Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.4.23.15 (renin)
 35,795 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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 present studies assessed the levels of [125I][Sar1,ILE8]angiotensin II-labelled angiotensin AT1 and AT2 receptor recognition sites in homogenates of various brain areas (including caudate nucleus, putamen, substantia nigra, hippocampus, frontal cortex, temporal cortex and cerebellum) from patients with clinically diagnosed Parkinson's disease, Huntington's disease and Alzheimer's disease and those from age-, sex- and post-mortem delay-matched neurologically and psychiatrically normal patients. Radiolabelled angiotensin AT1 receptor recognition site levels were significantly decreased by approximately 70%, 70% and 90% in the caudate nucleus, putamen and substantia nigra, respectively, from patients with Parkinson's disease relative to matched controls. Furthermore, radiolabelled angiotensin AT2 receptor levels were decreased by some 60% in the caudate nucleus of patients with Parkinson's disease relative to control patients. In brain tissue homogenates from patients with Huntington's disease, the angiotensin AT1 receptor recognition site levels were decreased by approximately 30% in putamen relative to the control patients whilst angiotensin AT2 receptor levels were increased by some 90% in the caudate nucleus relative to the control patients. In brain tissue homogenates from patients with Alzheimer disease, the angiotensin AT2 receptor recognition site levels were significantly increased by approximately 200% in the temporal cortex relative to the control patients. The present results indicate that the reduction of angiotensin AT1 and/or AT2 receptor recognition site levels in the caudate nucleus, putamen and substantia nigra correlates with the principal neuropathology associated with Parkinson's disease and as such indicates that at least a significant population of angiotensin AT1 and AT2 receptors are located on the human dopaminergic nigrostriatal pathway. In addition, the marked increase in the levels of angiotensin AT2 receptor recognition sites in temporal cortex from patients with Alzheimer's disease correlates with some other markers associated with the renin-angiotensin system previously investigated in tissue from patients with this neurological disease.
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PMID:Alterations in angiotensin AT1 and AT2 receptor subtype levels in brain regions from patients with neurodegenerative disorders. 866 63

During human and rat pregnancy, several hemodynamic and endocrine processes are markedly modified. These include activation of the renin-angiotensin system (RAS) and increase of plasma aldosterone. However, the rise of plasma aldosterone is greater than expected from the elevation of RAS activity. Gestational alterations in angiotensin II receptors (AT receptor) in the adrenal could explain this apparent hyperaldosteronism. This study was conducted to determine differences between AT receptor subtypes in the adrenal glands of non-pregnant and pregnant (22 days) rats. Using plasma membrane preparations from adrenal glomerulosa and medulla, we determined receptor density and affinity with 125I-angiotensin II (ANG II); the AT receptor subtypes were assessed by displacement of 125I-ANG II binding with subtype-specific antagonists (DuP753 and PD123319). In zona glomerulosa of non-pregnant and pregnant rats, AT1 receptors predominated (approximately 80%) with no statistical difference in receptor density (Bmax) and affinity (Kd) and the ratio of receptor subtypes between the two groups of rats. In adrenal medulla of both groups of rats, the major portion of 125I-ANG II binding (60-70%) was displaced by the AT2 receptor antagonist, PD123319. Neither Bmax nor Kd differed in this tissue during gestation. The results for AT1 receptor density were confirmed by Western blot. Northern blot analysis showed that AT1 mRNA level in the adrenal is not modified by gestation. These results indicate that the number, the affinity and the transcription of the AT1 receptor in the adrenal are not altered during pregnancy, indicating that the rise in aldosterone secretion during pregnancy could not be explained by increase of AT1 receptors in the zona glomerulosa, or modification of AT1/AT2 ratio.
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PMID:Angiotensin II receptor subtypes in the adrenals of pregnant rats. 867 42

A recent series of experiments in our laboratory were designed to elucidate the cellular changes that underlie the cardiac remodelling response following myocardial infarction (MI) in the rat as well as the potential role of the renin-angiotensin system (RAS) in this response. Inhibition of the RAS interferes with cardiomyocyte hypertrophy, interstitial cell DNA synthesis, and collagen deposition; these effects are mediated through the angiotensin II AT1 receptor subtype. Also, vascular outgrowth is functionally diminished, an effect that seems to depend on AT2 receptor activation. The intracardiac RAS may be involved in the wound healing response in the infarct area. However, we found no evidence for activation of the RAS in the remnant myocardium, which suggests that myocyte hypertrophy and interstitial fibrosis depend on activation of the systemic RAS. During the first weeks following MI, therapy of choice should thus inhibit the systemic RAS while allowing the wound-healing response of the intracardiac RAS, i.e. selective AT1 antagonists are appropriate early after MI. AT2 antagonists administered at that time can inhibit the cardiac vascularization response and cause a further decrease in level of cardiac function.
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PMID:Does ACE inhibition limit structural changes in the heart following myocardial infarction? 868 61

In addition to inhibition of the circulating renin-angiotensin system, specific inhibition of the cardiac effects of angiotensin II (Ang II) represents an important therapeutic goal in the treatment of clinical heart failure. Subtype 1-specific Ang II receptor (AT1) antagonists have been developed to overcome potential limitations of angiotensin converting enzyme inhibitors, e.g. insufficient control of tissue Ang II production and bradykinin-related side effects. Clinical studies have demonstrated beneficial effects of AT1 antagonists. In a single-dose study, the AT1 antagonist losartan decreased the mean arterial pressure and pulmonary arterial pressure while increasing the cardiac index. Effects were dose dependent. Haemodynamic effects were greater with higher doses, but neurohormonal counter-regulation probably also increased, leading to relatively high levels of circulating Ang II with the 150-mg dose, A decrease in plasma levels of noradrenaline, atrial natriuretic factor, and aldosterone reached partial significance. Administration of multiple doses of losartan for 12 weeks also led to favourable haemodynamic and clinical results. Arterial blood pressure, pulmonary capillary wedge pressure, and systemic vascular resistance decreased. The neurohormonal effects of 12 weeks' administration of AT1 antagonists consisted in a decrease in plasma aldosterone concentrations. Whereas AT1 antagonists may counteract the effects of Ang II on the vasculature, and therefore are effective vasodilators, their direct myocardial effects are less clear. The subtype AT2, which represents the dominant, receptor in both healthy and failing human myocardium, is not blocked by AT1 inhibition. Angiotensin receptors on isolated human cardiac fibroblasts stimulate cellular proliferation via a yet undertermined receptor subtype. AT1 antagonists exert beneficial haemodynamic and neurohormonal effects in human heart failure. Their direct myocardial effects require further investigation.
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PMID:Effects of angiotensin receptor antagonists in heart failure: clinical and experimental aspects. 868 68

Characterization and regulation of angiotensin II (AII) receptor binding sites was performed in rat membrane preparations from nonadipose (liver, lung) and adipose (interscapular (ISBAT) and periaortic (PA) brown adipose tissue; epididymal (EF) and retroperitoneal (RPF) white adipose tissue). In membrane preparations from brown and white adipose sources, [125I]AII saturation binding revealed a single, high affinity (Kd range of 0.3 -0.6 nM) binding site with a modest AII receptor density (Bmax range of 17-120 fmol/mg protein) comparable to rat lung (130 fmol/mg protein). White adipose tissue contained a greater number of AII receptor sites than brown adipose tissue. Competition displacement studies demonstrated the AT1 receptor is the only angiotensin receptor subtype localized in adipose tissue, with the rank order for competition of [125I]AII binding in all adipose tissues examined AIII > AII > losartan > angiotensin I (AI) > PD123319. The AT2 specific receptor antagonist, PD123319, was ineffective at displacing [125I]AII binding in all adipose tissues examined. Since components of the renin-angiotensin system are regulated in adipose tissue, we determined if the AII receptor is also regulated in the obese state. AII receptor binding characteristics were determined in liver, lung, ISBAT and EF membrane preparations from adult Zucker obese (fa/fa) and lean (Fa/?) rats. AII receptor density was decreased in liver from obese rats. In contrast, the affinity for [125I]AII binding was not altered in tissues from obese rats. In a separate group of obese and lean rats, regulation of the AII receptor by phenobarbital (PB) was examined. Administration of PB restored AII receptor density in liver from obese rats to levels obtained in lean rats. In summary, these results demonstrate the presence of AT1 receptor sites in brown and white adipose tissue. Moreover, AII receptor density is decreased in tissues from obese rats, with restoration of receptor density by administration of PB. Future studies will determine if PB regulates the AT1 receptor at the level of gene expression.
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PMID:Characterization and regulation of angiotensin II receptors in rat adipose tissue. Angiotensin receptors in adipose tissue. 872 84

The intrarenal renin-angiotensin system (RAS) contributes to the increased renal vascular resistance and reactivity observed in spontaneously hypertensive rats (SHR) and to the pathogenesis of high blood pressure (BP). Thus, we decided to characterize angiotensin II (ANG II) receptors in the renal arteries and glomeruli of 16-week-old SHR and their age-matched, normotensive Wistar-Kyoto (WKY) controls. SHR had significantly higher BP (153 +/- 4 v 96 +/- 10 mmHg) and heart weight (440 +/- 5 v 327 +/- 4 g/100 g body weight) than WKY rats. There was no difference in plasma renin activity between strains. Radioligand binding assays using non-peptide antagonists for AT1 (losartan) and AT2 (PD 123319) showed that renal preglomerular microvessels and glomeruli expressed a single receptor population (AT1) for ANG II. AT1 density tended to be lower in glomeruli of SHR compared to WKY (377 +/- 45 v 555 +/- 74 fmol/mg protein), but was significantly higher in preglomerular vessels (93 +/- 7 v 57 +/- 1 fmol/mg protein). No difference in receptor affinity was found in either preparation. Isolated kidney perfusion revealed that at low flow (3-10 ml/min), perfusion pressure was similar in both strains; however, at higher flow levels, SHR showed higher reactivity and less compliance than their controls. In addition, SHR presented a higher renal vascular reactivity to ANG II (but not to arterenol) than WKY rats. Thus, upregulation of ANG II receptors in the renal vasculature may mediate the hyperreactivity to ANG II observed in SHR kidney.
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PMID:Characterization and hemodynamic implications of renal vascular angiotensin II receptors in SHR. 872 67

The plasma and cardiac renin-angiotensin systems may be activated after myocardial infarction. The myocardium may therefore be exposed to increased concentrations of angiotension II, which may contribute to myocardial injury. The purpose of this study was to identify the potential sites of action of angiotensin II in the infarcted heart. Myocardial infarction was induced in rats by left coronary artery ligation, and the hearts were removed for study after 18 h, 7 days, or 8 months. The regional ventricular angiotensin II receptor density was assessed by [125I](Sar1,Ile8)angiotensin II binding and quantitative autoradiography. The [125I](Sar1,Ile8)angiotensin II binding was unchanged at 18 h, but was increased at 7 days in the infarcted region of the left ventricle (73.2 +/- 3.2 amol/mm2, mean +/- S.E.M.) compared with the non-infarcted region (1.6 +/- 0.2 amol/mm2, P < 0.0001) and with the left ventricular myocardium of sham-operated control animals (1.3 +/- 0.1 amol/mm2, P < 0.0001). The increased [125I](Sar1,Ile8)angiotensin II binding density was still present, but diminished, at 8 months after coronary ligation (49.0 +/- 5.7 amol/mm2, P < 0.0001 v control, P = 0.0058 v 7-day infarcts). The increased binding of [125I](Sar1,Ile8)angiotensin II was antagonised by losartan, an AT1 receptor antagonist, but not by an AT2 receptor antagonist. Microautoradiography of [125I](Sar1,Ile8) angiotensin II, and assessment of collagen deposition using picrosirius staining and immunostaining demonstrated that the regional increase in AT1 receptor density in the infarcted region of myocardium was associated with fibroblast infiltration and collagen deposition. The infarct scar and the cardiac fibroblasts within it express high levels of angiotension II receptors and therefore represent potential targets for the actions of angiotensin II after myocardial infarction.
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PMID:Regional changes in angiotensin II receptor density after experimental myocardial infarction. 872 73

The present study was undertaken in order to characterize and determine angiotensin (Ang) II receptors and renin in the porcine placenta and fetal membranes. High densities of Ang II receptors of subtype 2 (AT2 receptors) were demonstrated in all parts of the placenta and fetal membranes throughout gestation. AT1 receptors (subtype 1) were only found in the first part of the gestation and only in the allantochorion-endometrium at low densities. The total Ang II receptor density was increased in the allantochorion-endometrium in the last stage of gestation. Except for this finding the Ang II receptor density did not vary during gestation. Some of the highest receptor densities were found in the allantoamnionic membrane. The Ang II receptor densities did not correlate with the duration of the gestation in any part of the placenta. Enzymatically active renin was found in all parts of the porcine placenta and fetal membranes in concentrations similar to those found earlier in the blood plasma. The renin concentrations did not correlate with the Ang II receptor densities or the duration of the gestation in any part of the placenta. Compared with the human placenta, where the Ang II receptors are almost exclusively AT1 receptors and low receptor densities are found in the fetal membranes, the present results indicate profound species differences in the expression and function of the renin-angiotensin system in the placenta and fetal membranes.
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PMID:High densities of angiotensin II subtype 2 (AT2) receptors in the porcine placenta and fetal membranes. 873 Aug 84

L-163,017 (6-[benzoylamino]-7-methyl-2-propyl-3-[[2'-(N-(3-methyl-1-butoxy) carbonylaminosulfonyl)[1,1']-biphenyl-4-yl]methyl]-3H-imidazo[4,5- b]pyridine) is a potent, orally active, nonpeptide angiotensin II receptor antagonist. Conscious rats and dogs were dosed p.o. and i.v.; in both species the plasma bioequivalents are similar at the angiotensin AT1 and AT2 receptor sites indicating balanced activity is maintained in vivo. L-163,017 prevents the pressor response to intravenous (i.v.) angiotensin II in the conscious rat, dog, and rhesus monkey. L-163,017 also significantly reduces blood pressure in a renin-dependent model of hypertension, similar to an angiotensin converting enzyme inhibitor (Enalapril) and an angiotensin AT1 receptor-selective antagonist (L-159,282). These studies indicate that neither the angiotensin AT2 receptor nor bradykinin is important in the acute antihypertensive activity of angiotensin converting enzyme inhibitors or angiotensin II receptor antagonists.
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PMID:In vivo pharmacology of an angiotensin AT1 receptor antagonist with balanced affinity for AT2 receptors. 875 Jul 4


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