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Query: UMLS:C0020538 (hypertension)
 170,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The natriuretic peptide system consists of at least three endogenous ligands: atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP) and C-type natriuretic peptide (CNP), and three receptors, ANP-A receptor (guanylate cyclase A), ANP-B receptor (guanylate cyclase B) and clearance receptor (C receptor). ANP, the prototype of natriuretic peptides, is mainly produced in the atrium and secreted into the circulation as a cardiac hormone. ANP is also produced in the ventricle and in the central nervous system. BNP, first isolated from the porcine brain, has a marked divergence in its molecular size and sequence among species. In humans and rats, the major site of production of BNP is the ventricle of the heart. BNP is also secreted into the circulation as a cardiac hormone. The plasma BNP level in normal subjects is approximately one sixths of the plasma ANP level; however, the plasma BNP level markedly increases in heart failure, renal failure and hypertension and the augmentation of the BNP secretion is much larger than that of the ANP secretion. In addition, clearance of BNP from the circulation is slower than that of ANP. Furthermore, BNP is secreted more urgently than ANP in acute heart failure. CNP distributes mainly in the central nervous system and pituitary gland. No significant amount of CNP is detectable in the heart and plasma. Thus, CNP is a local regulator rather than a cardiac hormone. Three natriuretic receptors have ligand selectivity.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[Natriuretic peptide family]. 134 67

We have evaluated the genes for angiotensin converting enzyme (ACE) and guanylyl cyclase A/atrial natriuretic peptide receptor (GCA) for genetic effects on blood pressure response to high salt diet. In F2 rats derived from Milan normotensive and Dahl salt-hypertension sensitive (S) rats, both ACE and GCA cosegregated with blood pressure, and rats that were homozygous for the S allele at both the ACE and GCA loci had inordinately high blood pressure. In F2 derived from Wistar Kyoto (WKY) and S rats, GCA revealed positive cosegregation with blood pressure, but ACE did not. We conclude that certain alleles at the GCA and ACE loci (or at loci closely linked to them) have a significant genetic impact on blood pressure response to high salt in specific rat strains.
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PMID:Cosegregation of blood pressure with angiotensin converting enzyme and atrial natriuretic peptide receptor genes using Dahl salt-sensitive rats. 136 13

1. Ageing and hypertension are associated with changes in the way in which the body handles sodium. This may involve changes in plasma atrial natriuretic peptide concentration, since atrial natriuretic peptide is a regulator of sodium handling by the kidney and the plasma atrial natriuretic peptide concentration is increased in both ageing and hypertension. An increase in the plasma atrial natriuretic peptide concentration could also be associated with a change in atrial natriuretic peptide receptor density, possibly involving down-regulation. 2. To investigate these possibilities plasma atrial natriuretic peptide concentration and platelet atrial natriuretic peptide binding site density were measured in 18 young, 11 middle-aged and 12 elderly healthy subjects and in 23 patients with mild to moderate essential hypertension. 3. In normotensive subjects, the plasma atrial natriuretic peptide concentration increased with age (r = 0.49, P less than 0.01) and was significantly higher in elderly than young subjects (mean +/- SEM, 31.9 +/- 4.5 versus 18.3 +/- 2.0 pmol/l, P less than 0.05). The plasma atrial natriuretic peptide concentration increased with the mean arterial pressure in normotensive subjects (r = 0.47, P less than 0.01). Multiple regression analysis did not show independent relationships between the plasma atrial natriuretic peptide concentration and either age or mean arterial pressure in normotensive subjects alone. However, when normotensive subjects and hypertensive patients were considered together, multiple regression revealed both age and mean arterial pressure as independent predictors of the plasma atrial natriuretic peptide concentration (P less than 0.05, P less than 0.01, respectively). In normotensive subjects, the platelet atrial natriuretic peptide binding site density did not change with age (r = 0.19, P = 0.27).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Plasma atrial natriuretic peptide concentration and platelet atrial natriuretic peptide binding site density in ageing and hypertension. 165 97

To understand the molecular mechanisms of cellular signaling of atrial natriuretic peptide (ANP), we have studied its effect on the enzymatic activity of endogenous and overexpressed protein kinase C (PKC) in rat thoracic aortic vascular smooth muscle (RTASM) cells. Angiotensin II (ANG II), endothelin-1 (ET-1), and 12-O-tetradecanoylphorbol 13-acetate (TPA) stimulated fourfold to fivefold PKC activity in PKC-alpha cDNA-transfected RTASM cells. However, pretreatment of these cells with ANP significantly inhibited the agonist-stimulated PKC activity in a dose-dependent manner. The inhibitory effect of ANP was more effective if cells were transfected with both PKC-alpha and guanylyl cyclase-A/atrial natriuretic peptide receptor (Npra) cDNAs. The agonist-stimulated PKC activity was also inhibited if RTASM cells were pretreated with cGMP analog 8-bromo-cGMP; however, the treatment of cells with a cAMP analog, dibutyryl-cAMP, did not show any discernible effect. The pretreatment of cells with Npra antagonist A-71915, significantly blocked the production of cGMP as well as the inhibitory effect of ANP on PKC activity. To further examine whether the antagonistic action of ANP and 8-bromo-cGMP on agonist-stimulated PKC activity were mediated through cGMP-dependent protein kinase (PKG), cells were treated with ANP or 8-bromo-cGMP and activators of PKC in the presence of KT-5823, a specific inhibitor of PKG. The treatment of cells with KT-5823 significantly attenuated the inhibitory effects of both ANP and 8-bromo-cGMP on agonist-stimulated PKC activity. The results from these studies provide strong evidence that ANP antagonizes the activation of PKC in RTASM cells, involving guanylyl cyclase-A receptor Npra and second messenger cGMP. Our data further support the notion that ANP acts as a negative mediator of signaling cross-talks between Npra and PKC in a cGMP-dependent manner, probably involving cGMP-dependent protein kinase in this process.
Hypertension 1997 Jan
PMID:Expression of guanylyl cyclase-A/atrial natriuretic peptide receptor blocks the activation of protein kinase C in vascular smooth muscle cells. Role of cGMP and cGMP-dependent protein kinase. 903 36

Natriuretic peptides, produced in the heart, bind to the natriuretic peptide receptor A (NPRA) and cause vasodilation and natriuresis important in the regulation of blood pressure. We here report that mice lacking a functional Npr1 gene coding for NPRA have elevated blood pressures and hearts exhibiting marked hypertrophy with interstitial fibrosis resembling that seen in human hypertensive heart disease. Echocardiographic evaluation of the mice demonstrated a compensated state of systemic hypertension in which cardiac hypertrophy and dilatation are evident but with no reduction in ventricular performance. Nevertheless, sudden death, with morphologic evidence indicative in some animals of congestive heart failure and in others of aortic dissection, occurred in all 15 male mice lacking Npr1 before 6 months of age, and in one of 16 females in our study. Thus complete absence of NPRA causes hypertension in mice and leads to cardiac hypertrophy and, particularly in males, lethal vascular events similar to those seen in untreated human hypertensive patients.
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PMID:Hypertension, cardiac hypertrophy, and sudden death in mice lacking natriuretic peptide receptor A. 940 81

Recently, we reported that primary cultures of inner medullary collecting duct cells from Dahl salt-sensitive (S) rats absorb more Na+ than do cells cultured from Dahl salt-resistant (R) rats. To begin to evaluate the molecular basis for this difference, we selected four candidate gene products that on the basis of their physiology and genetics could participate in regulation of Na+ transport by these cells. During 24-hour exposure, inhibitors of the cytochrome P450 enzymes had no effect on Na+ transport by either S or R monolayers. Twenty-four-hour exposure to NG-monomethyl-L-arginine (0.5 mmol/L), a nonspecific inhibitor of NO synthase, also had no effect on Na+ transport by either S or R monolayers. Neither atrial natriuretic peptide 1-28 (100 nmol/L) nor 8-Br-cyclic GMP (100 micromol/L) had any short-term effect on Na+ transport by either S or R monolayers. 18-Hydroxy-11-deoxycorticosterone (100 nmol/L), an adrenocorticoid hormone that is produced in greater amounts in S rats, stimulated Na+ transport by both S and R monolayers via the mineralocorticoid receptor; however, its effect was less potent than aldosterone. Congenic rats in which the R isoform of the 11beta-hydroxylase gene was bred onto the S background had monolayers that transported Na+ at a rate similar to the S rats. These results demonstrate that neither cytochrome P450 genes, NO synthase genes, the atrial natriuretic peptide receptor gene, nor the 11beta-hydroxylase gene is a likely candidate to explain the difference in Na+ transport between S and R inner medullary collecting duct monolayers in primary culture.
Hypertension 1998 Feb
PMID:Candidate genes in the regulation of Na+ transport by inner medullary collecting duct cells from Dahl rats. 946 Dec 29

Mice lacking the gene (Npr1) encoding the natriuretic peptide receptor A (NPRA) have hypertension with elevated blood pressure and cardiac hypertrophy. In particular, Npr1 gene-deficient male mice exhibit lethal vascular events similar to those seen in untreated human hypertensive patients. Serum testosterone levels tend to be lower in hypertensive male humans than in normal males without hypertension, but the genetic basis for this tendency remains unknown. To determine whether Npr1 gene function affects the testosterone level, we measured serum testosterone in male hypertensive mice lacking a functional Npr1 gene, wild-type animals with two copies, and the gene-duplicated littermates expressing four copies of the gene. In the Npr1 gene-knockout (zero-copy) mice, the serum testosterone level was 62% lower than that in the two-copy control mice (80+/-10 ts. 120+/-14 ng/ml, respectively; P < 0.005). Serum testosterone in the four-copy mice was 144% (P < 0.005) of that in the two-copy wild-type control mice. To investigate the role of NPRA in testicular steroidogenesis, we analyzed atrial natriuretic peptide (ANP)-dependent guanylyl cyclase activation, accumulation of intracellular cGMP, and testosterone production in purified primary Leydig cells from animals with zero, two, or four copies of the Npr1 gene. Leydig cells lacking the Npr1 gene did not show ANP-stimulated guanylyl cyclase activation or cGMP accumulation and had no ANP-dependent testosterone production. ANP stimulation of Leydig cells from the four-copy males elicited a 2-fold greater production of cGMP compared to that in the two-copy wild-type counterparts (260+/-12 vs. 126+/-7 pmol/l x 10(6) cells; P < 0.001). Similarly, ANP-dependent testosterone production in Leydig cells was nearly twice as high in four-copy mice as in two-copy wild-type controls (561+/-18 vs. 325+/-11 ng/l x 10(6) cells; P < 0.001). ANP-dependent guanylyl cyclase activation and production of cGMP in Leydig cells increased progressively with the number of Npr1 gene copies. Our results establish the existence of an alternate mechanism for testicular steroidogenesis that is stimulated by NPRA-dependent cGMP signaling, in addition to that mediated by gonadotropins, via a cAMP pathway. These findings demonstrate the role of Npr1 gene function in the maintenance of serum testosterone levels and testicular steroidogenesis and provide a genetic link between hypertension associated with decreased NPRA and low testosterone levels.
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PMID:Hypertension associated with decreased testosterone levels in natriuretic peptide receptor-A gene-knockout and gene-duplicated mutant mouse models. 1053 39

The activity of the atrial natriuretic peptide receptor (Npr1) is altered in spontaneously hypertensive rats (SHR) in relation to its mRNA levels, suggesting abnormal transcriptional control in hypertension. A single-stranded conformational polymorphism caused by a repetitive dinucleotide segment of 10 TA in BN-Lx and of 40 TA in SHR was localized at position -943 relative to the transcription start site of the Npr1 gene, downstream of a putative cGMP-regulatory region, and was the only sequence difference noted between the two strains. Transient transfections of -1520 to -920 Npr1 promoter-SV40-luciferase fusion vector showed that the construct from BN-Lx stimulated the SV40 promoter, whereas that from SHR slightly inhibited it. In contrast to the BN-Lx construct, the activity of the SHR fragment was refractory to downregulation by atrial natriuretic peptide. Genotype-phenotype correlation studies in recombinant inbred strains (RIS) derived from BN-Lx and SHR crosses revealed significant correlations of the TA repeat with basal guanylyl cyclase activity and Npr1 mRNA levels. The correlations were heightened by a locus on chromosome 10 containing the Ace gene. The highest basal guanylyl cyclase activity and Npr1 mRNA values were found in RIS with both genes (Npr1/Ace) of BN genotypes, whereas the lowest were recorded in RIS, with the SHR genotypes at both loci. This was inversely correlated with diastolic blood pressure in these strains. In conclusion, the longer TA repeat unit in the promoter of Npr1 of SHR, in tandem with a putative cGMP responsive element, regulates the transcription of the Npr1 gene with consequences on diastolic blood pressure.
Hypertension 2003 Jan
PMID:TA repeat variation, Npr1 expression, and blood pressure: impact of the Ace locus. 1251 24

Atrial natriuretic peptide receptor A (NPRA) plays important role(s) in the control of extracellular fluid volume and blood pressure homeostasis. We have determined and analyzed the functional promoter region of Npr1 gene (coding for NPRA) and studied the effect of angiotensin (Ang) II on its promoter activity and expression in cultured mouse mesangial cells. The promoter analysis of Npr1 gene revealed the presence of positive regulatory cis-elements in the regions -1982 to -1841 bp and -916 to -496 bp and of the repressor elements in the regions -1841 to -916 bp and 56 to 382 bp relative to transcription start site. The Ang II pretreatment of cultured mouse mesangial cells transiently transfected with the promoter construct pNPRA-luc1 significantly inhibited the promoter activity in a time- and dose-dependent manner, with a maximum inhibition at 24 hours. The Ang II-dependent repression of Npr1 promoter activity was partially blocked by both angiotensin type 1 and type 2 antagonists candesartan and PD 123,319, respectively. The mRNA level of NPRA was also downregulated by Ang II treatment as determined by semiquantitative reverse transcriptase-polymerase chain reaction assay. The deletion analysis showed that the promoter region approximately 916 bp upstream of transcription start site contains the cis-elements involved in Ang II-mediated repression of transcription of Npr1 gene. The present study thus reveals the presence of functional cis-regulatory elements in the promoter region of the murine Npr1 gene and its transcriptional downregulation by vasoactive peptide Ang II.
Hypertension 2003 Mar
PMID:Angiotensin II-mediated negative regulation of Npr1 promoter activity and gene transcription. 1262 88

Cardiac hypertrophy is associated with ventricular arrhythmias and sudden death. The molecular mechanisms that predispose the hypertrophied heart to arrhythmias are not well understood. In mice, deletion of the gene coding for the atrial natriuretic peptide receptor, guanylyl cyclase A (GC-A-/-), causes arterial hypertension, cardiac hypertrophy and sudden death. We used this mouse model to study molecular mechanisms of arrhythmias in the hypertrophied heart. Right and left ventricular monophasic action potential durations (APD) were recorded in isolated, Langendorff-perfused hearts during pacing from the right atrium and ventricle. The atrioventricular (AV) node was ablated to provoke bradycardia. Intracellular Ca(2+) transients were measured in isolated INDO-1 loaded ventricular myocytes. Cardiac expression of Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) was analyzed by western blotting. Polymorphic ventricular arrhythmias (pVT) occurred spontaneously after mechanical AV block in 20/45 hearts from 12-month-old GC-A-/- mice (P < 0.05), but neither in age-matched GC-A+/+ hearts nor in hearts from 3-month-old mice of either genotype. Triggered activity preceded pVT. APD were prolonged and systolic Ca(i)(2+) levels were increased in GC-A-/- hearts independently of age. In 12-month-old GC-A-/- hearts only, dispersion of APD and expression levels of CaMKII were increased. CaMKII expression was particularly increased in hearts with pVT. Direct inhibition of CaMKII activation by KN93 (0.5 or 2 microM) or inhibition of Ca(2+)/calmodulin-dependent activation of CaMKII by W-7 (25 microM) suppressed pVT in GC-A-/- hearts (P < 0.05) while prolonging APD. The combination of increased CaMKII activity and altered action potential characteristics facilitates ventricular arrhythmias in hypertrophic GC-A-/- hearts.
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PMID:Ventricular arrhythmias, increased cardiac calmodulin kinase II expression, and altered repolarization kinetics in ANP receptor deficient mice. 1513 64


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