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

The 'discovery' of losartan represents three separate discoveries: (1) losartan as the unique biphenyltetrazole molecule and the first of a new chemical class; (2) losartan as a tool to identify AT1-subtype receptors; and (3) losartan as a specific probe for exploring the multiple roles of angiotensin II (Ang II) in normal physiology and pathologic states. Losartan is the first nonpeptide orally active Ang II receptor antagonist to reach clinical trials. Losartan was selected for its affinity for Ang II receptors, functional antagonism of Ang II, lack of agonist properties, and oral anti-hypertensive effects. Losartan has been widely used to define the distribution and function of AT receptor subtypes. Although possible roles of the AT2 subtype have been reported, virtually all of the known effects of Ang II are blocked by losartan. Specific AT1 receptor blockade has been broadly compared with ACE inhibition. Possible differences on the basis of AT1 selectivity, bradykinin potentiating effects and Ang II formed by non-ACE pathways are discussed. Losartan blocks the vascular constrictor effect of Ang II, the Ang II-induced aldosterone synthesis and/or release, and the Ang II-induced cardiovascular 'growth' in vitro and in vivo. In various models of experimental hypertension, losartan prevents or reverses the elevated blood pressure and the associated cardiovascular hypertrophy similar to ACE inhibitors. Likewise, in models of renal failure (for example reduced renal mass, puromycin, ochratoxin), losartan, like ACE inhibition, markedly reduced the elevation in blood pressure, proteinuria or sclerosis. In aortocaval shunt, coronary ligation and ventricular pacing models of heart failure, losartan demonstrated a pathological role for Ang II by reversing the associated haemodynamic findings. In SHR-stroke prone, losartan dramatically increased survival while having a limited effect on blood pressure, suggesting a non-pressure dependent effect of Ang II. These collective data show that Ang II exerts complex pathological effects in experimental models of vascular, cardiac, renal and cerebral disease. The effectiveness of losartan in experimental models of heart failure supports its evaluation in clinical trials with patients with heart failure.
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PMID:Discovery of losartan, the first angiotensin II receptor antagonist. 858 79

Biological actions of natriuretic peptide (NP) are determined by the condition of the receptor as well as that of the hormone. Although we previously demonstrated in hypertensive rats the up-regulation of NP-A receptor that mediates various biological actions of NPs, the pathophysiologic significance of NP-C receptor, another subtype thought to be related to clearance of NPs and possibly to biological actions, remains unknown. In the present study, we determined NP-C receptor messenger RNA (mRNA) level in the aortic tissue of stroke-prone spontaneously hypertensive rats (SHR-SP/Izm) and in cultured aortic smooth muscle cells by ribonuclease protection assay. The aortic NP-C receptor mRNA level in SHR-SP/Izm was significantly lower than that in the control WKY/Izm. Oral administration of an angiotensin (Ang) II receptor (AT1) antagonist, TCV-116, but not a calcium channel blocker, manidipine, reversed the down-regulated NP-C receptor mRNA in SHR-SP/Izm to the level in WKY/Izm, whereas the latter was more potent in decreasing the blood pressure. In cultured aortic smooth muscle cells, the NP-C receptor was the predominant subtype. Ang II decreased the NP-C receptor mRNA level in a dose-dependent manner, but this effect was reversed by an AT1 antagonist, CV-11974. Neither the NP-A nor NP-B receptor mRNA level was altered by Ang II. These findings indicate that vascular NP-C receptor is down- regulated via Ang-II-mediated mechanism in SHR-SP/Izm. The phenomenon, together with the up-regulation of the NP-A receptor, may play an important role in counteracting hypertension by enhancing the action of NPs.
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PMID:Angiotensin II-dependent down-regulation of vascular natriuretic peptide type C receptor gene expression in hypertensive rats. 860 80

Angiotensin-(1-7) [Ang-(1-7)] was recently recognized to have novel biological functions that are distinct from those of Ang II. In these studies, we determined the vasoactive effects of Ang-(1-7) together with the endothelium-dependent mediator(s) of these responses in canine coronary arteries. Isometric tension was measured in intact canine coronary artery rings suspended in organ chambers perfused with 95% O2/5% CO2 at 37 degrees C. Ang-(1-7) caused significant concentration-dependent vascular relaxation (2.73 +/- 0.58 micromol/L, EC50) of rings precontracted with the thromboxane A2 analogue U46,619. Pretreatment with the nitric oxide synthase inhibitor N(omega)-nitro-L-arginine (1 mol/L) abolished the vasodilator response to Ang-(1-7), whereas treatment with the cyclooxygenase inhibitor indomethacin (10 micromol/L) was without effect. The vasodilator response produced by Ang-(1-7) was blocked by 75% with the bradykinin B2 receptor antagonist Hoe 140 (1 micromol/L) or by 80% with the nonselective Ang II antagonist [Sar1,Thr8]-Ang II (1 micromol/L). In contrast, the selective AT1 or AT2 Ang II antagonists CV 11974 (1 micromol/L), and PD 123319 (1 micromol/L), respectively, were ineffective in inhibiting the Ang-(1-7)-elicited vasodilation. Furthermore, pretreatment of the coronary rings with 2 micromol/L Ang-(1-7) markedly potentiated the bradykinin response. These results suggest that Ang-(1-7) elicits coronary vasodilation that is specifically mediated by the endothelium-dependent release of nitric oxide. These responses involve a B2 bradykinin receptor and a non-AT1, non-AT2, angiotensin receptor. These data suggest that increases in circulating levels of Ang-(1-7) accompanying long-term administration of converting enzyme inhibitors or Ang II receptor blockers may contribute to the cardioprotective actions of these drugs.
Hypertension 1996 Mar
PMID:Angiotensin-(1-7) dilates canine coronary arteries through kinins and nitric oxide. 861 97

We have reported that the angiotensin II (Ang II) AT1 receptor antagonist losartan markedly lowers arterial pressure in sodium-replete, normotensive rats. We hypothesized that this action of losartan was mediated by its blocking the effects of endogenous Ang II. To test this hypothesis, rats were instrumented with arterial and venous catheters for measurement of arterial pressure and infusion of losartan, respectively. After 3 days of control measurements, losartan was infused for 10 days (10 mg/kg/d) in rats on a normal daily sodium intake (NNa; approximately 2 mmol/d, n=6) and rats on a high daily sodium intake (HNa; approximately 15 mmol/d, n=7) to suppress endogenous Ang II. Although basal plasma renin activity was markedly suppressed in HNa rats (0.9 +/- 0.4 ng Ang I/ mL/h) compared with NNa rats (4.0 +/- 0.3 ng Ang I/mL/h), control arterial pressure was not different between NNa (113 +/- 4 mm Hg) and HNa (113 +/- 2 mm Hg) rats. Losartan decreased arterial pressure from control levels in NNa rats on the first day of infusion (-12 +/- 2 mm Hg) but had no effect on arterial pressure in HNa rats (+4 +/- 4 mm Hg). Furthermore, by day 10 of losartan infusion, arterial pressure had decreased further from control levels in NNa rats (-32 +/- 2 mm Hg) but remained unchanged compared with control in HNa rats (+5 +/- 6 mm Hg). A second study was conducted to test the hypothesis that the area postrema, a circumventricular organ proposed to mediate the long-term neurogenic pressor activity of Ang II is a site of action for losartan. After 3 control days, losartan was administered for 10 days to area postrema-lesioned rats (APx; n=11) or sham-lesioned rats (n=10) consuming an NNa diet. Control arterial pressure was similar in sham (95 +/- 3 mm Hg) and APx (96 +/- 2 mm Hg) rats. Basal plasma renin activity was not different between groups (sham, 4.1 +/- 1.5 versus APx, 5.3 +/- 1.6 mm Hg Ang I/mL/h). On day 1 of losartan treatment, arterial pressure decreased to a significantly lower level in sham (80 +/- 2 mm Hg) compared with APx (90 +/- 3 mm Hg) rats. This trend continued through day 4 of losartan infusion, in which arterial pressure in sham rats (72.2 +/- 2 mm Hg) was significantly lower than in APx rats (83 +/- 4 mm Hg). However, during the remainder of the losartan infusion, there were no significant differences between groups with the exception of day 8 (sham, 72 +/- 2 mm Hg; APx, 84 +/- 2 mm Hg). Taken together, these results support the hypothesis that the hypotensive actions of losartan in sodium-replete, normotensive rats are due to blockade of the physiological effects of endogenous Ang II. Furthermore, an intact area postrema is essential for full expression of the hypotensive actions of losartan in normal rats.
Hypertension 1996 Mar
PMID:Hypotensive response to losartan in normal rats. Role of Ang II and the area postrema. 861 10

We performed studies to further elucidate the mechanisms of angiotensin II (Ang II)-induced angiogenesis of the microvasculature. Rats were placed on a high salt diet (4% NaCl), and Ang II was infused at a subpressor rate (5 ng/kg per minute) for 3 days. Blood pressure was measured daily for 2 control and 3 infusion days. Microvessel density in the cremaster muscle was measured at the end of the infusion. Vessel density in rats that received subpressor Ang II infusion increased by 12.6% compared with rats that received vehicle infusion. When the angiotensin type 2 (AT2) receptor antagonist PD 123319 was coinfused with Ang II, blood pressure was elevated and vessel density increased above that observed with Ang II infusion alone (23% increase). When the AT1 receptor antagonist losartan was coinfused with Ang II, blood pressure was lower than control and vessel density was reduced compared with the Ang II group but was still greater than control (7.8% increase). In this study, Ang II stimulated angiogenesis in the rat cremaster muscle; this effect was enhanced by AT2 antagonism and inhibited by AT1 antagonism. Ang II infusion at a subpressor dose resulted in a pressor response with AT2 antagonism and a depressor response with AT1 antagonism. This suggests that in the microvasculature, the AT1 receptor mediates angiogenesis and vasoconstriction, and the AT2 receptor mediates an inhibition of angiogenesis and vasodilation.
Hypertension 1996 Mar
PMID:Opposing actions of angiotensin II on microvascular growth and arterial blood pressure. 861 37

Two distinct types of cell-surface angiotensin II receptors (AT1 and AT2) have been defined pharmacologically and cDNAs encoding each type have been identified by expression cloning. These pharmacological studies showed the AT1 receptors to mediate all the known functions of angiotensin II in regulating salt and fluid homeostasis. Further complexity in the angiotensin II receptor system was revealed when homology cloning showed the existence of two AT1 subtypes in rodents and in situ hybridization and reverse transcription-polymerase chain reaction analyses showed their level of expression to be regulated differently in different tissues: AT1A is the principal receptor in the vessels, brain, kidney, lung, liver, adrenal gland and fetal pituitary, while AT1B predominates in the adult pituitary and is only expressed in specific regions of the adrenal gland (zona glomerulosa) and kidney (glomeruli). Expression of AT1A appears to be induced by angiotensin II in vascular smooth-muscle cells but is inhibited in the adrenal gland. Preliminary analysis of the AT1 promoters is also suggestive of a high degree of complexity in their regulation. Investigation of a potential role for altered AT1 receptor function has commenced at a genetic level in several diseases of the cardiovascular system. No mutations affecting the coding sequence have been identified in Conn adenoma and no linkage has been demonstrated with human hypertension by sib-pair analysis. None the less, certain polymorphisms that do not alter the protein structure have been found to be associated with hypertension and to occur at an increased frequency in conjunction with specific polymorphisms in the ACE gene in individuals at increased risk for myocardial infarction. Further characterization of the regions of the AT1 gene that regulate its expression are therefore needed. The physiological importance of the AT2 gene product still remains a matter of debate.
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PMID:Angiotensin II receptors: protein and gene structures, expression and potential pathological involvements. 864 Feb 85

In the past decade there have been considerable advances in basic knowledge of the renin-angiotensin system (RAS). The most important new development has been the appreciation of a tissue based RAS that can be independently regulated from the renal and vascular RAS. Greater insight into the mechanism by which angiotension-II (AII) exerts its action has been achieved through the study of molecular biology and pharmacological characterization of multiple receptor subtypes. This review summarises the features and distribution of several binding subtypes that may mediate the diverse functions of AII. Of these AT1 subtype is the most well known receptor which preferentially binds AII and AIII. The AT1 receptor site appears to mediate the classic angiotensin responses concerned with the body water balance and the maintenance of blood pressure. Less is known about the AT2 sites which also bind AII and AIII and may play a role in vascular growth. Recently, an AT3 has been discovered in cultured neuroblastoma cells and an AT4 site which preferentially binds AIV. It has been implicated in memory aquisition and retrieval and in the regulation of blood flow. Another important aspect covered is the primary and secondary messengers involved during the signal transduction after the binding of AII with receptors. A stress has also been given on the regulation of density and affinity of AII receptors by various physiological parametres as they affect the responses of RAS. Autoregulation by RAS, salt intake, development and aging and some of the hormones are important variables which could affect the AII receptors. Interactions of AII with various neuroeffector transmission involved in the regulation of water-electrolyte balance and BP regulation play an important role in the maintenance of the homeostasis. AII has been suggested to increase the NAergic transmission by enhancing synthesis, release, inhibiting reuptake by the presynaptic nerve terminals as well as enhancing cell responsiveness to the transmitter. The finding of existence of AII receptors in vagal afferent nerve terminals suggests that its baroreflex inhibitory effect is mediated by inhibiting neurotransmitter release at NTS in the baroreflex arc. Moreover, AII acts on the central receptors to stimulate AVP and ACTH secretion, drinking and peripherally increase synthesis and secretion of aldosterone. Interactions of RAS with kallikrein-kinin system and prostaglandins strongly support the existence of a balance between renal depressor and pressor substances. AII is now considered a growth promotor in cardiovascular tissues and the resultant vascular hypertrophy could contribute in the maintenance of hypertension. AII also plays a role in the kidney, not only as a regulator of hemodynamics but also in the structural changes occurring in a variety of renal disorders. In addition to the more well studied functions of RAS in RVH the review also highlights the potential contribution by the RAS to other clinically relevant syndromes such as aortoarterities induced RVH, hyperaldosteronism, heavy metal induced cardiovascular effects, diabetes mellitus and thyroid dysfunction. Although the receptor subtypes involved in these pathological states have not been definitely identified, research efforts in this direction are ongoing.
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PMID:Angiotensin II--receptor subtypes characterization and pathophysiological implications. 864 21

The renin-angiotensin system regulates normal cardiovascular homeostasis and is activated in certain forms of hypertension and in heart failure. Angiotensin II has multiple physiological effects and we have shown recently that its growth-promoting effects on vascular smooth muscle require autocrine activation of the IGF I receptor. To study the effect of angiotensin II on circulating IGF I, we infused rats with 500 ng/kg/min angiotensin II for up to 14 d. Angiotensin II markedly reduced plasma IGF I levels (56 and 41% decrease at 1 and 2 wk, respectively) and IGF binding protein-3 levels, and increased IGF binding protein-2 levels, a pattern suggestive of dietary restriction. Compared with sham, angiotensin II-infused hypertensive rats lost 18-26% of body weight by 1 wk, and pair-feeding experiments indicated that 74% of this loss was attributable to a reduction in food intake. The vasodilator hydralazine and the AT1 receptor antagonist losartan had comparable effects to reverse angiotensin II-induced hypertension, but only losartan blocked the changes in body weight and in circulating IGF I and its binding proteins produced by angiotensin II. Moreover, in Dahl rats that were hypertensive in response to a high-salt diet, none of these changes occurred. Thus, angiotensin II produces weight loss through a pressor-independent mechanism that includes a marked anorexigenic effect and an additional (likely metabolic) effect. These findings have profound implications for understanding the pathophysiology of conditions, such as congestive heart failure, in which the renin-angiotensin system is activated.
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PMID:Angiotensin II causes weight loss and decreases circulating insulin-like growth factor I in rats through a pressor-independent mechanism. 864 43

Losartan, a selective angiotensin II (AT1) receptor antagonist for hypertension, is metabolized to an active carboxylic acid metabolite, E-3174, which has a longer half-life. To investigate the effects of induction of cytochrome P450 on the metabolism of losartan, we evaluated the effects of phenobarbital on the plasma profiles of losartan and E-3174 in 15 healthy male subjects. Ten subjects received a single 100 mg oral dose of losartan before and during phenobarbital administration (100 mg/day for 16 days), and five subjects received losartan before and during placebo. Urinary excretion of 6-beta-hydroxycortisol (relative to 17-hydroxycorticosteroids) was measured as an endogenous marker of cytochrome P450 induction. The geometric mean area under the plasma concentration-time curve ratios (with/without phenobarbital and 90% confidence intervals) for losartan and its metabolite (E-3174) were 0.795 (0.723, 0.875) and 0.799 (0.778, 0.820), respectively, indicating that phenobarbital treatment significantly but to a clinically minor extent reduced plasma concentrations of losartan and E-3174 (p<0.01). Half-life values of losartan and E-3174 were unchanged. The ratio of 6-beta-hydroxycortisol to 17-hydroxycorticosteroids doubled in the phenobarbital group (p < 0.001) and did not change appreciably in the placebo group.
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PMID:Phenobarbital minimally alters plasma concentrations of losartan and its active metabolite E-3174. 865 89

Angiotensin II (AII) was found to upregulate tissue inhibitor of metalloproteineses-1 (TIMP-1) gene expression in rat heart endothelial cells in a dose and time-dependent manner. The maximal stimulation of TIMP-1 mRNA was achieved by 2 h after the addition of AII. This effect was blocked by losartan, an AT1 receptor antagonist and by calphostin C, a protein kinase C inhibitor. Addition of cycloheximide superinduced and actinomycin D abolished the induction. These results suggest that AII stimulates TIMP-1 production by a protein kinase C dependent pathway which is dependent upon de novo RNA synthesis. Immunoprecipitation experiment showed an enhanced band of 28 kDa from the conditioned medium of AII-treated cultures. Immunoblot analysis revealed that TIMP-1 was detectable in the conditioned medium 4 h after AII stimulation. Since endothelial cells line the blood vessels and sense the rise in AII associated with hypertension, the TIMP-1 released by these cells may provide an initial trigger leading to cardiac fibrosis in angiotensin-renin dependent hypertension.
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PMID:Angiotensin II induces TIMP-1 production in rat heart endothelial cells. 866 44


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