(Stroke. 1995;26:1700-1706.)
© 1995 American Heart Association, Inc.
Articles |
Hypertensive Cerebrovascular Disease and the Renin-Angiotensin System
From the Departments of Clinical and Internal Medicine (A.R.), University of Padua, University Hospital, Padua, Italy.
Correspondence to G.P. Rossi, MD, FACC, Clinica Medica 1, Hypertension Unit, University Hospital, via Giustiniani 2, 35126 Padova, Italy.
 |
Abstract |
|---|
 Top Abstract IntroductionVascular and Cellular Effects...Experimental HypertensionGenetic FactorsThe Renin-Angiotensin System and...Clinical HypertensionProtective Role of ACE...ConclusionsReferences |
|---|
Background Arterial hypertension is the leading cause of cardiovascular disease and is associated with an increased risk of stroke and heart attack. These complications have been largely attributed to the remodeling of the arterial wall, including accelerated atherosclerosis occurring in hypertensive patients. Although the risk of haemorrhagic stroke seems to be directly related to the level of blood pressure elevation, no such tight relationship has been found between blood pressure levels and atherosclerosis. This observation has led to the concept that a number of genetic, humoral, and cellular factors may be involved in atherogenesis in hypertensive patients.
Summary of Review The experimental and clinical evidence concerning the role of the renin-angiotensin system in cardiovascular remodeling and atherogenesis of the cerebrovascular bed as well as the data supporting an association between angiotensin II and thrombotic stroke are examined.
Conclusions The contribution of the renin-angiotensin system to the pathogenesis of accelerated carotid artery atherosclerosis and particularly of cerebrovascular disease remains to be definitively proven. However, the bulk of experimental and clinical data are consistent with the hypothesis that the renin-angiotensin system may play a detrimental role.
Key Words: carotid artery diseases • hypertension • renin-angiotensin • ultrasonics
|
Introduction |
|---|
|
TopAbstractIntroductionVascular and Cellular Effects...Experimental HypertensionGenetic FactorsThe Renin-Angiotensin System and...Clinical HypertensionProtective Role of ACE...ConclusionsReferences |
|---|
Arterial hypertension is the leading cause of cardiovascular disease in industrialized countries and represents an emerging health problem in many developing nations. Epidemiological studies, including the Framingham Study,1 have clearly demonstrated that hypertension markedly increases the risk of coronary artery disease, stroke, and renal failure. It has been estimated that 250 000 deaths per year can be attributed to hypertension in the United States and that, if untreated, approximately 50% of hypertensive patients would die of coronary heart disease, 33% of stroke, and 10% to 15% of renal failure.2 Hypertension is currently considered the most important factor contributing to the 500 000 annual cases of stroke in the United States,2 and the incidence of brain infarcts is 5 to 30 times greater in hypertensive than in normotensive subjects.1 Hypertension predisposes individuals to stroke by (1) aggravating atherosclerosis in the aortic arch and cervicocerebral arteries; (2) causing arteriosclerosis and lipohyalinosis in the small-diameter penetrating cerebral end arteries; and (3) promoting heart disease that may be complicated by stroke.3 4 5 6 The most common cause of stroke (64% of all cases) is atherothrombotic brain infarction, whereas less frequent causes are cerebral cardiogenic embolism and subarachnoid and intracerebral hemorrhages.7 Hemorrhagic strokes appear to be directly related to the level of blood pressure elevation, whereas ischemic stroke is largely accounted for by atherosclerotic lesions of the extracranial and/or intracranial cerebral arteries and by arteriosclerotic changes in small cerebral arteries, which are the hallmark of uncontrolled hypertension, ie, accelerated atherosclerosis.8 The severity of atherosclerotic lesions varies quite widely in different patients for the same degree of blood pressure elevation; accordingly, a number of humoral and cellular factors have been suspected to be implicated in the pathogenesis of atherosclerosis.9 10 A higher incidence of stroke and heart attack has been reported in high-renin hypertensives compared with both normal and low-renin subjects.11 Thus, it has been hypothesized that the renin-angiotensin system may play an important role in the pathogenesis of accelerated atherosclerosis and thrombotic events in hypertension.11 12
In this article we reviewed the experimental and clinical evidence supporting the concept that the renin-angiotensin system has a detrimental impact on the arterial wall of the cerebrovascular tree.
|
Vascular and Cellular Effects of the Renin-Angiotensin System |
|---|
|
TopAbstractIntroductionVascular and Cellular Effects...Experimental HypertensionGenetic FactorsThe Renin-Angiotensin System and...Clinical HypertensionProtective Role of ACE...ConclusionsReferences |
|---|
At the cellular level the influence of the renin-angiotensin system on vascular structure has been widely studied in vitro and in vivo and found to consist of direct and indirect effects (Table
). Renin was shown to cause the
production of neutrophil chemoattractant
activity.13 In rat aorta, in vivo infusion of Ang II
increased the gene expression of fibronectin, a connective tissue
protein relevant for arterial wall damage.14
Ang II was found to stimulate DNA and protein synthesis in vascular
tissue,15 to induce hypertrophy in cultured
rat aortic SMCs,16 and to increase growth rate and cell
size in cultured human SMCs.17 Ang II–induced
hypertrophy of SMCs was associated with increased
expression of the A-chain of platelet-derived growth factor and of
the proto-oncogene c-myc.18 Finally, Ang II was
reported to promote neointimal hyperplasia after vascular
injury in vivo.19
|
To date the exact mechanisms whereby Ang II directly influences wall structure are unknown. Ang II may bind to receptors on nuclear chromatin and initiate nuclear events that result in protein synthesis and cell proliferation.15 19 20 Alternatively, occupation of the Ang II receptor could increase nuclear activity by accelerating hydrolysis of polyphosphoinositide lipids.21 In addition, Ang II could indirectly cause proliferation and damage of vascular SMCs by stimulating the secretion of other mediators that are involved in vascular remodeling in hypertension. At nerve endings, Ang II potentiates sympathetic activity by enhancing the release of norepinephrine and epinephrine, which are known to increase the growth rate of cultured vascular SMCs.22 By transactivating a responsive element on the 5' region of the preproendothelin-1 gene, Ang II enhances synthesis and release of endothelin-1, a well-known mitogen and vasoconstrictor,23 24 from endothelial and SMC cells in vitro.25 26 27 28
Both Ang II and aldosterone were associated with the development of myocardial fibrosis in hypertension29 ; however, the administration of spironolactone, an aldosterone antagonist, before the induction of either RVH or hyperaldosteronism inhibited perivascular and interstitial myocardial fibrosis, even at the low doses that did not affect blood pressure, thereby suggesting that aldosterone was directly responsible for fibrosis.29 Rats affected by secondary aldosteronism due to RVH show an increase of coronary artery permeability, and this effect could also be reproduced with intravenous infusion of Ang II.29 No other experimental data supporting such a direct effect of aldosterone on the arterial wall are available yet, although the results of a clinical study are consistent with this possibility (see below and Reference 30).
Thus, the bulk of recent experimental evidence suggests that activation of the renin-angiotensin system may be directly or indirectly responsible for vascular lesions.
|
Experimental Hypertension |
|---|
|
TopAbstractIntroductionVascular and Cellular Effects...Experimental HypertensionGenetic FactorsThe Renin-Angiotensin System and...Clinical HypertensionProtective Role of ACE...ConclusionsReferences |
|---|
In the Watanabe heritable hyperlipidemic rabbit, which is deficient in low-density lipoprotein receptors, the flux of labeled albumin across the carotid artery wall studied in situ,31 as well as aortic atherosclerosis,14 were increased by one-kidney, one clip hypertension.
McGill et al32 observed larger extension and greater severity of carotid atherosclerosis in two groups of hypertensive baboons (one with two-kidney, one clip and the other with perinephritis-induced hypertension) than in normotensive controls. They also reported a greater extent of atherosclerotic lesions and a greater prevalence of fibrous plaques in the hypertensive animals with renal artery stenosis and higher renin than in those with low-renin bilateral perinephritis.
In contrast to these findings, renal and cerebral vascular lesions occurred more often and earlier in SHR when they were given a high-salt diet, which suppressed the renin-angiotensin system, than when they were given a normal-salt diet.33 In stroke-prone SHR, however, kidney renin activity was found to be increased, suggesting that the activation of the renal renin-angiotensin system is related to hypertensive vascular lesions in this strain.34 When they were fed a high-sodium diet, they exhibited a paradoxical rise in plasma renin activity, which was associated with increased mortality, stroke, and cerebrovascular disease rates.34 Renal hypertensive rats with a normal or suppressed renin-angiotensin system were also observed to develop vascular lesions similar to those seen in SHR on a high-sodium diet.35 It was noted, however, that in renal hypertension the plasma renin levels are inappropriately "normal" in relation to exchangeable sodium and to the elevation of blood pressure, which should turn off renin secretion; therefore, they may not accurately reflect the degree of activation of the vascular tissue renin-angiotensin system.36
Overturf et al37 38 39 40 fed hypertensive rabbits with different degrees of hypertension a cholesterol-rich diet and showed that plasma renin activity does not play a role in accelerated atherogenesis; they hypothesized the existence of a critical level of blood pressure elevation and cholesterolemia at which accelerated atherogenesis occurs.
Thus, some controversy still exists regarding the relative role of pressure load and/or activation of the renin-angiotensin system on the cerebrovascular bed in experimental hypertension.
|
Genetic Factors |
|---|
|
TopAbstractIntroductionVascular and Cellular Effects...Experimental HypertensionGenetic FactorsThe Renin-Angiotensin System and...Clinical HypertensionProtective Role of ACE...ConclusionsReferences |
|---|
The importance of genetic factors in cerebrovascular diseases was first noted by Morgagni41 in 1761 and thereafter corroborated by anecdotal observations as well as by epidemiological studies.42 43 44 An obvious familial aggregation of stroke has been observed in patients with congenital abnormalities of the coagulation/fibrinolytic cascade45 46 ; in addition, a strong association of parental history of stroke, transient ischemic attack, and coronary artery disease with stroke was observed in the Framingham Study.44 Recent molecular genetics techniques allowed the identification of polymorphism of genes of the renin-angiotensin system,47 including a deletion/insertion polymorphism at intron 16 of the ACE (kininase II) gene.48 Subjects homozygous for the D allele, who have a twofold increase of plasma ACE levels compared with the II homozygous,49 were found to have a higher risk of cardiovascular complications, including acute myocardial infarction; dilated, hypertrophic, and ischemic cardiomyopathy; sudden death; and restenosis after percutaneous transluminal coronary angioplasty.50 51 52 53 54 The D allele was found to be associated with parental history of fatal myocardial infarction.55 In vitro and in vivo experiments with a novel gene transfer technique demonstrated that ACE is a rate-limiting step for Ang II generation in the arterial wall.56 57 Transfection experiments with ACE cDNA resulted in an increased synthesis of DNA, RNA, and protein; this effect was inhibited by the specific Ang II AT1 receptor antagonist losartan. Cotransfection of renin and ACE cDNA resulted in further enhancement of RNA synthesis compared with ACE or renin cDNA alone and therefore confirmed that transfected components of the renin-angiotensin system can modulate vascular SMC growth in an autocrine-paracrine fashion through the endogenous production of vascular Ang II.57 As significantly higher plasma levels of ACE were found in patients with carotid intimal-medial thickening compared with control subjects,58 an intensive effort is currently devoted to identifying the role of the deletion/insertion polymorphism as a risk factor for cerebrovascular disease.
|
The Renin-Angiotensin System and Fibrinolytic Function |
|---|
|
TopAbstractIntroductionVascular and Cellular Effects...Experimental HypertensionGenetic FactorsThe Renin-Angiotensin System and...Clinical HypertensionProtective Role of ACE...ConclusionsReferences |
|---|
The observation that the administration of ACE inhibitors to patients with left ventricular dysfunction after myocardial infarction results in reduced rates of recurrent thrombosis raises the possibility that Ang II may be directly involved in the thrombotic process. In keeping with this hypothesis, it was found that the infusion of Ang II to normotensive and hypertensive patients increases in a dose-dependent fashion the circulating levels of PAI-1, the most important physiological inhibitor of TPA, without affecting circulating levels of TPA.59 This observation was further corroborated by the in vitro demonstration that Ang II selectively induces the production and secretion of PAI-1 in different cell types.60 61 Furthermore, it was found to enhance gene expression and synthesis of PAI-1 and TPA by vascular SMCs.62 It has been speculated that the increase of PAI-1, a marker of recurrent coronary thrombosis,63 might contribute to explaining the clinical observations linking the renin-angiotensin system and thrombotic events. Since vascular SMCs can digest the extracellular matrices through plasminogen-dependent mechanisms, the increase of TPA might also be important for the cell migration occurring in atherogenesis.62 The recent observation that captopril therapy decreases PAI-1 activity in men with recent, uncomplicated myocardial infarction is consistent with the possibility that Ang II is associated with increased thrombotic risk.64
|
Clinical Hypertension |
|---|
|
TopAbstractIntroductionVascular and Cellular Effects...Experimental HypertensionGenetic FactorsThe Renin-Angiotensin System and...Clinical HypertensionProtective Role of ACE...ConclusionsReferences |
|---|
The common and internal carotid arteries are of particular interest in hypertension for several reasons. They contribute greatly to cerebral flow and contain baroreceptor endings, which are largely involved in the regulation of blood pressure.65 At present the initial portion of the carotid artery, an elective site for atherosclerotic lesions, is readily accessible to noninvasive evaluation by high-resolution duplex ultrasound instruments.
From a clinical standpoint, RVH and PA offer a unique opportunity to investigate the effects of an activated and a suppressed renin-angiotensin system on carotid artery structure.
RVH is the most common cause of curable hypertension. It is due to atherosclerotic obstruction of the renal arteries in approximately two thirds of cases and to fibrodysplasia in the remaining third.66 The decrease of renal perfusion pressure due to renal artery obstruction turns on transcription of the renin gene and renin secretion, which raises systemic blood pressure and thereby tends to maintain perfusion pressure and glomerular filtration rate to normal values. Patients with RVH may present with more severe hemodynamic abnormalities67 and more pronounced cardiovascular disease and can be more difficult to treat than patients with PH, possibly due to the activation of the renin-angiotensin system. Clinical studies suggested that high-renin hypertensives are particularly prone to develop cardiovascular complications, ie, stroke and heart attack.11 12 Left ventricular dilatation and septal hypertrophy were found to be enhanced in RVH compared with PH patients with a similar severity of hypertension.68 Pulmonary edema69 and vascular damage, such as the vasculitic lesions associated with accelerated and malignant hypertension,70 were also more frequent in RVH than in PH patients. Ischemic stroke, which is often related to obstructive lesions of the extracranial and/or intracranial carotid arteries, also appeared to be more frequent in high-renin hypertensives.11 Despite this evidence and the fact that atherosclerosis (endoarteritis chronica deformans) of the common carotid artery was described in necropsy studies almost 100 years ago,71 anecdotal reports of concomitant cerebrovascular and renal artery lesions in RVH only due to fibrodysplasia42 72 existed, but no study of the prevalence of carotid artery atherosclerosis in RVH was available.
We have investigated prospectively by a high-resolution duplex system the prevalence of carotid artery lesions in 19 patients with confirmed RVH compared with control patients with PH.73 RVH and PH patients were individually matched for blood pressure levels, duration of hypertension, smoking habits, and all known risk factors for atherosclerosis; as a result, two groups quite similar in their overall cardiovascular risk profile were obtained. The total number of carotid artery lesions, ranging from intimal-medial thickening to tight stenoses, was significantly higher in RVH than in control PH patients. In a larger prospective study we confirmed that the prevalence of carotid artery lesions was increased approximately twofold (83%) in these patients compared with PH patients (43%, P<.0001).74 In the RVH patients, who were totally asymptomatic from a cerebrovascular standpoint, we found hemodynamically relevant stenoses in 10% of the cases compared with 3% in the PH group. Moreover, in RVH patients lesions tended to occur at a younger age. The higher prevalence of carotid artery lesions was not confined to patients with atherosclerotic RVH, who had lesions in 100% of cases (versus 55% in PH control subjects; P<.0001), but was also seen in the fibrodysplasic RVH group, in whom 57% of the examined arteries had lesions compared with 27% in PH control subjects (P<.02). This is worth noting because in the former the excess prevalence and severity of carotid artery lesions might be attributable to the widespread nature of atherosclerosis. However, this explanation seems untenable in our patients with renal fibrodysplasia, who were generally younger and had a low cardiovascular risk profile. Therefore, we concluded that regardless of its etiology, RVH is associated with more detrimental effects on carotid arteries than primary hypertension even in the presence of a similar hemodynamic load, possibly because of activation of the renin-angiotensin system.
High-resolution sonography allows an accurate evaluation of the carotid arterial wall, but information is limited to the common carotid artery, bifurcation, and a short tract of internal carotid artery. Thus, in another study we investigated 16 RVH patients at the time of percutaneous transluminal renal angioplasty with digital subtraction angiography of the aortic arch, which allowed a more complete examination of the cerebral arterial tree, including intracerebral vessels and vertebral arteries.75 They were prospectively compared with 16 hypertensives, studied in the same period, who were found to have no renal artery disease and normal plasma renin activity. The cerebrovascular bed was divided into 17 different segments, and the presence and absence of lesions involving these sites were evaluated blindly by three different experienced angiographers using a score system. In RVH patients the total score was 10-fold higher than in PH patients (181±32 versus 17±9; P<.001). Furthermore, in a 21-year-old patient with severe hypertension who had a juxtaglomerular cell tumor secreting large amounts of both active renin and prorenin, we observed severe carotid artery lesions and elongation.76
RVH and primary reninism, which are characterized by secondary
aldosteronism, do not allow ascertainment of the relative role of Ang
II and aldosterone in cardiovascular
remodeling. Therefore, it may prove useful to investigate patients with
PA, in whom the renin-angiotensin system is suppressed. In
a study of consecutive patients with confirmed PA, we found that the
prevalence of lesions in carotid arteries evaluated by duplex
ultrasound was 59%, ie, not significantly different from 53% of a
control group of patients with PH
(Figure).30 In the majority of cases, the
lesions found in PA patients were intimal-medial thickenings (55% of
all lesions), whereas only 45% of lesions were atherosclerotic
plaques, which were hemodynamically relevant in only
3% of the carotid arteries examined.
|
Further clinical data concerning the role of the renin-angiotensin system in cerebrovascular disease come from the results of our studies on patients with CRF.77 CRF includes many different diseases, and therefore the role of the renin-angiotensin system may vary considerably in different patients and at different stages of the same disease, thus precluding any simple generalization.78 However, the vast majority of hypertensive patients with end-stage renal disease are salt sensitive and have plasma renin and Ang II levels within the normal range but inappropriately elevated in relation to exchangeable sodium, and 10% to 20% clearly have a renin-dependent hypertension.78 79 80 81 82
In a duplex study of the carotid arteries of subjects with different
stages of nondiabetic CRF, we found a significantly higher frequency of
carotid artery lesions than in control patients (52.3% versus 37.5%;
P<.01) (Figure
).77 Thus, renal
ischemia and different stages of renal disease, but not
hypertension due to excess aldosterone secretion, appear to
be associated with an excess prevalence of carotid artery lesions, in
keeping with the hypothesis that activation of the
renin-angiotensin system and elevated plasma levels of Ang
II play a cardinal role in this context. Further support for this
concept was recently provided by two sets of evidence. First, a
case-control duplex study of a French population showed a significant
relationship between plasma ACE activity and carotid artery thickening
and suggested that chronic exposure to high plasma ACE levels could
induce structural changes of the arterial
wall.58 Second, ACE was found to be present not only
in endothelial cells but also in the tunica media and
adventitia; furthermore, expression of its gene was found to increase
markedly with hypertension and particularly with
RVH.83 84 85
However, a word of caution in drawing conclusions is advisable since other factors can be involved as well, including autoimmune mechanisms,86 and since a protective role of Ang II against stroke, at least of the hemorrhagic type, has also been advocated.87 This was based on the finding of a greater reduction in the incidence of stroke in the patients of the Medical Research Council trial treated with bendrofluothiazide, which stimulates renin, than in those on propranolol, which suppresses it. However, both ß-blockers and diuretics can exert several other effects in addition to altering renin secretion, and therefore the interpretation of those results is not univocal.
|
Protective Role of ACE Inhibitors In Vivo |
|---|
|
TopAbstractIntroductionVascular and Cellular Effects...Experimental HypertensionGenetic FactorsThe Renin-Angiotensin System and...Clinical HypertensionProtective Role of ACE...ConclusionsReferences |
|---|
ACE inhibitors have been shown to prevent vascular damage in experimental studies and to provide vascular protection and prevent vascular disease and complications.88 In SHR, the ACE inhibitor captopril was found to be more effective than a direct vasodilator (hydralazine) and a ß-blocker (propranolol) in preventing increases in aortic SMC content, medial SMC weight, and percentage of polyploid SMCs.89 It was also found to reduce SMC volume in both SHR and Wistar-Kyoto rats. In mesenteric arteries of SHR, captopril induced a long-lasting decrease in wall-to-lumen ratio and simultaneously decreased aortic wall and myocardial hypertrophy for up to 2 months after treatment withdrawal.89 90 In two-kidney, one clip hypertensive rats, ACE inhibition reversed hypertrophy of aortic SMCs without regression of the increased absolute amount of collagen content.91 Furthermore, captopril was found to reduce the cross-sectional wall area of first-order arterioles in one-kidney, one clip hypertensive rats.92 ACE inhibitors were also found to decrease collagen and elastin accumulation and the cross-sectional wall area of the media in arteries of growing Wistar rats independent of their effects on blood pressure.93
ACE inhibitors were effective in preventing myointimal proliferation after vascular injury in rats94 but not in pigs.95 They reduced atherogenesis in rabbits96 as well as in cholesterol-fed monkeys97 and the prevalence of stroke and kidney dysfunction in SHR.98 However, the Ang II receptor antagonist SC-51316 did not attenuate atherogenesis, suggesting that an ACE-dependent factor can also play a role in reducing the progression of atherosclerosis, probably by modulating the effects of cholesterol on cellular elements, which are involved in the early stages of plaque formation.99
|
Conclusions |
|---|
|
TopAbstractIntroductionVascular and Cellular Effects...Experimental HypertensionGenetic FactorsThe Renin-Angiotensin System and...Clinical HypertensionProtective Role of ACE...ConclusionsReferences |
|---|
A definite proof of the contribution of the renin-angiotensin system to the pathogenesis of accelerated carotid artery atherosclerosis and particularly of cerebrovascular disease is still lacking, but the bulk of experimental as well as clinical data is consistent with this hypothesis. The availability of effective agents with opposite effects on the renin-angiotensin system offers an opportunity to further verify this possibility in ongoing longitudinal large-scale intervention trials.
|
Selected Abbreviations and Acronyms |
|---|
|
Received April 4, 1995; revision received June 12, 1995; accepted June 12, 1995.
|
References |
|---|
|
TopAbstractIntroductionVascular and Cellular Effects...Experimental HypertensionGenetic FactorsThe Renin-Angiotensin System and...Clinical HypertensionProtective Role of ACE...ConclusionsReferences |
|---|
1. Castelli WP, Anderson K. A population at risk: prevalence of high cholesterol levels in hypertensive patients in the Framingham Study. Am J Med. 1986;80(suppl 2A):23-27.
2. Monthly Vital Statistics Report. Hyattsville, Md: National Center for Health Statistics; 1987. Publication 35, No. 13.
3.
Bots ML, Breslau PJ, de Bruyn AM, van Vliet HHDM, van
den Ouweland F, de Jong PTVM, Grobee DE.
Cardiovascular determinants of carotid artery
disease: the Rotterdam elderly study.
Hypertension. 1992;19:717-720.
4. Karalis DG, Chandrasekaran K, Victor MF, Ross JJ Jr, Mintz GS. Recognition and embolic potential of intra-aortic atherosclerosis debris. J Am Coll Cardiol. 1991;17:73-78. [Abstract]
5. Fisher CM. The arterial lesions underlying lacunes. Acta Neuropathol (Berl). 1969;12:1-15.
6.
Phillips SJ, Whisnant JP. Hypertension and the
brain. Arch Intern Med. 1992;152:938-945.
7. Cupples LA, D'Agostino RB. Some risk factors related to the annual incidence of cardiovascular disease and death using pooled repeated biennial measurements: Framingham Heart Study, 30 year follow-up, section 34. In: Kannel WB, Wolf PA, Garrison RJ, eds. The Framingham Study: An Epidemiological Investigation of Cardiovascular Disease. Bethesda, Md: National Heart, Lung, and Blood Institute; 1987:2703. Publication NIH 87.
8. Kaplan NM. Systemic hypertension: mechanisms and diagnosis. In: Braunwald E, ed. Heart Disease: A Textbook of Cardiovascular Medicine. Philadelphia, Pa: WB Saunders Co; 1988:826-832.
9. Ross R. The pathogenesis of atherosclerosis: a perspective for the 1990s. Nature. 1993;362:801-809. [Medline] [Order article via Infotrieve]
10. Rossi GP, Pavan E, Pessina AC. Role of genetic, humoral and endothelial factors in hypertension-induced atherosclerosis. J Cardiovasc Pharmacol. 1994;23(suppl 5):S75-S84.
11. Brunner HR, Laragh IH, Baer L, Newton MA, Goodwin FT, Krakoff LR, Bard RH, Bühler FR. Essential hypertension: renin and aldosterone, heart attack and stroke. N Engl J Med. 1972;286:441-449.
12. Alderman MH, Madhavan S, Ooi WL, Cohen H, Sealey JE, Laragh JH. Association of the renin-sodium profile with the risk of myocardial infarction in patients with hypertension. N Engl J Med. 1991;324:1098-1104. [Abstract]
13.
Farber HW, Center DM, Rounds S. Bovine and human
endothelial cell production of neutrophil
chemoattractant activity in response to components of the
angiotensin system. Circ Res. 1985;57:898-902.
14.
Chobanian AV, Lichtenstein AH, Nilakhe V, Haudenschild
CC, Drago R, Nickerson C. Influence of hypertension on aortic
atherosclerosis in the Watanabe rabbit.
Hypertension. 1989;14:203-209.
15. Khairallah PA, Robertson AL, Davila D. Effects of angiotensin II on DNA, RNA and protein synthesis. In: Genest J, Koiw E, eds. Hypertension 1972. Berlin, Germany: Springer-Verlag; 1972:212-220.
16.
Geisterfer AAT, Peach MJ, Owens GK.
Angiotensin II induces hypertrophy, not
hyperplasia, of cultured rat aortic smooth muscle cells.
Circ Res. 1988;62:749-756.
17. Campbell-Boswell M, Robertson AL. Effects of angiotensin II and vasopressin on human smooth muscle cells in vitro. Exp Mol Pathol. 1981;62:265-276.
18. Naftilan AJ, Pratt RE, Dzau VJ. Induction of platelet-derived growth factor A-chain and c-myc gene expressions by angiotensin II in cultured smooth muscle cells. J Clin Invest. 1989;83:1419-1424.
19.
Daemen MJAP, Lombardi DM, Bosman FT, Schwartz SM.
Angiotensin II induces smooth muscle cell
proliferation in the normal and injured rat arterial
wall. Circ Res. 1991;68:450-456.
20. Re RN, MacPhee A, Fallon J. Specific nuclear binding of angiotensin II by rat liver and spleen nuclei. Clin Sci. 1981;61:S245-S250.
21. Heagerty AM, Ollerenshaw JD. The phosphoinositide signaling system and hypertension. J Hypertens. 1987;5:515-524. [Medline] [Order article via Infotrieve]
22. Carlsson L, Abrahamsson T. Ramipril attenuates the local release of noradrenaline in the ischaemic myocardium. Eur J Pharmacol. 1989;166:157-164. [Medline] [Order article via Infotrieve]
23. Yanagisawa M, Kurihara H, Kimura S, Tomobe Y, Kobayashi M, Mitsui Y, Yazaki Y, Goto K, Masaki T. A novel vasoconstrictor peptide produced by vascular endothelial cells. Nature. 1988;332:411-415. [Medline] [Order article via Infotrieve]
24. Nakaki T, Nakayama M, Yamamomoto S, Kato R. Endothelin-mediated stimulation of DNA synthesis in vascular smooth muscle cells. Biochem Biophys Res Commun. 1989;158:880-883. [Medline] [Order article via Infotrieve]
25. Simonson MS, Wann S, Mené P, Dubyak GR, Kester M, Nakazato Y, Sedor JR, Dunn MJ. Endothelin-stimulated phospholipase C, Na+/H+ exchange, c-fos expression and mitogenesis in rat mesangial cells. J Clin Invest. 1989;83:708-712.
26. Dubin D, Pratt RE, Cooke JP, Dzau VJ. Endothelin, a potent vasoconstrictor, is a vascular smooth muscle mitogen. J Vasc Med Biol. 1989;1:150-154.
27. Emory T, Hirata Y, Ohta K, Shichiri M, Marumo F. Secretory mechanism of immunoreactive endothelin in cultured bovine endothelial cells. Biochem Biophys Res Comm. 1989;160:93-100. [Medline] [Order article via Infotrieve]
28. Resink TJ, Scott-Burden T, Bühler FR. Activation of phospholipase A2 by endothelin in cultured vascular smooth muscle cells. Biochem Biophys Res Commun. 1989;158:708-712.
29.
Weber KT, Brilla CG. Pathological
hypertrophy and cardiac interstitium: fibrosis and
renin-angiotensin-aldosterone system.
Circulation. 1991;83:1849-1865.
30. Rossi GP, Rossi A, Zanin L, Calabrò A, Pessina AC. Prevalence of extracranial carotid artery lesions at duplex in primary aldosteronism. Am J Hypertens. 1993;6:8-14. [Medline] [Order article via Infotrieve]
31. Chobanian AV, Brecher PI, Haudenschild CC. Effects of hypertension and of antihypertensive therapy on atherosclerosis. Hypertension. 1986;8(suppl I):I-15-I-21.
32.
McGill H, Carey KD, McMahan A, Marinez YN, Cooper TE,
Mott GE, Schwartz CJ. Effects of two forms of hypertension on
atherosclerosis in the hyperlipidemic
baboon. Arteriosclerosis. 1985;5:481-493.
33. Saito N, Mukaino S, Ogino K, Kawai C. Vascular lesions in hypertensive rats under salt loading: kidney renin and lysosomal enzymes. Clin Sci Mol Med. 1976;51:49s-51s.
34.
Volpe M, Camargo MJF, Mueller FB, Campbell WG Jr,
Sealey JF, Pecker MS, Sosa RE, Laragh JH. Relation of plasma
renin to end organ damage and to protection of K+ feeding
in stroke-prone hypertensive rats.
Hypertension. 1990;15:318-326.
35. Dietz R, Haebara H, Luth B, Mast G, Nemes Z, Schomig A, Szokol M. Does the renin-angiotensin system contribute to the vascular lesions in renal hypertensive rats? Clin Sci Mol Med. 1976;51:33s-35s.
36. Laragh JH, Sealey JE. Renin profiling for diagnosis, risk assessment, and treatment of hypertension. Kidney Int. 1993;44:1163-1175. [Medline] [Order article via Infotrieve]
37. Overturf M, Sybers H, Schaper J, Taegtmeyer H. Hypertension and atherosclerosis in cholesterol-fed rabbits, part I: mild, two-kidney, one-clip Goldblatt hypertension treated with enalapril. Atherosclerosis. 1986;59:283-299. [Medline] [Order article via Infotrieve]
38. Overturf ML, Aschenbrener C, Druilhet R, Kirkendall WM. Renin as a risk factor for atherogenesis: effects of hypercholesterolemia and two-kidney-one-clip hypertension in the rabbit. Atherosclerosis. 1981;38:97-119.[Medline] [Order article via Infotrieve]
39. Overturf M, Sybers H, Druilhet R, Kirkendall WM. Renin as a risk factor for atherogenesis, part III: effects of hypercholesterolemia, hyporeninemia and one-kidney-one-clip hypertension in the rabbit. Atherosclerosis. 1982;42:141-160. [Medline] [Order article via Infotrieve]
40. Overturf M, Sybers H, Schaper J, Taegtmeyer H. Hypertension and atherosclerosis in cholesterol-fed rabbits, II: one kidney, one clip Goldblatt hypertension treated with nifedipine. Atherosclerosis. 1987;66:63-76. [Medline] [Order article via Infotrieve]
41. Morgagni GB. De Sedibus et Causis Morborum per Anatomen Indagatis, Vol 1. Venice, Italy: Remondiana; 1761.
42. Ouchi Y, Tagawa H, Yamakado M, Takanashi R, Tanaka S. Clinical significance of cerebral aneurysm in renovascular hypertension due to fibromuscular dysplasia: two cases in siblings. Angiology. 1989;40:581-588.
43. Graffagnino C, Gasecki AP, Doig GS, Hachisnki VC. The importance of family history in cerebrovascular disease. Stroke. 1994;25:1599-1604. [Abstract]
44.
Kiely DK, Wolf PA, Cupples LA, Beiser AS, Myers RH.
Familial aggregation of stroke: the Framingham Study.
Stroke. 1993;24:1366-1371.
45.
Nagayama T, Shinohara Y, Nagayama M, Tsuda M, Yamamura
M. Congenitally abnormal plasminogen in juvenile
ischemic cerebrovascular disease. Stroke. 1993;24:2104-2107.
46.
Franken DG, Vreugdenhil A, Boers GHJ, Verrips A, Blom
HJ, Novakova IRO. Familial cerebrovascular accidents due to
concomitant hyperhomocystinemia and protein C deficiency type
1. Stroke. 1993;24:1599-1600.
47. Rossi GP, Zanin L, Lippolt A, Pessina AC. Le basi genetiche dell'ipertensione arteriosa: nuove acquisizioni dalle metodologie di indagine molecolare. G Ital Cardiol. 1994;24:1125-1135. [Medline] [Order article via Infotrieve]
48.
Rigat B, Hubert C, Corvol P, Soubrier F. PCR
detection of the insertion/deletion polymorphism of the human
angiotensin converting enzyme (DCP1)
(dipeptidylcarboxypeptidase 1). Nucleic Acids Res. 1992;20:1433.
49. Rigat B, Hubert C, Alhenc-Gelas F, Cambien F, Corvol P, Soubrier F. An insertion/deletion polymorphism in the angiotensin I-converting enzyme gene accounting for half the variance of serum enzyme levels. J Clin Invest. 1990;86:1343-1346.
50. Cambien F, Poirier O, Lecerf L, Evans A, Cambous JP, Arveiler D, Luc G, Bard JM, Bara L, Ricard S, Tiret L, Amouyel P, Alhenc-Gelas F, Soubrier F. Deletion polymorphism in the gene for angiotensin-converting enzyme is a potent risk factor for myocardial infarction. Nature. 1992;359:641-644. [Medline] [Order article via Infotrieve]
51. Zhao Y, Higaki J, Kamitani A, Miki T, Mikami H, Ogihara T. Significance of deletion polymorphism of the ACE gene as a risk factor for myocardial infarction in Japanese. J Hypertens. 1994;12(suppl 3):S-71. Abstract.
52. Raynolds MV, Bristow MR, Bush EW, Abraham WT, Lowes BD, Zisman LS, Taft CS, Perryman MB. Angiotensin-converting enzyme DD genotype in patients with ischaemic or idiopathic dilated cardiomyopathy. Lancet. 1993;42:1073-1075.
53. Marian AJ, Yu QT, Workman R, Greve G, Roberts R. Angiotensin-converting enzyme polymorphism in hypertrophic cardiomyopathy and sudden cardiac death. Lancet. 1993;342:1085-1086. [Medline] [Order article via Infotrieve]
54. Ohishi M, Fuji K, Minamino T, Higaki J, Kamitani A, Rakugi H, Zhao Y, Mikami H, Miki T, Ogihara T. Deletion polymorphism of the ACE gene as a possible risk factor of restenosis of emergency PTCA. J Hypertens. 1994;12(suppl 3):4. Abstract.
55. Tiret L, Kee F, Poirier O, Nicaud V, Lecerf L, Evans A, Cambou JP, Arveiler D, Luc G, Amouyel P, Cambien F. Deletion polymorphism in angiotensin-converting enzyme gene associated with parental history of myocardial infarction. Lancet. 1993;341:991-992. [Medline] [Order article via Infotrieve]
56.
Morishita R, Gibbons GH, Kaneda Y, Ogihara T, Dzau VJ.
Novel in vitro gene transfer method for study of local
modulators in vascular smooth muscle cells.
Hypertension. 1993;21:894-899.
57. Morishita R, Gibbons GH, Kaneda Y, Ogihara T, Dzau VJ. Novel and effective gene transfer technique for study of vascular renin angiotensin system. J Clin Invest. 1993;91:2580-2585.
58.
Bonithon-Kopp C, Ducimetière P, Touboul PJ,
Fève JM, Billaud E, Courbon D, Hèraud V. Plasma
angiotensin-converting enzyme activity and carotid wall
thickening. Circulation. 1994;89:952-954.
59.
Ridker PM, Gaboury CL, Conlin PR, Seely EW, Williams
GH, Vaughan DE. Stimulation of plasminogen
activator inhibitor in vivo by infusion of
angiotensin II: evidence of a potential interaction between
the renin-angiotensin system and fibrinolytic
function. Circulation. 1993;87:1969-1973.
60. Olson JA Jr, Shiverick KT, Ogilvie S, Buhi WC, Raizada MK. Angiotensin II induces secretion of plasminogen activator inhibitor 1 and a tissue metalloprotease inhibitor-related protein from rat brain astrocytes. Neurobiology. 1991;88:1928-1932.
61. Vaughan DE, Shen C, Lazos SA. Angiotensin II induces plasminogen activator inhibitor (PAI-1) in vitro. Circulation. 1992;86(suppl I):I-557. Abstract.
62.
Van Leeuwen RTJ, Kol A, Andreotti F, Kluft C, Maseri A,
Sperti G. Angiotensin II increases
plasminogen activator inhibitor
type 1 and tissue-type plasminogen activator
messenger RNA in cultured rat aortic smooth muscle cells.
Circulation. 1994;90:362-368.
63. Hamsten A, Wiman B, DeFaire U, Blomback M. Increase plasma levels of a rapid inhibitor of tissue plasminogen activator in young survivors of myocardial infarction. N Engl J Med. 1985;313:1557-1563. [Abstract]
64. Wright RA, Flapan AD, Alberti KGMM, Ludlam CA, Fox KAA. Effects of captopril therapy on endogenous fibrinolysis in men with recent, uncomplicated myocardial infarction. J Am Coll Cardiol. 1994;24:67-73. [Abstract]
65. Safar M, Asmar M, Bouthier J, Lacolley P, Laurent S. Converting enzyme inhibition and the common carotid artery circulation in older patients with sustained hypertension. Eur Heart J. 1988;9(suppl D):75-78.
66.
Simon N, Franklin SS, Bleifer KH, Maxwell MM.
Clinical characteristics of renovascular hypertension.
JAMA. 1972;220:1209-1218.
67.
Frohlich ED, Ulrych M, Tarazi RC, Dustan H, Page IH.
A hemodynamic comparison of essential and
renovascular hypertension: cardiac output and total
peripheral resistance: supine and tilted patients.
Circulation. 1967;35:289-297.
68. Vensel LA, Devereux RB, Pickering TG, Herrold EM, Borer JS, Laragh JH. Cardiac structure and function in renovascular hypertension produced by unilateral and bilateral renal artery stenosis. Am J Cardiol. 1986;58:575-582. [Medline] [Order article via Infotrieve]
69. Pickering TG, Sos TA, James GD, Vaughan ED, Sealey JE, Laragh JH. Recurrent pulmonary oedema as a manifestation of renovascular hypertension and its treatment by renal revascularization. Circulation. 1987;76(suppl IV):IV-274. Abstract.
70. Davis BA, Crook HE, Vestar RE, Oates JA. Prevalence of renovascular hypertension in patients with grade III or IV hypertensive retinopathy. N Engl J Med. 1979;301:1273-1276. [Medline] [Order article via Infotrieve]
71. Chiari H. Ueber das Verhalten des Teilungswinkels der Carotis communis bei der Endarteriitis chronica deformans. Verh Dtsch Pathol. 1905;Tag 9:326-330.
72. Rybka SJ, Novick AC. Concomitant carotid, mesenteric and renal artery stenosis due to primary intimal fibroplasia. J Urol. 1983;129:798-800. [Medline] [Order article via Infotrieve]
73. Rossi A, Rossi GP, Zanin L, Calabrò A, Pessina AC. Elevata prevalenza di lesioni ostruttive delle carotidi extracraniche nell'ipertensione renovascolare. G Ital Cardiol. 1990;20:291-299. [Medline] [Order article via Infotrieve]
74. Rossi GP, Rossi A, Zanin L, Calabrò A, Feltrin GP, Pessina AC, Crepaldi G, Dal Palú C. Excess prevalence of extracranial carotid artery lesions in renovascular hypertension. Am J Hypertens. 1992;5:8-15. [Medline] [Order article via Infotrieve]
75. Chiesura-Corona M, Feltrin GP, Savastano S, Miotto D, Torraco A, Castellan L, Rossi GP. Excess prevalence of supra-aortic lesions in renovascular hypertension: an arteriographic study. Cardiovasc Intervent Radiol. 1994;17:264-270. [Medline] [Order article via Infotrieve]
76. Rossi GP, Zanin L, Dessi-Fulgheri P, Savastano S, Cavazzana A, Prayer-Galetti T, Rappelli A, Pessina AC. A renin-secreting tumour with severe hypertension and cardiovascular disease: a diagnostic and therapeutic challenge. Clin Exp Hypertens. 1993;15:325-338.
77. Rossi A, Bonfante L, Calabrò A, Giacomini A, Mastrosimone S, Beccari L, De Silvestro L, Baldo-Enzi G, Baiocchi MR, Abbruzzese E, Borsatti A, Crepaldi G. Prevalence of extracranial carotid artery lesions at duplex in patients affected by non-diabetic non-nephrotic renal failure. Int Angiol. 1994;13:19. Abstract. [Medline] [Order article via Infotrieve]
78.
Kaplan NM. Renin profiles.
JAMA. 1977;238:611-613.
79. Laragh JH, Brenner BM. Hypertension. Pathophysiology, Diagnosis, and Management. New York, NY: Raven Press Publishers; 1990;2:2219.
80. Bakris GL, Gavras H. Renin in acute and chronic renal failure: implications for treatment. In: Robertson JI, Nicholls MG, eds. The Renin-Angiotensin System: Biochemistry, Physiology, Pathophysiology, Therapeutics. London, England: CV Mosby Co; 1993:56.1-56.14.
81. Stokes GS, Mani MK, Stewart JH. Relevance of salt, water and renin to hypertension in chronic renal failure. Br Med J. 1970;3:126-131.
82. Weidmann P, Maxwell MH, Lupu AN, Lewin AJ, Massry SG. Plasma renin activity and blood pressure in terminal renal failure. N Engl J Med. 1971;285:757-763.
83.
Shiota N, Miyazaki M, Okunishi H. Increase of
angiotensin converting enzyme gene expression in the
hypertensive aorta. Hypertension. 1992;20:168-174.
84.
Okamura T, Miyazaki M, Inagami T, Toda N.
Vascular renin-angiotensin system in two-kidney, one
clip hypertensive rats. Hypertension. 1986;8:560-565.
85.
Arnal JF, Battle T, Rasetti M, Challah M, Costerousse
O, Vicaut E, Michel JB, Alhenc-Gelas F. ACE in three tunicae of
rat aorta: expression in smooth muscle and effect of renovascular
hypertension. Am J Physiol. 1994;267:H1777-H1784.
86. Rossi GP, Ossi E, Perrone A, Mazzucco B, Albertin G, Zanin L, Pessina AC. Autoimmune mechanisms may be involved in renovascular hypertension due to fibrodysplasia but not to atherosclerosis. J Hypertens. 1993;11(suppl 5):S206-S207.
87. Brown MJ, Brown J. Does angiotensin-II protect against stroke? Lancet. 1986;2:427-429. [Medline] [Order article via Infotrieve]
88. Dzau VJ, Gibbons GH, Pratt RE. Molecular mechanisms of vascular renin-angiotensin system in myointimal hyperplasia. Hypertension. 1991;18(suppl II):II-100-II-105.
89. Freslon JL, Giudicelli JF. Compared myocardial and vascular effects of captopril and dihydralazine during hypertension development in spontaneously hypertensive rats. Br J Pharmacol. 1983;80:533-543. [Medline] [Order article via Infotrieve]
90.
Owens GK. Influence of blood pressure on
development of aortic medial smooth muscle hypertrophy in
spontaneously hypertensive rats.
Hypertension. 1987;9:178-187.
91.
Levy BI, Michel JB, Salzmann JL, Azizi M, Poitevin P,
Safar M, Camilleri JP. Effects of chronic inhibition of
converting enzyme on mechanical and structural properties of arteries
in rat with renovascular hypertension. Circ
Res. 1988;63:227-239.
92.
Wang D-H, Prewitt RL. Captopril reduces aortic
and microvascular growth in hypertensive and normotensive rats.
Hypertension. 1990;15:68-77.
93. Keeley FW, Johnson DJ, Elmoslhi A, Leenen FHH. Enalapril suppresses normal accumulation of elastin and collagen in cardiovascular tissues of growing rats. In: Program and Abstracts of the 13th Scientific Meeting of the International Society of Hypertension; June 24-29, 1990; Montreal, Canada. Abstract IC.24.
94.
Powell JS, Clozel JP, Muller RKM, Kuhn H, Hefti F,
Hosang M, Baumgartner HR. Inhibitors of
angiotensin-converting enzyme prevent myointimal
proliferation after vascular injury. Science. 1989;245:186-188.
95.
Lam JYT, Lacoste L, Bourassa MG. Cilazapril and
early atherosclerotic changes after balloon injury of porcine carotid
arteries. Circulation. 1992;85:1542-1547.
96.
Chobanian AV, Haudenschild CC, Nickerson C, Drago R.
Antiatherogenic effect of captopril in the Watanabe heritable
hyperlipidemic rabbit.
Hypertension. 1990;15:327-331.
97. Aberg G, Ferrer D. Antiatherosclerotic effect of captopril in cynomolgus monkeys. J Cardiovasc Pharmacol. 1990;15(suppl 5):S65-S72.
98.
Stier CT, Benter IF, Ahmad S, Zuo H, Selig N, Roethel
S, Levine S, Itskovitz HD. Enalapril prevents stroke and kidney
dysfunction in salt-loaded stroke-prone spontaneously hypertensive
rats. Hypertension. 1989;13:115-121.
99. Schuh JR, Blehm DJ, Frierdich GE, McMahon E, Blaine EH. Differential effects of renin-angiotensin system blockade on atherogenesis in cholesterol-fed rabbits. J Clin Invest. 1993;91:1453-1458.
This article has been cited by other articles:
 |
|
 |
|
  G. P. Rossi, G. Bernini, G. Desideri, B. Fabris, C. Ferri, G. Giacchetti, C. Letizia, M. Maccario, M. Mannelli, M.-J. Matterello, et al. Renal Damage in Primary Aldosteronism: Results of the PAPY Study Hypertension, August 1, 2006; 48(2): 232 - 238. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Testa, F. A. Benedetto, B. Spoto, A. Pisano, G. Tripepi, F. Mallamaci, L. S. Malatino, and C. Zoccali The E-selectin gene polymorphism and carotid atherosclerosis in end-stage renal disease Nephrol. Dial. Transplant., July 1, 2006; 21(7): 1921 - 1926. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. B. Gorelick Stroke Prevention Therapy Beyond Antithrombotics: Unifying Mechanisms in Ischemic Stroke Pathogenesis and Implications for Therapy: An Invited Review Stroke, March 1, 2002; 33(3): 862 - 875. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Rizzoni, M. L. Muiesan, E. Porteri, M. Salvetti, M. Castellano, G. Bettoni, G. Tiberio, S. M. Giulini, C. Monteduro, G. Garavelli, et al. Relations between cardiac and vascular structure in patients with primary and secondary hypertension J. Am. Coll. Cardiol., October 1, 1998; 32(4): 985 - 992. [Abstract] [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||