Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0004135 (ATM)
 13,001 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Mice harboring a functional deletion of the pro-atrial natriuretic peptide (ANP) gene (-/-) develop salt-sensitive hypertension relative to their wild-type (+/+) counterparts after prolonged (>1 wk) maintenance on high-salt (HS, 8% NaCl) diet. We reported recently that the sensitization of arterial blood pressure (ABP) to dietary salt in the -/- mice is associated with failure to downregulate plasma renin activity. To further characterize the role and mechanism of ANG II in the sensitization of ABP to salt in the ANP "knockout" mice, we measured ABP, heart rate (HR), and plasma catecholamine and aldosterone concentrations in -/- and +/+ mice maintained on HS for 4 wk and treated with daily injections of AT1 receptor antagonist DuP-753 (losartan) or distilled water (control). Daily food and water intake and fluid and electrolyte excretion were also measured during the first and last weeks of the dietary regimen. Cumulative urinary excretion of fluid and electrolytes did not differ significantly between genotypes and was not altered by chronic treatment with losartan. Basal ABP and HR were significantly elevated in control -/- mice compared with control +/+ mice. Losartan did not affect ABP or HR in +/+ mice, but reduced ABP and HR in the -/- mice to the levels in the +/+ mice. Total plasma catecholamine was elevated by approximately ten-fold in control -/- mice compared with control +/+ mice. Losartan reduced plasma catecholamine concentration significantly in -/- mice and abrogated the difference in plasma catecholamine between -/- and +/+ mice on HS diet. Plasma aldosterone did not differ significantly between genotypes and was not altered by losartan. We conclude that salt sensitivity of ABP in ANP knockout mice is mediated, at least in part, by a synergistic interaction between ANG II and sympathetic nerve activity.
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PMID:Salt-sensitive hypertension in ANP knockout mice is prevented by AT1 receptor antagonist losartan. 1048 77

The Ca2+ -and receptor-dependencies of the basal tone seen in angiotensin II (Ang II)-conditioned rabbit thoracic aortic rings were investigated. Ca2+ -free Krebs significantly and partially reversibly reduced basal tone in aortic rings that had recovered from an earlier challenge with Ang II; rings not previously exposed to Ang II were unaffected. The effect of Ca2+ -free Krebs was similar to the reduction in basal tone evoked by atrial natriuretic peptide (ANP), but was smaller than that seen with exposure to Ca2+ -free Krebs+EGTA+sodium nitroprusside (SNP). Pretreating rings with Ca2+ free Krebs blocked the vasorelaxant effects of ANP and Ca2+ -free Krebs+EGTA+SNP. Losartan, an AT1 receptor antagonist, significantly attenuated ANP-induced relaxation, but did not otherwise alter basal tension in either unstimulated or Ang II-conditioned rings. The AT2 receptor antagonist, PD 123319, had no effect. These data suggest that transient exposure to Ang II induces prolonged, AT1-dependent increases in intracellular free Ca2+ which are antagonized by ANP.
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PMID:Losartan reduces the vasorelaxant effect of atrial natriuretic peptide on basal tone in aorta. 1057 12

1. The renal medulla plays an important role in regulating body sodium and fluid balance and blood pressure homeostasis through its unique structural relationships and interactions between renomedullary interstitial cells (RMIC), renal tubules and medullary vasculature. 2. Several endocrine and/or paracrine factors, including angiotensin (Ang)II, endothelin (ET), bradykinin (BK), atrial natriuretic peptide (ANP) and vasopressin (AVP), are implicated in the regulation of renal medullary function and blood pressure by acting on RMIC, tubules and medullary blood vessels. 3. Renomedullary interstitial cells express multiple vasoactive peptide receptors (AT1, ETA, ETB, BK B2, NPRA and NPRB and V1a) in culture and in tissue. 4. In cultured RMIC, AngII, ET, BK, ANP and AVP act on their respective receptors to induce various cellular responses, including contraction, prostaglandin synthesis, cell proliferation and/or extracellular matrix synthesis. 5. Infusion of vasoactive peptides or their antagonists systemically or directly into the medullary interstitium modulates medullary blood flow, sodium excretion and urine osmolarity. 6. Overall, expression of multiple vasoactive peptide receptors in RMIC, which respond to various vasoactive peptides and paracrine factors in vitro and in vivo, supports the hypothesis that RMIC may be an important paracrine target of various vasoactive peptides in the regulation of renal medullary function and long-term blood pressure homeostasis.
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PMID:Renomedullary interstitial cells: a target for endocrine and paracrine actions of vasoactive peptides in the renal medulla. 1087

In spite of several drugs for the treatment of hypertension, there are many patients with poorly controlled high blood pressure. This is partly due to the fact that all available drugs are short-lasting (24 hr or less), have side effects, and are not highly specific. Gene therapy offers the possibility of producing longer-lasting effects with precise specificity from the genetic design. Preclinical studies on gene therapy for hypertension have taken two approaches. Chao et al. have carried out extensive studies on gene transfer to increase vasodilator proteins. They have transferred kallikrein, atrial natriuretic peptide, adrenomedullin, and endothelin nitric oxide synthase into different rat models. Their results show that blood pressure can be lowered for 3-12 weeks with the expression of these genes. The antisense approach, which we began by targeting angiotensinogen and the angiotensin type 1 receptor, has now been tested independently by several different groups in multiple models of hypertension. Other genes targeted include the beta 1-adrenoceptor, TRH, angiotensin gene activating elements, carboxypeptidase Y, c-fos, and CYP4A1. There have been two methods of delivery antisense; one is short oligodeoxynucleotides, and the other is full-length DNA in viral vectors. All the studies show a decrease in blood pressure lasting several days to weeks or months. Oligonucleotides are safe and nontoxic. The adeno-associated virus delivery antisense to AT1 receptors is systemic and in adult rodents decreases hypertension for up to 6 months. We conclude that there is sufficient preclinical data to give serious consideration to Phase I trials for testing the antisense ODNs, first and later the AAV.
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PMID:Gene therapy for hypertension: the preclinical data. 1188 75

1. The aim of the present study was to determine whether the regulation of vascular natriuretic peptide receptors (NPR) is related to the local renin-angiotensin system (RAS). 2. Male Sprague-Dawley rats were made two-kidney, one-clip (2K1C) and deoxycorticosterone acetate (DOCA)-salt hypertensive to activate and inhibit the RAS, respectively. Another model of hypertension was induced by treatment with an inhibitor of nitric oxide synthesis, namely NG-nitro-L-arginine methyl ester (L-NAME). 3. The mRNA expression of NPR-A, NPR-C, angiotensin- converting enzyme (ACE) and angiotensin AT1 receptors was determined in the thoracic aorta by semiquantitative reverse transcription-polymerase chain reaction. The particulate guanylyl cyclase activity stimulated by atrial natriuretic peptide (ANP) was also determined in the membrane fraction of the thoracic aorta. 4. The plasma concentrations of ANP were increased significantly in the three models of hypertension. Plasma renin activity was increased in 2K1C hypertension, decreased in DOCA-salt hypertension and not significantly altered in L-NAME hypertension. 5. The mRNA expression of NPR-A and NPR-C was decreased, whereas that of ACE and AT1 receptors was increased in 2K1C and L-NAME hypertension. The mRNA expression of NPR-A and NPR-C was increased, whereas that of ACE and AT1 receptors was decreased in DOCA-salt hypertension. 6. The particulate guanylyl cyclase activity was decreased in 2K1C and L-NAME hypertension and increased in DOCA-salt hypertension. 7. The vascular expression of NPR may be reciprocally regulated by local RAS activity.
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PMID:Altered expression of vascular natriuretic peptide receptors in experimental hypertensive rats. 1198 39

The aim of this study was to evaluate the medium-term effects of the selective AT1-blocker irbesartan on atrial natriuretic peptide (ANP) levels in patients with moderate essential hypertension. The drug was given orally in a daily dose of 300 mg for 30 days. Plasma ANP levels increased by 15.7% despite the drop in blood pressure and the slight decrease of atrial and ventricular diameters. These findings indicate that AT,-blockers like irbesartan exert part of their antihypertensive action by increasing ANP plasma levels.
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PMID:Plasma atrial natriuretic peptide in essential hypertension after treatment with irbesartan. 1203 77

Mice with a genetic deletion of the atrial natriuretic peptide (ANP) receptor, guanylyl cyclase A (GC-A -/-), have chronic arterial hypertension and cardiac hypertrophy from the first day of life. To characterize the role of the angiotensin II and endothelin systems in the development of this cardiovascular phenotype, the effects of chronic treatment with either the angiotensin type I (AT1) receptor antagonist losartan or the endothelin A receptor antagonist BSF208075 were tested. Losartan almost completely reversed systemic arterial hypertension and left ventricular hypertrophy of GC-A -/- mice. This was accompanied by a marked regression of the left ventricular mRNA expression of cardiac hypertrophy markers such as ANP and brain natriuretic peptide and a significant reduction of left ventricular and pulmonary interstitial collagen accumulation. BSF208075 had no effect on any of these cardiovascular parameters. Intriguingly, GC-A -/- mice also showed a very marked right ventricular hypertrophy, which was not reversed by losartan or BSF208075 treatment. Analyses of components of the renin-angiotensin system (RAS) revealed an inhibition of renal and systemic RAS contrasting with increased local left ventricular angiotensin II levels in GC-A -/- mice. Collectively, the results suggest that RAS plays a more important role than the endothelin system in the pathogenesis of arterial hypertension as well as left ventricular hypertrophy and fibrosis in GC-A gene-disrupted mice.
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PMID:Left but not right cardiac hypertrophy in atrial natriuretic peptide receptor-deficient mice is prevented by angiotensin type 1 receptor antagonist losartan. 1240 81

We have previously demonstrated that stimulation of the angiotensin (Ang) II type 2 receptor in vascular smooth muscle cells caused bradykinin production by activating kininogenase in transgenic mice. The aim of this study was to determine whether overexpression of AT2 receptors in cardiomyocytes attenuates Ang II-induced cardiomyocyte hypertrophy or interstitial fibrosis through a kinin/nitric oxide (NO)-dependent mechanism in mice. Ang II (1.4 mg/kg per day) or vehicle was subcutaneously infused into transgenic mice and wild-type mice for 14 days. The amount of cardiac AT2 receptor relative to AT1 receptor in transgenic mice was 22% to 37%. Ang II caused similar elevations in systolic blood pressure (by approximately 45 mm Hg) in transgenic mice and wild-type mice. Myocyte hypertrophy assessed by an increase in myocyte cross-sectional area, left ventricular mass, and atrial natriuretic peptide mRNA levels were similar in transgenic and wild-type mice. Ang II induced prominent perivascular fibrosis of the intramuscular coronary arteries, the extent of which was significantly less in transgenic mice than in wild-type mice. Inhibition of perivascular fibrosis in transgenic mice was abolished by cotreatment with HOE140, a bradykinin B2 receptor antagonist, or L-NAME, an inhibitor of NO synthase. Cardiac kininogenase activity was markedly increased (approximately 2.6-fold, P<0.001) after Ang II infusion in transgenic mice but not in wild-type mice. Immunohistochemistry indicated that both bradykinin B2 receptors and endothelial NO synthase were expressed in the vascular endothelium, whereas only B2 receptors were present in fibroblasts. These results suggest that stimulation of AT2 receptors present in cardiomyocytes attenuates perivascular fibrosis by a kinin/NO-dependent mechanism. However, the effect on the development of cardiomyocyte hypertrophy was not detected in this experimental setting.
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PMID:Cardiac angiotensin II type 2 receptor activates the kinin/NO system and inhibits fibrosis. 1251 37

Data derived from a 10 years research program of our team demonstrate that many categories of antihypertensive drugs like beta-adrenergic blockers, alpha1-adrenergic blockers, ACE inhibitors, AT1-receptor antagonists and calcium-entry blockers increase plasma atrial natriuretic peptide (ANP) levels after a medium-term treatment of patients suffering from moderate essential hypertension. ANP always increases despite the drop of the arterial pressure and the fact that the left atrial and ventricular diameters remain unchanged or slightly reduced. These findings indicate that the increase of ANP plasma levels is not the result of a mechanical overload in the left cardiac chambers but the result of a pharmacological action. In conclusion, ANP is a universal factor contributing to the antihypertensive action of many drugs.
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PMID:Atrial natriuretic peptide contributes to the antihypertensive action of many drugs. 1450 65

Blockade of AngII (angiotensin II) and ET (endothelin)-1, established and potential therapeutic strategies respectively, for heart failure, may have an adverse effect on the cardiac secretion of the natriuretic peptides, hormones with actions beneficial in this disease. The present study investigates the roles of AngII and ET-1 in regulating the stretch-induced release of the natriuretic peptides during the development of heart failure. On seven separate days, eight sheep underwent incremental left ventricular pacing (155, 190 and 225 beats/min for 90 min each) with concurrent infusions of a vehicle control, AngII, ET-1, AngII+ET-1, losartan [AT1 (AngII type 1) receptor antagonist], bosentan (ET(A)/ET(B) receptor antagonist) or losartan+bosentan. Pacing-induced rises in LAP (left atrial pressure) were amplified by the simultaneous administration of separate AngII and ET-1, and attenuated following blockade of the peptides, with maximum effects observed during combined treatments. Although these changes in atrial pressure were paralleled by concomitant alterations in circulating levels of both ANP (atrial natriuretic peptide) and BNP (brain natriuretic peptide), the plasma natriuretic peptide/atrial pressure relationship tended to be augmented by AngII and ET-1 and diminished by their blockade. A significant difference was demonstrated between the enhanced plasma BNP response to increasing LAP during combined AngII+ET-1 administration and decreased response during losartan+bosentan treatment ( P <0.05). A similar, but non-significant, trend was evident for ANP. The present study indicates dual AngII/ET-1 blockade diminishes BNP (and to a lesser extent ANP) secretion in developing heart failure, suggesting that augmentation of the natriuretic peptide system during the combination of these therapies may be of benefit.
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PMID:Combined inhibition of angiotensin II and endothelin suppresses the brain natriuretic peptide response to developing heart failure. 1472 2


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