摘要:

SUMMARY1Angiotensin II (AngII) evokes a variety of physiological responses in the adrenal gland. It is the major regulator of aldosterone secretion, in the medulla it enhances catecholamine release and it exerts trophic effects in the adrenal and stimulates growth factor secretion.2Angiotensin II acts via binding to specific receptors, located on the plasma membrane. Two pharmacologically distinct AngII receptor subtypes, type 1 (AT1) and type 2 (AT2) receptors, have been identified using the non‐peptide antagonists Dup753 and PD 123177, respectively, and cDNA encoding each type have been identified.3In the adrenal, the AT1receptor modulates all the known biological effects of AngII. The expression of the AT1receptor is modulated at the mRNA and protein levels by many factors: conditions that increase levels of AngII (low sodium diet, renovascular hypertension, AngII infusion) up‐regulate AT1receptor mRNA levels and binding and increase aldosterone secretion.4A tissue renin‐angiotensin system has been found in the adrenal, suggesting an important paracrine role for AngII in aldosterone regulation.5The possible involvement of AT1receptors in human disease has been investigated by examining the role of AngII receptors in adrenal tumours. Binding and gene expression studies have shown that AngII receptors are abundantly expressed in aldosterone‐producing adenoma (APA).6Densitometric analysis of AT1expression in APA showed no significant differences compared with normal and nontumorous adrenal. In addition, no mutations in the coding sequence of the AT1receptor have been found to date in adrenal

ISSN:0305-1870    

DOI:10.1111/j.1440-1681.1996.tb03072.x

出版商:Blackwell Publishing Ltd    

年代:1996

数据来源: WILEY

摘要:

SUMMARY1Modification of endogenous angiotensin II (AngII)‐mediated processes by inhibitors of the angiotensin‐converting enzyme (ACE) and antagonists of the angiotensin type 1 (AT1) receptor is dependent upon both the levels of each agent in the plasma and tissues and on the concomitant changes in plasma and tissue AngII levels.2Both ACE inhibitors and AT1receptor antagonists increase renin secretion and angiotensin peptide formation in plasma and extrarenal tissues. Clinical doses of ACE inhibitors produce incomplete inhibition of ACE and the increased AngI levels act to restore AngII towards basal levels. Clinical doses of AT1receptor antagonists produce incomplete blockade of AT1receptors and the increased AngII levels in plasma and extrarenal tissues counteract (to an unknown degree) the effects of the antagonist.3The effects of ACE inhibitors and AT1receptor antagonists on AngII levels show tissue specificity. Angiotensin II‐mediated processes in the kidney are most sensitive to inhibition by these agents. ACE inhibitors reduce renal AngII levels at doses much less than those required to reduce AngII levels in plasma and other tissues. Moreover, in contrast to increased AngII levels in plasma and extrarenal tissues, renal AngII levels do not increase in response to AT1receptor antagonists. The inhibition of AngII‐mediated processes in the kidney may, therefore, play a primary role in mediating the effects of ACE inhibitors and AT1receptor antagonists on blood pressure and other aspects of cardiovascular function and structure.4Combination of an ACE inhibitor with an AT1receptor antagonist prevents the rise in plasma AngII levels that occurs with AT1receptor antagonism alone. This combination would, therefore, be predicted to produce more effective inhibition of endogenous AngII‐mediated processes than either agent alone. We must await further studies to determine whether the combination of ACE inhibition and AT1receptor antagonism results in superior clinical

ISSN:0305-1870    

DOI:10.1111/j.1440-1681.1996.tb03073.x

出版商:Blackwell Publishing Ltd    

年代:1996

数据来源: WILEY

摘要:

SUMMARY1There is strong evidence for a renal basis to the development of hypertension in the spontaneously hypertensive rat (SHR). Alterations of the SHR renal vasculature, including the glomerulus, may be involved in the initiation and maintenance of hypertension in this animal model.2The arterial walls of pre‐glomerular vessels of the SHR are hypertrophied compared with WKY vessels. Unlike other vascular beds in the SHR, this hypertrophy is independent of angiotensin II (AngII).3Glomerular number and volume are similar between SHR and the normotensive Wistar‐Kyoto (WKY) rats. These results provide no support for the theory that a reduced filtration surface area within the kidneys of the SHR contributes to the elevated blood pressure in these animals.4Intrarenal hypertrophy may have similar haemodynamic consequences to clipping of the main renal artery, as in Goldblatt hypertension. Further analysis of the role of pre‐glomerular arterial hypertrophy is warranted to determine its involvement in the initiation and maintenance of hypertension in th

ISSN:0305-1870    

DOI:10.1111/j.1440-1681.1996.tb03074.x

出版商:Blackwell Publishing Ltd    

年代:1996

数据来源: WILEY

摘要:

SUMMARY1While the haemodynamic influences that cause cardiac hypertrophy are well known, the cellular and molecular mechanisms by which a mechanical stimulus is translated into a growth response by cardiac muscle have remained uncertain.2Current evidence suggests that a number of trophic factors may be released by cellular constituents of the heart, acting in an autocrine or paracrine manner to influence the growth response and phenotype of neighbouring cells.3Angiotensin II, acting via the AT1receptor subtype, and both basic fibroblast growth factor and heparin‐binding epidermal growth factor have been shown to exert hypertrophic actionsin vivoandin vitro.Studies also indicate that cardiac myocytes themselves are capable of releasing all of these cytokines in response to increased mechanical loa

ISSN:0305-1870    

DOI:10.1111/j.1440-1681.1996.tb03075.x

出版商:Blackwell Publishing Ltd    

年代:1996

数据来源: WILEY

摘要:

SUMMARY1The availability of orally active specific angiotensin receptor antagonists (AT1antagonists) has opened new therapeutic choices and provided probes to test the specific role of the renin‐angiotensin system in the pathogenesis of cardiovascular disease.2The data available so far suggest that the antihypertensive efficacy of angiotensin receptor antagonists is comparable to that of angiotensin‐converting enzyme (ACE) inhibitors. This provides further evidence that this latter class of drugs exerts its effect mainly through blockade of the renin‐angiotensin enzymatic cascade. As expected, the association of a diuretic exerts an equally strong additive effect to the antihypertensive efficacy of both classes of drugs.3The most common side effect of ACE inhibitors, dry cough, does not occur with AT1antagonists, which confirms the long‐held view that this untoward effect of the ACE inhibitors is due to renin‐angiotensin‐independent mechanisms.4Long‐term studies with morbidity/mortality outcome results are needed, before a definite position can be assigned to this newcomer in the orchestra of modern antihypertensive drugs. Notwithstanding, this new class of agents already represents an exciting new addition to our therapeutic

ISSN:0305-1870    

DOI:10.1111/j.1440-1681.1996.tb03076.x

出版商:Blackwell Publishing Ltd    

年代:1996

数据来源: WILEY

摘要:

SUMMARY1Angiotensin II (AngII) receptor subtypes in adult human kidney were pharmacologically characterized byin vitroautoradiography using the AngII receptor subtype‐selective antagonists, losartan and PD 123319, and the sensitivity to the reducing agent, dithiothreitol.2High densities of AngII AT1receptor binding occur in the glomeruli and the inner stripe of the outer medulla, while a moderate AT1receptor binding is localized in the proximal convoluted tubules.3AT2receptor binding is observed predominantly in the intrarenal large blood vessels, including the arcuate, inter‐ and intra‐lobular arteries, and in the renal capsule.4In the major renal artery, AT1receptor binding is abundant in the media and adventitia, while AT2receptor binding is observed mainly in the adventitia.5At the light microscopic level using emulsion autoradiography, AT1receptors are localized in the glomeruli and juxtaglomerular apparatus, as expected. However, in larger renal blood vessels, including the arcuate arteries, inter‐ and intra‐lobular arteries, intense AT2receptor labelling occurs primarily in the adventitia, while the endothelium and vascular smooth muscle layers contain only low levels of AngII receptor binding.6These results indicate that the adult human kidney displays two pharmacologically distinct AngII receptor subtypes, with AT1predominating in the glomeruli, juxtaglomerular apparatus, proximal tubules and the inner stripe of the outer medulla, while AT2predominates in the adventitia of the arcuate and interlobular arteries and the renal capsule. The functional significance of AT2receptor binding sites in the adventitia of adult human kidney vessels remains to be e

ISSN:0305-1870    

DOI:10.1111/j.1440-1681.1996.tb03077.x

出版商:Blackwell Publishing Ltd    

年代:1996

数据来源: WILEY