANP (10(-7) M) significantly reduced thymidine uptake in TA by 31% +/- 2% (P < or = 0.01) but not in PA (P > or = 0.05). 4. In parallel experiments, BNP (10(-7) M) significantly reduced thymidine uptake in TA (-22% +/- 5%, P < or = 0.01), but not in PA cells (P > or = 0.05). 5. CNP (10(-7) M) did not significantly alter thymidine uptake in TA cells exposed to FCS, but it did significantly reduce uptake in PA (-28.5% +/- 4%) 2(P < or = 0.05). 6. Blunting by ANP (10(-7) M) of the A-II (10(-8) M)-induced increase in protein synthesis was significantly greater in PA than in TA cells. 7. However, BNP and CNP (10(-7) M) exerted similar antihypertrophic effects on TA and PA cells exposed to A-II. 8. The antiproliferative effects of BNP and ANP exceed those of CNP in TA SMCs, but CNP appears to be the most effective antiproliferative agent in PA SMCs. In addition, PA-derived SMCs are more sensitive to the antihypertrophic effects of ANP than TA-derived cells, suggesting phenotypic differences. The findings indicate that the natriuretic peptides may play complementary roles in modulating SMC proliferation and protein synthesis.     

Circadian urinary excretion of catecholamine, plasma atrial natriuretic peptide, endothelin and neuropeptide Y in obese patients with hypertension

Obesity increases the risk of developing hypertension by two-to fourfold, with more that one third of all cases of hypertension attributable to obesity. The present study tested the role of atrial natriuretic peptide (ANP), endothelin-1,2 (ET-1,2) and neuropeptide Y (NPY) in pathogenesis of obesity hypertension. The plasma concentrations of ANP, ET-1,2 and NPY were determined in the peripheral venous blood by radioimmunoassay in 27 obese hypertensive patients (group I), in 24 obese normotensive patients (group II), and in 35 normal subjects (group III). RESULTS: Mean plasma ANP was significantly higher in obese than in normal subjects. ANP levels were higher in patients group I than in those group II and I. In patients of group I plasma ANP concentrations correlated with III BMI and mean blood pressure. Plasma levels of ET-1,2 and NPY were similar in patients group I, II and III.     

Cardiopulmonary adaptations to pneumonectomy in dogs. IV. Membrane diffusing capacity and capillary blood volume

Lung diffusing capacity for carbon monoxide (DLco) and its components, membrane diffusing capacity (Dmco) and capillary blood volume (Vc), as well as pulmonary blood flow (Qc), were measured at rest at several lung volumes and during treadmill exercise by a rebreathing technique in four adult dogs after right pneumonectomy (R-PNX) and in six matched control dogs (Sham) 6-12 mo after surgery. In both groups, lung inflation at rest was associated with a small increase in DLco and Dmco but not in Vc. After R-PNX, total DLco was lower by 30% at peak exercise compared with control values. When compared with DLco in a normal left lung, DLco in the remaining lung continued to increase along the normal relationship with respect to Qc up to a cardiac output equivalent to 34 l/min through both lungs of the Sham dog. There was no evidence of an upper limit of DLco being reached. The augmentation of DLco from rest to exercise was associated with corresponding increases in Dmco and Vc; after R-PNX, both Dmco and Vc continued to increase with respect to Qc along similar relationships as in control dogs without reaching an upper limit, suggesting a much larger alveolar-capillary reserve for gas exchange by diffusion than previously recognized. At higher levels of blood flow through the remaining lung, DLco was greater in adult dogs after R-PNX than after left pneumonectomy (Carlin et al. J. Appl. Physiol. 70: 135-142, 1991), suggesting that additional sources of compensation, e.g., lung growth, exist after removal of > 50% of lung.     

Comparison of the stability of technetium-labeled peptides to challenge with cysteine

-Tacrolimus (FK 506) is a powerful, widely used immunosuppressant. The clinical utility of FK 506 is complicated by substantial hypertension and nephrotoxicity. To clarify the mechanisms of FK 506-induced hypertension, we studied the chronic effects of FK 506 on the synthesis of endothelin-1 (ET-1), the expression of mRNA of ET-1 and endothelin-converting enzyme-1 (ECE-1), the endothelial nitric oxide synthase (eNOS) activity, and the expression of mRNA of eNOS and C-type natriuretic peptide (CNP) in rat blood vessels. In addition, the effect of the specific endothelin type A receptor antagonist FR 139317 on FK 506-induced hypertension in rats was studied. FK 506, 5 mg. kg-1. d-1 given for 4 weeks, elevated blood pressure from 102+/-13 to 152+/-15 mm Hg and increased the synthesis of ET-1 and the levels of ET-1 mRNA in the mesenteric artery (240% and 230%, respectively). Little change was observed in the expression of ECE-1 mRNA and CNP mRNA. FK 506 decreased eNOS activity and the levels of eNOS mRNA in the aorta (48% and 55%, respectively). The administration of FR 139317 (10 mg. kg-1. d-1) prevented FK 506-induced hypertension in rats. These results indicate that FK 506 may increase blood pressure not only by increasing ET-1 production but also by decreasing NO synthesis in the vasculature.     

Vascular action of circulating and local natriuretic peptide systems is potentiated in obese/hyperglycemic and hypertensive rats

Hypertension is commonly associated with diabetes mellitus. The aim of the present study was to explore the pathophysiological significance of the natriuretic peptide (NP) system in hypertension associated with genetically obese/hyperglycemic Wistar fatty rats. The messenger RNA (mRNA) levels of the two biologically active NP receptors, NP-A receptor [more specific for atrial natriuretic peptide (ANP)] and NP-B receptor [more specific for C-type natriuretic peptide (CNP)], and CNP mRNA levels were determined in the aorta and kidney by ribonuclease protection assay. Plasma ANP levels were determined by RIA. Both NP-A and NP-B receptor mRNA levels in the aortae of Wistar fatty rats were double those in Wistar lean rats. Plasma ANP levels and CNP mRNA levels in the aorta of Wistar fatty rats were also significantly higher than those in Wistar lean rats. In contrast, there was no significant difference in renal levels of the mRNA for both NP receptors and CNP between the two strains. Administration of a NP-A and -B receptor antagonist, HS-142-1, to Wistar fatty rats resulted in a significant increase in systolic blood pressure and a larger decrease in plasma cGMP level than that in Wistar lean rats, with no difference in the extents of decrease in urine volume and urinary sodium excretion between the two strains. These results suggest that both the ANP/NP-A system and the CNP/NP-B system in vessels are up-regulated at the level of gene expression and may, thus, play an important role in counteracting the hypertension associated with diabetes mellitus.     

Endothelin antiserum decreases volume-stimulated and basal plasma concentration of atrial natriuretic peptide

BACKGROUND: Endothelin-1 (ET-1) is the most powerful factor known to release atrial natriuretic peptide (ANP) in vivo and in cultured cardiac myocytes or preparations of atrium. We tested the role of endogenous ET-1 in the regulation of ANP release by passive immunization in anesthetized rats. METHODS AND RESULTS: Intravenous injection of antiserum against ET-1 was shown to decrease basal and volume-stimulated plasma concentrations of ANP, whereas control serum was without effect. Antiserum generated in rabbits cross-reacted 100% with endothelin-2 and -3. In pentobarbital-anesthetized Wistar rats treated with ET-1 antiserum, plasma ANP concentration measured by radioimmunoassay was reduced by 37% from starting level after 10 minutes and by 30% after 60 minutes. Control rat serum had no effect on plasma ANP. Rapid intravenous infusion of 8 mL of 0.9% NaCl caused a sixfold increase of plasma ANP concentration in control rats but only twofold in rats pretreated with ET-1 antiserum (P < .01). This effect of ET-1 antiserum was dose dependent. ET-1 antiserum changed neither blood pressure nor heart rate significantly in anesthetized rats. Pretreatment with ET-1 antiserum did not affect the initial hypotensive response to intravenous ET-1 0.5 nmol/kg but significantly attenuated the subsequent hypertensive response to endothelin. CONCLUSIONS: Endothelin may be a physiological modulator of both basal and stimulated ANP release.     

Natriuretic peptide family as a novel antimigration factor of vascular smooth muscle cells

Vascular smooth muscle cell (SMC) migration is proposed to be an important process in the initiation and/or progression of atherosclerosis. The present study examined the effects of the natriuretic peptide family (atrial, brain, and C-type natriuretic peptides; ANP, BNP, and CNP) on the migration of cultured rat SMCs, using Boyden's chamber methods. Fetal calf serum (FCS) and platelet-derived growth factor (PDGF)-BB potently stimulated SMC migration. Rat ANP(1-28), rat BNP-45, and rat CNP-22 clearly inhibited SMC migration stimulated with FCS or PDGF-BB in a concentration-dependent manner. CNP-22 had the most potent inhibitory effect compared with other natriuretic peptides. When PDGF-BB-induced migration was separated into chemotactic and chemokinetic activities, the chemotactic component was strongly inhibited by these natriuretic peptides. Such inhibition by these natriuretic peptides was paralleled by an increase in the cellular level of cyclic GMP. The addition of a cyclic GMP analogue, 8-bromo cyclic GMP, and an activator of the cytosolic guanylate cyclase, sodium nitroprusside, significantly inhibited FCS- and PDGF-BB-stimulated migration in a concentration-dependent manner. These results suggest that natriuretic peptides, especially CNP-22, inhibit FCS- or PDGF-BB-stimulated SMC migration at least in part through a cyclic GMP-dependent process. Thus, the natriuretic peptide family may play a role as an antimigration factor of SMCs under certain circumstances.     

Effects of natriuretic peptides and dopamine on single-unit activity of dorsomedial arcuate neurons in rat brain slices

The effects of atrial natriuretic peptide (ANP) and C-type natriuretic peptide (CNP) on single-unit activity of dorsomedial arcuate (DM-ARC) neurons were reported. The modulatory effect of CNP on dopamine's (DA) action was also studied. ANP alone in 0.05-0.5 nmol doses induced 26% inhibition and 14% excitation of 37 DM-ARC neurons; the majority (60%) were not responsive. CNP, however, inhibited 46% and excited 4% of 74 DM-ARC neurons. Dose-dependent inhibitory effects of CNP were also observed. In 71 neurons tested with both CNP and DA, more neurons were inhibited by DA (66%) than those by CNP (46%). About one-third (34%) of them were inhibited by both. Furthermore, in 41 neurons inhibited by DA, more than half (54%) of their responses were potentiated by co-administration of CNP. In conclusion, CNP by itself exhibited a predominantly inhibitory action on DM-ARC neurons; and it also potentiated the inhibitory effect of DA on these neurons.     

Umbilical venous guanosine 3',5'-cyclic phosphate (cGMP) concentration increases in asphyxiated newborns

Guanosine 3',5'-cyclic phosphate (cGMP) is known to be the second messenger of natriuretic peptides and nitric oxide (NO). To investigate the involvement of natriuretic peptides in the regulation of the feto-placental circulation, specific radioimmunoassays were used to measure the concentrations of atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP) and cGMP in the umbilical venous plasma of normal and asphyxiated newborns. The plasma concentrations of ANP, BNP and cGMP in asphyxiated newborns were 48.3 +/- 12.9 pm, 24.5 +/- 9.4 pm and 4.4 +/- 1.6 nM (mean +/- s.e.m., n = 10), respectively. These values were significantly higher than those in the normal newborns (17.4 +/- 1.9 pm, 4.7 +/- 1.0 pm, and 0.78 +/- 0.14 nM, respectively). Moreover, the expression of both ANP-A and ANP-B receptor, biologically active receptors for natriuretic peptides, was detected in term human placenta by Northern bolt analysis. The expression of natriuretic peptide receptors was further confirmed by binding assay using [125I]-labelled ANP and solubilized crude membrane preparations of placental tissue. These findings suggest that cGMP is produced in the placenta, at least partly, by the action of ANP and BNP secreted from fetal heart, in pathophysiological conditions such as fetal hypoxia.     

The endocrine heart and natriuretic peptides: histochemistry, cell biology, and functional aspects of the renal urodilatin system

This review focuses on some selected aspects of the endocrine heart and natriuretic peptides. The endocrine heart is composed of specific myoendocrine cells of the cardiac atria. The myoendocrine cells synthesize and secrete the natriuretic peptide hormones which exhibit natriuretic, diuretic, and vasorelaxant properties. Immunohistochemical analyses show that natriuretic peptides of the A-type and B-type are localized not only in the specific granules of these myoendocrine cells but also in many other organs including the brain, adrenal medulla, and kidney. Also, their receptors are detected in many organs showing the multiple functions of these regulatory peptides. Of the members of the natriuretic peptide family, ANP (ANP for atrial natriuretic peptide; also denominated cardiodilatin, CDD), brain natriuretic peptide (BNP), C-type natriuretic peptide (CNP), and the A-type, including its renal form, urodilatin, are emphasized in this review. Urodilatin is localized in the kidney, differentially processed, and secreted into the urine. The intrarenal synthesis and secretion is the basis for a paracrine system regulating water and sodium reabsorption at the level of the collecting duct. CDD/ANP-1-126, cleaved from a precursor of 126 amino acids in the heart to a 28-amino acid-containing circulating molecular form (CDD/ANP-99-126), and urodilatin (CDD/ANP-95-126) share similar biochemical features and biological functions, but urodilatin may be more involved in the regulation of body fluid volume and water-electrolyte excretion, while circulating CDD/ANP-99-126 is responsible for blood pressure regulation. The physiological and pharmacological properties of these peptides have great clinical impact, and as a consequence urodilatin is involved in drug development for the treatment of acute renal failure, cardiomyopathia, and acute asthma.     

Induction of type 2 deiodinase activity by cyclic guanosine 3',5'-monophosphate in cultured rat glial cells

We investigated the effects of cyclic guanosine 3',5'-monophosphate (cGMP) on type 2 iodothyronine deiodinase (D2) in cultured rat glial cells. Rat glial cells were cultured in Dulbecco's modified Eagle's medium supplemented with 15% fetal bovine serum. When cells were cultured in the presence of 8-bromo cGMP (8-Br cGMP), an analogue of cGMP, D2 activity was increased in a time- and concentration-dependent manner. Lineweaver-Burk plots revealed that the stimulation of D2 activity by 8-Br cGMP (10(-3) M) was associated with fivefold increase in maximum velocity but without a significant change in Michaelis-Menten constant, suggesting that cGMP increases D2 activity via new enzyme synthesis. Both atrial natriuretic peptide (ANP) and C-type natriuretic peptide (CNP) are well known to increase the intracellular cGMP level via their guanylate cyclase-linked receptors in rat glial cells. In the present study, ANP (10(-6) M) and CNP (10(-6) M) significantly increased the D2 activity in rat glial cells (1.9-fold [ANP] or 2.3-fold [CNP] compared with control activity, respectively). Northern blot analysis demonstrated that D2 mRNA level increased in the presence of 8-Br cGMP (10(-3) M), and reached a plateau (six-fold) after 4 hours of incubation. The increment of D2 mRNA level by 8-Br cGMP was comparable with the increase of the D2 activity by this agent. Our data suggest that cGMP induces rat D2 activity, at least in part, at the pretranslational level, and that ANP and CNP increase D2 activity most likely via their guanylate cyclase-linked receptors in rat glial cells.