Renin, angiotensin and hypertensive vascular damage: A review

Renin, Angiotensin and Hypertensive Vascular Damage: A Review

JQRN GIESE. Copenhagen,

M.D. Denmark

From the Department of Clinical Physiology, Glostrup Hospital, Copenhagen, Denmark. Requests for reprints should be addressed to Dr. J&n Giese.

This article provides an overview of the pathogenesis of hypertensive arteriolar disease, with particular consideration being given to the possible role of the renin-angiotensin system in the causation of vascular lesions. The penetration of macromolecules from the plasma stream into the arteriolar wall is found to be a fundamental pathogenetic process in the development of vascular damage. The induction of acute vascular disease by components of the renin-angiotensin system is reviewed in some detail. The emergence of abnormal arteriolar reaction patterns during states of severe hypertension is described. The formation of localized arteriolar dilations, with consequential distention of localized arteriolar dilatations, with consequential distenof basic importance for the development of focal permeability changes with ensuing segmental arteriolar lesions. Conceptual problems in evaluating the dynamic state of the renin-angiotensin system are discussed as a requisite introduction to the examination of the relations between the level of blood pressure, the state of the renin system and the development of hypertensive arteriolar disease. Activation of the renin-angiotensive system is not a necessary condition for the emergence of necrotizing arteriolar lesions in hypertensive disease, but there are strong indications that the action of a,ngiotensin II on vascular receptors can accelerate or aggravate the development of malignant vascular lesions. Despite considerable progress in medical and surgical therapy, hypertension remains one of the most serious diseases of modern man. Since the prognosis in the individual hypertensive patient is determined, above all, by the extent and severity of vascular lesions in vital organs, one of the most important problems within the field of hypertension research is elucidation of the mechanisms of vascular damage in this condition. During the last decade, the extent of studies on the components of the renin-angiotension-aldosterone system in hypertensive patients has been increasing steadily. Recently, the question about a possible relationship between the state of activity of the renin system and the progression of arterial disease has been brought into focus in a new context [l-4]. This revival of interest in angiotoxic effects of renin with potential relevance to hypertensive disease in man makes it appropriate to analyze

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the available evidence related to this problem, which has been a subject of continuous controversy over the years within the field of experimental medicine. With respect to the development of arterial disease, is the prognosis definitely better in hypertensive patients with a low plasma renin concentration than in patients with a normal or high plasma renin level? I certainly am not able to give a final answer to this important question. What I can do is to review selected data on the effects of the renin-angiotensin system on the vascular tree, together with pertinent information on the mechanisms of vascular damage in various types of hypertensive disease in experimental animals and man. This approach may, hopefully, lead to a definition of fundamental problems requiring further study. The theme of the review has a great many facets, and no pretence to completeness is made. EXPERIMENTAL INDUCTION OF ACUTE VASCULAR LESIONS BY ADMINISTRATION OF RENAL EXTRACTS, RENIN AND ANGIOTENSIN The concept of a release from damaged kidney tissue of substances with a capacity to injure the vascular system was explored in the classic studies by Winternitz and his collaborators [5]. These investigators induced necrotizing arterial lesions in dogs by bilateral ligation of the renal arteries or, alternatively, by the administration of kidney extract to nephrectomized animals. Since very few vascular lesions were found in a control series of nephrectomized dogs, the experiments were interpreted as demonstrating the release of an angiotoxic substance from ischemic kidney tissue. Due attention was paid to the fact that hypertension was a very rare finding after simple nephrectomy and that high blood pressure was regularly observed after bilateral renal artery ligation and in nephrectomized dogs given injections of extract of renal tissue. Masson et al. [6] confirmed and extended these observations by their demonstration of “accelerated hypertensive vascular disease” in nephrectomized dogs subjected to salt excess and to injection of large doses of renin. Acute hypertension with rapid development of disseminated arteriolar necroses can be induced in the rat by a very simple procedure: The application of narrow silver clips to both renal arteries [7]. The vascular lesions are particularly prominent in the pancreas, the intestines and the mesentery. Morphologically, the salient features of these hyperacute arteriolar lesions are the formation of periodic acid-Schiff-positive deposits in the

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vascular walls and degenerative changes of the smooth muscle cells. In this model disease, the experimental renal ischemia is associated with necrosis of kidney tissue and suppression of renal excretory function. In an attempt to establish an analogous experimental situation crude saline extracts of rat kidneys were administered to nephrectomized rats, and the findings in rats with bilateral narrow renal artery clips were duplicated [8]. These results supported the primary assumption, that a substance released from degenerating kidney tissue was responsible for the production of vascular lesions. Next, it was shown that an identical syndrome could be induced by administering semipurified hog renin to nephrectomized rats. Since no pure renin preparation was available, attempts to identify the substance responsible for inducing hyperacute arteriolar lesions were carried further by infusing synthetic angiotensin II into nephrectomized rats. Lesions in small arteries and arterioles, indistinguishable from those observed in rats subjected to the procedures previously mentioned, were readily induced. From these several experiments it was concluded that the very severe arteriolar lesions observed after the experimental induction of extreme bilateral kidney ischemia in rats are caused by a release of renin from degenerating kidney tissue with subsequent in vivo formation of large amounts of angiotensin. Thus, the pressor octapeptide angiotensin II was considered to be the biologic compound responsible for the production of necrotizing arteriolar lesions. At the same time, Asscher and Anson [9] performed similar experiments on the effects of kidney extracts in nephrectomized rats. They reported identical results and demonstrated that renal medullary extracts were inactive whereas the activity of extracts prepared from kidney cortex was similar to that of whole kidney extract. It was further shown that infusion of large doses of angiotensin II into normal rats can induce arteriolar lesions identical to those observed in nephrectomized rats. The administration of renin preparations to normal rats with intact kidneys induces very few vascular lesions [S]. The sensitization to renin after bilateral nephrectomy was believed to be due to several factors, including changes in renin substrate concentration with abnormally increased angiotensin formation, and a very pronounced and prolonged blood pressure response to renin [lO,ll]. Studies on the blood pressure responses in rats subjected to bilateral kidney ischemia, or nephrectomy with subsequent administration of renal

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extracts or angiotensin, demonstrated one feature in common: the development of acute severe hypertension, maintained over many hours [12]. Masson and his collaborators have published a series of papers on the induction of acute arterial lesions by administration of renin to rats pretreated with adrenocortical hormones and sodium chloride. The classic “steroid-renin syndrome” was produced by giving DOCA-hypertensive rats injections of large doses of renin [13]. Pretreatment with other steroids, such as cortisone, hydrocortisone or aldosterone, together with salt will induce the same abnormal sensitivity to renin [14-161. There is no doubt that the arteriolar lesions elicited in these experimental syndromes are identical to those observed in the nephrectomized rat given injections of renin. It is well known that rats treated with DOCA and salt show a very prolonged and pronounced rise in blood pressure after an injection of renin, just like the nephrectomized rat [17,18]. In conclusion, it has been shown beyond doubt that acute arteriolar lesions, conceptually associated with and morphologically similar or identical to the characteristic lesions of experimental malignant hypertension, can be induced by the administration or endogeneous release of renin and angiotensin I I under experimental conditions allowing the development and maintenance of a state of acute severe hypertension. THE PATHOGENESIS OF ACUTE ARTERIAL LESIONS INDUCED BY COMPONENTS OF THE RENIN-ANGIOTENSIN SYSTEM AND BY UNRELATED PRESSOR AGENTS One of the outstanding lines of thought in the study of the morphogenesis of arterial lesions in hypertensive disease, particularly those observed in malignant hypertension, is now generally referred to as the concept of plasmatic vasculosis. The term, as originally suggested by Goldblatt and further developed by Lendrum [19,20] covers vascular lesions with a demonstrable extravasation of plasma from the blood stream, with subsequent deposition in the vascular wall of one or more plasmatic constituents. The fundamental studies of Schijrmann and MacMahon [21] have been essential to the formulation of this concept. The possible applicability of this concept to the vascular lesions induced by acute hypertension in the rat has been investigated in various ways. As an initial approach, I utilized direct fluorescent protein tracing [22]. Homologous serum proteins were conjugated with a fluorescent dye. After intravenous injection of the tracer protein into rats, localization of the fluorescent serum proteins in

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Figure

1. Rat subjected to bilateral severe renal ischemia. Intravenous injection of tluorochrome-conjugated rat serum proteins. Fluorescence photomicrograph (ultraviolet-blue light). Left, ouginal magnif/cation X 100. Section of pancreas shows !arge vein with tracer-containing plasma in lumen. At upper and lower left, arterioles show fluorescent tracer deposits in media [7]. Right, same preparation; original magnification X rescent

185. Section tracer deposit

of pancreatic in media [ 71.

artery

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the tissues of these animals could be studied by examining unstained sections under the fluorescence microscope. The fluorochrome-conjugated proteins were administered to six control rats and eight experimental rats. The control rats subsequently received repeated intravenous injections of small volumes of saline solution, whereas the experimental rats were exposed to a series of injections of synthetic angiotensin II, leading to repeated episodes of acute hypertension. Six of eight angiotensin-treated rats showed deposits of tracer protein in the walls of small arteries or arterioles of the pancreas, the intestines or the mesentery, whereas no fluorescent deposits were observed in the control rats. A similar deposition of fluorescent tracer protein in the walls of small arteries can be demonstrated in rats subjected to bilateral renal ischemia [7] (Figure 1). After examination under the fluorescence microscope, some of the sections were stained by the periodic acid-schiffprocedure and studied by ordinary light microscopy. This technic established a close topographic correspondence between the fluorescent deposits and the subsequently demonstrated periodic acidSchiff-positive deposits, and signs of degeneration in the smooth muscle cells of the media in the affected vessels were observed. Thus, it was shown that labelled serum proteins can penetrate into the walls of small arteries during states of acute hy-

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Figure 2. Rat subjected

to nephrectomy and continuous infusion of angiotensin. Intravenous injection of colloidal carbon particles. Formaiinfixed preparation, dehydration in alcohols, clearing in methyl benzoate and oil of anise. Top, original magnification X 250, reduced by 35 per cent. Mesenteric artery shows heavy deposits of carbon in the wall, arranged in streaks perpendicular to the long axis of the vessel [23]. Bottom, same preparation; original magnification X 70, reduced by 35 per cent. Arteries at the mesenteric border of the small intestine demonstrate pronounced carbon deposits in ring-like arrangements around the circumference of the vessel. A labelled dilated blanch leads to an area of heavy diffuse lqbelling (indicating plasma leakage from minute vessels) [23].

pertension, induced by administration or endogeneous generation of large amounts of angiotensin. In further studies [23], colloidal carbon particles were used as another tracer substance providing information on the pathways for macromolecules escaping from the intravascular compartment [24]. Injections of colloidal suspensions of particles with an indicated average particle size of 200 A were given intravenously to nephrectomized rats during acute hypertension induced by angiotensin infusion. These particles are retained and accumulate within the wall of leaking vessels, so that “vascular labelling” occurs. Penetration of carbon particles into the walls of small arteries during acute hypertension was readily demonstrated (Figure 2) whereas in control rats given infusions of saline solution arteriolar carbon de-

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posits were absent. The carbon deposits were found either as a continuous investment for a variable distance along the arteriole or as focal “cufflike” deposits. The mechanisms responsible for the emergence of focal abnormalities of arteriolar wall permeability during states of acute hypertension were investigated by means of vital microscopy, performed through an abdominal window made of plexiglass [23]. Direct observation of the small arteries on the surface of the intestines showed a striking change of the regular vascular configuration when the blood pressure of the experimental animal was abruptly raised by the infusion of synthetic angiotensin I I. A very characteristic pattern of alternating constricted and dilated segments appeared along the course of the arteries (Figure

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3). This pattern could be maintained over long periods of observation during sustained infusion of angiotensin I I. Intravenous administration of colloidal carbon particles after induction of the abnormal constriction-dilatation pattern permitted a direct topographic localization of the abnormally permeable segments of the arteriolar tree in that the penetration of the carbon particles into the arteriolar walls could be observed through the stereomicroscope. The most important finding was that deposition of carbon particles took place in the dilated arteriolar segments, whereas no penetration was observed in the constricted segments. Thus, the focal abnormalities of artericlar wall permeability were confined to the zones of vascular distention. In separate experiments, it was demonstrated that the tracer particles could penetrate into the walls of dilated arteriolar segments even during the first few minutes after induction of acute severe hypertension. Particular attention was paid to these observations. The astonishing rapidity in the

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development of hyperpermeable zones of the arteriolar tree gives strong support to the contention that a deposition of plasmatic macromolecules within the arteriolar wall is an initial phenomenon in the series of events leading eventually to acute hypertensive vascular damage. In this series of experiments it was also observed that similar abnormal vascular reaction patterns, although at times with a slightly different distribution of the dilated and constricted zones, could be induced by the administration of other pressor agents such as noradrenaline and methoxamine. Again, the abnormal permeability was confined to dilated arteriolar segments. These technics have been utilized in a series of studies by Olsen [25-281. The reproducibility of the abnormal vascular reaction pattern was confirmed, and the presence of discontinuities of the internal elastic lamina in hyperpermeable zones of arteriolar dilatation was demonstrated. The relative distribution within the arteriolar wall of fluorescent serum proteins and carbon particles, respectively, was investigated, and studies on the

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rates and routes of elimination of the tracer substances from the vascular wall were carried out. A thorough analysis of the perivascular inflammatory cellular reactions, occurring as a response to acute hypertensive vascular damage, was performed, with particular emphasis on the immunologic aspects of this phenomenon. Kincaid-Smith et al. [29] used similar methods in studying structural alterations of arterioles following the infusion of vasoactive compounds. They demonstrated the presence of focal zones of narrowing and dilatation in renal interlobular arteries and afferent arterioles after the administration of angiotensin. With angiotensin plus noradrenaline, pronounced caliber irregularities were observed in the mesenteric vessels. The ultrastructural studies pointed to endothelial cell contraction as one important change which would have particular consequences in dilated segments. Endothelial cell irregularity with distortion of the media was a prominent ultrastructural feature in dilated parts of the arteries. The possible importance of superimposed intravascular coagulation was discussed. Very recently, Goldby and Beilin have published two very informative papers [30,31] on the experimental induction of acute hypertensive vascular damage. They observed pronounced irregularity of caliber in the mesenteric arterioles of the rat after the administration of angiotensin I I, renal extract and noradrenaline. They measured increases in arteriolar diameter by as much as 50 per cent of the resting value on the dilated segments, whereas the diameter decreased by as much as 40 per cent on the constricted segments. They confirmed that dilated segments of arterioles were permeable to carbon particles but that constricted segments were not. It was demonstrated that there is a correlation between the mean blood pressure during a 4 hour experimental period and the percentage of arterioles bearing carbon deposits. When a rise in blood pressure was prevented by the intravenous administration of hydralazine prior to the infusion of angiotensin II or the administration of renal extract, no signs of increased vascular permeability were found. There was a sharp increase in permeability to carbon particles when the mean blood pressure was above 150 mm Hg, which would suggest that the majority of mesenteric arterioles become dilated when the mean pressure is above 150 mm Hg. It was concluded that exposure of arterioles to very high filling pressures may overcome contractility of vascular smooth muscle, with resulting dilatation and subsequent structural damage. In their second paper, Goldby and Beilin [Jl]

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showed that gut arterioles under the influence of angiotensin-induced acute hypertension develop focal breaks in the endothelium, with amorphous deposits in the media displacing and disrupting smooth muscle cells. When carbon particles were injected intravenously, they could be found in the amorphous deposits. The vascular damage was patchy and confined to the dilated segments of the arterioles. The ultrastructural appearances of the lesions were consistent with the passage of plasma constituents into the media through the damaged endothelium. In conclusion, it has been shown beyond doubt that acute severe hypertension in the rat, induced by pressor compounds, is associated with the development of a bizarre arteriolar pattern of alternating constrictions and dilatations. Abnormal permeability of the arteriolar wall is confined to dilated segments. The temporal sequence of events makes it highly probable that the influx of macromolecules from the plasma into the vessel wall is a primary and crucial phenomenon in the initiation of vascular damage. These experimental observations make it pertinent to examine a number of questions. What is known about the effects of the renin-angiotensin system on endothelial permeability? What is the evidence on the occurrence of abnormal vascular reaction patterns in more chronic forms of hypertension? What is the evidence for focally increased arteriolar permeability in hypertensive disease? THE RENIN-ANGIOTENSIN VASCULAR ENDOTHELIAL

SYSTEM AND PERMEABILITY

The effect of renin on the permeability of one particular vascular area has been recognized for many years. Injection of renin into experimental animals will induce proteinuria [32]. Morphologic studies on the glomerular capillaries by Deodhar et al. [33] and Pessina et al. [34] have shown that this phenomenon is due to an increase in glomerular permeability to macromolecules. Pessina and Peart [35] investigated renal hemodynamic changes in this experimental condition and showed that the decisive change was an increase in filtration fraction, presumably brought about by a dominant contraction of the efferent arteriole. Identical effects can be produced by administration of angiotensin II. Studies on the excretion of poiymer fractions of different molecular weight provided further support for the contention that the proteinuria is caused by an increase in glomerular pressure with a concomitant stretching of a small fraction of the total pore area [34]. This analysis provides no support for the as-

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sumption favored by the early investigators of this phenomenon, i.e., that renin or angiotensin has a specific “permeability effect“ on the endothelial membrane lining the vascular bed. The essential point seems to be a differential action of angiotensin on sequential parts of the arteriolar tree, so that mechanical stretching or distention effects would be responsible for the leakage of proteins. A similar distinction between modes of action is relevant to the discussion of permeability effects of renin in other vascular beds. Asscher and Anson [9] showed that administration of rat kidney extract to nephrectomized rats produces a lethal syndrome involving the formation of large serous effusions in the pleural and peritoneal cavities together with pronounced edema of pancreatic and mesenteric tissue, in addition to the disseminated arteriolar lesions described in a preceding section. The experimental animals show pronounced contraction of the plasma volume with a considerable rise in hematocrit. Completely identical syndromes can be produced by constriction of both renal arteries [7] and by administration of semipurified hog renin to nephrectomized rats [8]. Tissue edema of the abdominal organs can similarly be produced by the administration of angiotensin and methoxamine in the nephrectomized rat [8,12] and has been observed in rats with malignant hypertension induced by renal clips [36] and in steroid-renin syndromes [ 141. All these experimental situations are characterized by severe hypertension. In some of these conditions a penetration of plasma proteins into the arteriolar wall has been demonstrated. It is evident, that a transarteriolar exudation of fluid and protein from the plasma stream could be involved in the formation of tissue edema and effusions. Furthermore, there are observations in angiotensin-treated rats indicating that distention of an arteriole may spread peripherally until the whole vessel is affected [30]. This would expose the terminal microcirculation to a very high hydrostatic pressure-a breakthrough phenomenon 1371. The vascular labeiling tracer technic has demonstrated, in addition to the focal carbon deposits in small arteries, areas of leakage of plasma from minute vessels (231 (cf. Figure 2), and the relationship to dilated arterioles was taken to support the idea of a distal transmission of pressure. Thus, the pathogenesis of edema formation during acute severe hypertension is certainly complicated, but these manifestations could well be secondary to hemodynamic changes at the arteriolar level in the sense that increased permeability might be due to a structural deformation

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and functional maladjustment of the arteriolar bed occurring under conditions of acute severe hypertension. It should be added at this point that the permeability effects of kidney extracts have been analyzed very thoroughly by Cuthbert and collaborators [38,39], who utilized biochemical fractionation technics. They presented very convincing evidence that the “permeability factor” contained in such extracts is in fact the enzyme renin. They also emphasized that a considerable and sustained rise of blood pressure occurred in all experiments in which vascular permeability was increased. Some recent studies have been concerned with the effects of angiotensin on vascular endothelium in a more direct sense. Constantinides and Robinson [40] studied the effects on arterial endotheliurn of angiotensin amide, applied locally in very high concentration. They observed a widening of the interendothelial junctions and a thinning of the endothelial cytoplasm. The observations were compatible with the assumption that angiotensin can make endothelial cells contract. Robertson and Khairallah published somewhat similar observations [41,42]. Contraction of endothelial cells was induced by intracardiac or intraaortic injections of angiotensin I I. With electron markers, they demonstrated a temporary widening of intercellular junctions with the appearance of tortuous interendothelial channels or gaps. The formation of gaps was followed within 1 or 2 minutes by closure of these channels, with trapping of colloidal particles in the intimal and medial layers of the arterial wall, a “trap door effect.” The possible involvement of damage to blood platelets was considered. In conclusion, a very impressive effect of the renin-angiotensin system on vascular endothelial permeability has been demonstrated in a number of experimental situations. It is important to realize that these experiments have been performed under rather extreme conditions involving either the administration or endogenous release of very large amounts of renin or angiotensin. Any extrapolation from these animal experiments to pathologic conditions in man will be fraught with difficulties. THE OCCURRENCE OF ABNORMAL ARTERIOLAR REACTION PATTERNS IN ESTABLISHED HYPERTENSION Byrom’s work [43] has been of outstanding importance in this field. His ingenious technic for inserting cranial windows into the calvaria of rats permitted the observation of cerebral arteries in the

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normotensive state and after the experimental induction of renal hypertension [36]. In rats with hypertensive encephalopathy, intense vascular constriction was a common finding, either as a uniform narrowing of small arteries or as localized constrictions, associated with localized beads of considerable dilatation. The arterial pattern could be completely normalized by removal of the renal artery clip. In addition, Byrom [36,43] reported observations on the intestinal arteries of rats with severe chronic renal hypertensi,on, with or without hypertensive encephalopathy. In all cases, intense focal arterial spasm with associated dilated arterial segments was observed on loop after loop of the intestine. Recently, Goldby and Beilin [44] reported similar observations. The photographic documentation demonstrates quite clearly that the reaction pattern of gut arterioles in chronic experimental hypertension of the rat is absolutely identical to that observed in rats with acute hypertension as induced by infusion of pressor agents. This fact strongly supports the contention that the mechanisms of vascular damage disclosed in acute experiments are relevant to the pathogenesis of arteriolar disease in chronic hypertension. The retinal arterioles of the hypertensive rat can be investigated without surgical interference. Abt and Bruckner [45] and Byrom [46,47] have demonstrated the frequent occurrence of circumscript constrictions together with pronounced localized dilatations of the retinal arteriolar tree. Rodda and Denny-Brown [48] induced experimental hypertension in cynomolgus monkeys by bilateral renal artery constriction. By direct observation of the vessels of the cerebral cortex they recorded a constriction-dilatation pattern in the pial arterioles, which seems identical to that observed in the rat with acute and chronic hypertension. The segmental arteriolar constrictions were more marked in animals with a fluctuant pattern of raised blood pressure. In a very thorough study of vascular disease in steroid-induced rat hypertension, Hill and Heptinstall [49] paid much attention to the topographic coincidence of arteriolar dilatation and severe vascular damage. They stressed that the lesions were focally distributed and that they were never found in constricted arteries. They made further important observations utilizing the microangiographic technic, which allowed the demonstration of dilatations with intervening constricted segments in the renal arterial tree. Thus, these studies proved the occurrence of a similar constriction-dilatation pattern in the kidney arterioles of

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rats with another form of experimental hypertension. It should be noted at this point that histologic evidence on the occurrence of dilated arterioles with severe hypertensive vascular lesions is available from a very large series of publications 1503. These papers describe the morphology of acute hypertensive vascular lesions [8,14] as well as the vascular pathology in more chronic types of hypertension [21,51,52]. There are, of course, difficulties in the extrapdation from the appearance of fixed tissue to the state of contraction or dilatation of living arteries; furthermore, a dilated state of a necrotic artery might simply reflect passive dilatation following severe injury to the arterial wall. However, these histologic characteristics are compatible with the basic assumption developed on the basis of vital microscopic evidence. Vascular damage occurs in arterial segments which become distended when adjacent segments are severely constricted. The available information on arteriolar reaction patterns in man is very limited indeed. The retinal vasculature is the only part of the arteriolar system readily accessible for study in man. The literature on retinal vascular changes in human hypertension is very extensive, and many difficulties persist in regard to terminologic problems and pathogenetic interpretations [53,54]. Most ophthalmologists seem to agree that retinal arteriolar constriction is the all important finding in severe hypertension, and there are very few indications of the occurrence of focal arteriolar dilatations. The possibility remains that the largest arterioles near the optic disc may be slightly distended during severe hypertension whereas the smaller peripheral arterioles are severely constricted ]55]. Recently, Page [56] pointed out that “string-ofbead constrictions” can occasionally be observed at coronary angiography in patients with coronary atherosclerosis, as demonstrated by Sones. In conclusion, an abnormal arteriolar reaction pattern, characterized by focal bead-like dilatations and intervening constricted segments, has been identified in different vascular areas in experimental animals with chronic hypertension induced by various methods. There is little information on the presence or absence of similar vascular patterns in hypertensive man. FOCAL ARTERIOLAR PERMEABILITY CHANGES IN CHRONIC HYPERTENSION The important fact that necrotizing arteriolar lesions are focally distributed along the course of the small arterial vessels was already emphasized

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in Goldblatt’s classic paper on the experimental induction of malignant hypertension in the dog [57]. Longitudinal sections of a vessel may show entirely normal segments of an arteriole immediately adjacent to a completely necrotic part. This observation has been confirmed again and again in a large number of histologic studies. Evidently, the distinctly focal appearance of fibrinoid necrosis along the course of the arteriole indicates a focal process. The early evidence for the presence of increased permeability of the arteriolar wall at the site of such focal lesions was derived from histologic studies. Morphologic terminology within this field of pathology has presented certain difficulties, since descriptive terms like “fibrinoid” or “hyaline” have been used with a somewhat divergent meaning by different investigators. It is not within the scope of this review, nor within my competence, to clarify these complex issues. It is, however, quite clear that the use and acceptance of the concept embodied in the term plasmatic vasculosis has become much more widespread. In fact, considerable evidence has been obtained in favor of the assumption that a deposition of plasma proteins in the walls of small arteries takes place in severe or malignant hypertension. Studies utilizing several different technics, such as fibrin stains [58-601, histochemical methods [61], and immunohistologic procedures [62,63], all tend to support the concept. Readers particularly interested in these morphologic questions are referred to a masterly review of the subject by Lendrum [20]. The presence of deposits is by no means the only change in the vessel wall at the site of lesions. Another important feature is a varying degree of smooth muscle degeneration, with frank necrosis as the most severe change. In all fairness it should be made clear that some investigators have considered smooth muscle degeneration to be the initial and crucial event. This theory was strongly advocated in a series of publications by Montgomery and Muirhead [64-671. Sanerkin [68] has recently advocated the importance of necrosis of medial smooth muscle cells. The vascular lesions of malignant essential hypertension were considered to result from ischemia caused by obliterative spasm. Recently, more direct information on the permeability of arterioles in animals with chronic hypertension has been presented in a series of studies based upon the use of different tracer particles or substances in conjunction with light or electron microscopy. Utilizing counting procedures and autoradiography, Ooneda et al. [69]

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demonstrated penetration of 1311-labelled rat plasma proteins into the walls of mesenteric arteries in rats with experimental hypertension induced by renal clips. Kojimahara [70] utilized colloidal lg8Au with similar results. Wiener et al. 1711 employed colloidal carbon particles, and again hyalinized arteries and arterioles were found to be permeable to the tracer particles in contrast to the vessels of normotensive control rats. The affected vessels showed discontinuities of the endothelial coating, varying from separations of the intercellular junctions to areas denuded of endothelial cells. In studies by Jellinek et al. [72] a distinction between varying degrees of pathologic permeability was made possible by the use of two different tracer substances. Similarly, Giacomelli et al. [73] found hyalinized arterioles of the cerebral cortex of hypertensive rats to be permeable to horseradish peroxidase but not to carbon particles. Endothelial contraction was thought to be responsible for the focal increase of vascular permeability. Peroxidase tracer technics were also utilized in studies on the retinal vasculature [74]. Suzuki et al. [75] suggested, on the basis of their experiments with ferritin and carbon particles, that macromolecules from plasma may penetrate into the vessel wall via different pathways, depending upon the physical dimensions of the molecules. Goldby and Beilin [44] observed an increased permeability to carbon particles in dilated segments of the gut arterioles in rats with hypertension induced by renal artery clips. Endothelial damage at the site of patchy arteriolar dilatations was the initial event, whereas constricted arteriolar segments were undamaged. Three types of lesions were found in the dilated segments with definite signs of a flow of plasma constituents into the media and subsequently the intima. The lesions described were considered to represent phases in a continuous cycle of damage and healing processes. Byrom [43] has described his recent studies on the structural basis of focal edema of the brain in experimental hypertension. Zones of focal cerebral damage were located by injection of trypan blue. Serial sectioning showed that arteriolar lesions were always present in such zones. Byrom favored the assumption that focal overstretching of the arterioles allows plasma constituents to escape into and through the vessel wall. There are some data, obtained by fluorescein angiography of the retina in human subjects with malignant hysuggesting that a similar process pertension, might be of importance in the formation of retinal exudates [76-781. It is interesting that the idea of

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a transarteriolar exudation was formulated by Traube a hundred years ago [79]. In conclusion, there is an impressive body of data proving the occurrence of focal increases in arteriolar wall permeability in hypertensive disease. Focal hyperpermeability is consistently demonstrable in arteriolar segments showing morphologic stigmata, and there is every reason to envisage an intimate relationship between the emergence of focal arteriolar dilatations, the influx of macromolecules from the plasma into the arteriolar wall, and the subsequent processes of damage and healing within the vessel wall. CONCEPTUAL PROBLEMS IN EVALUATING THE DYNAMIC STATE OF THE RENIN-ANGIOTENSIN SYSTEM The enzyme renin is produced and stored within the juxtaglomerular apparatus of the kidney [80]. The enzyme is secreted into the blood stream via the renal vein and also into the renal interstitium. Renin acts as a proteolytic enzyme on one or more plasma proteins, operationally described as renin substrate or angiotensinogen, to generate the decapeptide angiotensin I. During passage through the pulmonary vascular bed, angiotensin I is converted into the octapeptide angiotensin I I. This is the effector substance of the renin system, whereas renin per se is devoid of physiologic actions. Angiotensin I I is subsequently degraded into smaller peptides and amino acids. The wealth of data on plasma renin levels in human disease entities or stages of disease is quite impressive. However, measurement of renin activity or renin concentration in a plasma sample provides no more than a static assessment of the renin system, relevant to the time of sampling. Much discussion has been concerned with the distinction between normal and abnormal plasma renin concentration levels. Our aim in the future should be to make a distinction between states of appropriate and inappropriate renin secretion. This is not merely a matter of semantics. The concept implies the general desirability and necessity of a more dynamic approach, paying due attention to the steadily increasing knowledge on factors determining the rate of renin secretion from the kidney, under normal as well as pathologic conditions. Measurements of plasma renin concentration are not influenced by interfering factors, such as changes of renin substrate concentration in plasma [81-831. Therefore, this type of analysis is the more satisfactory from a biochemical point of view. On the other hand, determinations of plasma renin activity [84] can be biologically more relevant in certain circumstances in that this type of

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analysis gives an integrated measure of the possibilities or potential for angiotensin generation in the plasma sample under study. Determination of renin secretion rate from the individual kidney has proved clinically useful in certain circumstances [85,86]. Conceptually, such measurements represent a step forward towards the attainment of more informative parameters. The advent of clinical measurements of plasma angiotensin II concentration [87-901 is a further significant advance in that these radioimmunologic procedures provide an integrated measure of the sequential processes determining the plasma level of the final effector substance of the renin system. There is now very strong evidence that the renin secretion rate of the kidney may be influenced by an array of factors, with sodium balance at the top of the list. Furthermore, there is also evidence that the vascular effects of the renin system, i.e., the pressor effect of angiotensin I I, may be significantly modified by changes in sodium balance and in certain experimental disease states [91,92]. The concept of vascular receptor affinity to angiotensin II will no doubt be of great importance to further investigations. One example may illustrate the practical and conceptual implications of reflections on the appropriateness of a given level of renin secretion. Bianchi et al. [93] presented a retrospective evaluation of preoperative plasma renin concentration, plasma volume and extracellular volume in a series of patients with documented renovascular hypertension, i.e., patients who were cured of their disease by surgical intervention. He found that the fluid spaces were, on an average, increased in the patients with normal plasma renin concentration when compared to those with an elevated plasma renin concentration. In view of the known sensitizing effects of sodium retention, leading to expansion of the intravascular and extracellular spaces of the body, with respect to the vascular effects of renin we may rightly ask: Should patients with a normal plasma renin concentration and probable sodium retention be considered to have a normal state of renin secretion? This type of question brings the necessity for a dynamic and integrated evaluation of the state of the renin system into focus. On the basis of these conceptual reflections, we have to admit that we are in a somewhat difficult position when trying to elucidate the possible relationship between the activity of the renin system and the occurrence of manifestations of vascular disease in human and experimental hypertension. The inherent defects of the available in-

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THE RELATIONSHIPS BETWEEN HIGH ARTERIAL PRESSURE,THE DYNAMIC STATE OF THE RENIN SYSTEM AND THE DEVELOPMENT OF ARTERIAL DISEASE A large number of publications have been concerned with the importance of high arterial pressure per se in the causation of vascular lesions. In general, a fair correlation has been found between the level of blood pressure and the severity of vascular lesions in clinical materials. Pickering [94,95] has based his contention, that malignant hypertension with the associated necrotizing arteriolar lesions is essentially simply a manifestation of a very severe hypertension, upon several lines of convincing evidence. It should not be overlooked, however, that other authorities [96-981 have presented alternative interpretations based upon extensive clinicopathologic studies [96,97] or upon reports of selected cases demonstrating an unusual course of hypertensive disease 1981. In experimental studies, several investigators have observed animals with high blood pressure but no or rather inconspicuous vascular lesions [99,100]. Conversely, hypertensive arteriolar lesions have been observed in experimental animals that showed no elevation of blood pressure during the course of the experiment [17,101]. There are several difficulties in the performance and evaluation of such experiments. The frequency of blood pressure determinations is, of course, all important. However, it seems clear that the absolute level of blood pressure is not the only decisive factor, and it is evident that the arterial system of different animal species may at times tolerate high intravascular pressure without suffering damage. There are some indications that the rate of rise of blood pressure may be an important factor, but under certain circumstances even a rapidly rising blood pressure may fail to produce vascular disease [102]. The experience obtained in the clinical and experimental use of antihypertensive drugs has shown that a lowering of the blood pressure will inhibit the development of vascular lesions [50]. There is a possibility that widely fluctuating blood pressures, as observed in experiments on intermittent administration of hypotensive drugs, may result in particularly severe arterial lesions [70]. One important piece of information is available from the study of morbid anatomy in hypertensive patients or experimental animals with localized stenoses in the arterial circulation. It has been

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shown repeatedly that no or less severe vascular lesions are found in the area irrigated by the stenosed artery than elsewhere in the arterial circulation. Thus, the regional normotension, or at least lower arterial pressure, distal to an arterial stenosis definitely protects against the development of vascular lesions [50]. Further information on the importance of high intra-arterial pressure per se is provided by reports on patients in whom necrotizing acute arterial lesions developed in the vasculature distal to a coarctation of the aorta after resection with end to end anastomosis [103]. In these cases, the sudden exposure of the distal vascular area to a higher level of pressure would seem to be the decisive factor. It is pertinent that fibrinoid arterial necrosis can be induced experimentally by mechanical distention of the arterial system by repeated forceful intra-arterial injections of fluid [104,105]. It is evident that the importance of intra-arterial pressure per se in the causation of arteriolar lesions is clearly demonstrable in some experimental and clinical situations but much less impressive in other contexts. As regards the protective effect of arteriolar stenoses and the sequelae to sudden elevation of filling pressure in regional vascular beds, little information is available on the hemodynamic conditions prevailing within the vascular areas in question. Fundamental problems remain concerning the functional state of the arteriolar system in such areas, particularly with respect to the state of constriction or dilatation. The clinical entity of malignant hypertension provides an excellent illustration of the difficulties inherent in elucidating the complicated interrelationships between high blood pressure, the state of the renin system and the development of vascular disease. Malignant hypertension is characterized by severe hypertension, high plasma concentrations of renin and the rapid progression of necrotizing arteriolar disease. But the precise relationship among the three salient features of this most serious condition is far from clear. Activation of the renin system has been conceived of as a sequel to grave disturbances of the renal circulation or, alternatively, as an important factor in the genesis of high arterial pressure. These views have been combined in the concept of a vicious circle. With respect to arterial disease, the release of renin might be instrumental in producing such lesions or, conversely, renin release from the kidney might be viewed as a consequence of progressive renal arteriolar damage. Fortunately, the available information levels in different types of experimental

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sion does permit a few deductions. At the very outset, attention should be drawn to publications describing the induction of so-called renoprival hypertension in experimental animals. In this particular experimental condition, activity of the renal renin system has been excluded by the very nature of the experiment, i.e., by performance of bilateral nephrectomy. It has been shown repeatedly that in animals with this type of experimental hypertension widespread necrotizing arteriolar disease can develop, with morphologic features similar to those encountered in other types ,of experimental malignant hypertension [106-l 081. It might be added at this point that acute vascular lesions can be produced in the nephrectomized rat by the administration of a number of synthetic pressor agents [12]. In this model, the participation of the renin system has similarly been excluded. The lesions show a rather similar morphology and an identical mode of development when compared to the lesions induced by angiotensin [23,30]. A time-honored method for inducing chronic experimental hypertension in rats involves treatment with DOCA and high sodium intake. This type of experimental hypertensive disease is characterized by a decreased content of renin in the kidneys and the plasma. Very severe hypertensive arteriolar lesions of typical morphology are regularly observed at autopsy [109-l 111. Experimental renovascular hypertension in the rat may be produced by placing a clip on one renal artery and removing the contralateral kidney. Alternatively, the contralateral kidney may be left intact. There are several indications, that the state of activity of the renin system is quite different in these two models [112-l 141. The plasma renin levels are generally much higher in animals with an intact contralateral kidney. To the best of my knowledge, equally severe arteriolar lesions can be produced with these two types of renal intervention. A direct comparison of vascular lesions in hypertensive rats with a “low renin” and a “high renin” type of experimental hypertension was recently presented by a group of Swiss investigators [115,116]. “High renin” hypertension was induced by unilateral partial renal artery constriction, whereas DOCA-hypertension served as the “low renin” model. The blood pressure went considerably higher in the renal clip rats than in the DOCA-treated rats. Plasma renin activity was 20 times higher in the clipped rats than in the steroid-treated rats. Assessment of hypertensive angiopathy in the two groups, scored under blind

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conditions, showed that lesions were more pronounced in the DOCA-treated rats. There were no qualitative morphologic differences between the two groups. Within the renal clip group of animals, there was no significant correlation between plasma renin activity and severity of vascular lesions. In human hypertension caused by autonomous hypersecretion of aldosterone from an adenoma of the adrenal cortex, the clinical descriptions of this syndrome have drawn attention to the infrequent occurrence of malignant hypertension [117], notwithstanding the fact that a few cases with so-called malignant fibrinoid arteriolar changes have been described [118]. In this disease entity, the renin system is characteristically suppressed. Hypertension is a common problem in patients with terminal renal failure receiving intermittent hemodialysis. Normal blood pressure levels can be achieved in most patients by measures aiming at a reduction of the sodium and water content of the organism, whereas a smaller group is refractory to such treatment. In this latter group of patients, very high plasma renin concentration is a common finding, and bilateral nephrectomy may be followed by a dramatic restoration of normotension [119,120]. This particular type of patient may represent one of the few examples of a clear-cut renin-dependent hypertensive state in man. It would probably be very difficult to draw conclusions on the basis of comparisons of these two groups of patients with respect to blood pressure levels, plasma renin concentration and the extent of arteriolar damage, since one would be concerned with a study of very late stages of disease without sufficient information on the preceding period. In human essential hypertension, low, normal and high plasma concentrations of renin may be encountered. The ideas of Laragh and his group [l-4] on the relationship between renin levels and the progression of vascular disease in human essential hypertension were mentioned in the introductory section. Since the writing of the present review was actually undertaken at the request of the originator of these ideas, I am inclined to consider this whole review as one contribution to the debate raised by this provocative reappraisal of the role of the renin system in the causation of arterial disease. More direct evaluations of the Columbia University studies have appeared [1211231, and the argumentation will undoubtedly continue. In conclusion, it can be stated with confidence that neither hypersecretion of renin nor even the

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presence of the kidneys are necessary conditions for the development of necrotizing arteriolar lesions in animals with experimental hypertension. On the other hand, it can certainly not be excluded that the occurrence of a high concentration of angiotensin II in the plasma or at vascular receptor sites could be an important aggravating factor under special circumstances. The experimental induction of hyperacute, fulminating arteriolar lesions by administration of renin to rats sensitized by DOCA-hypertension is but one illustrative example [13,124]. VASCULAR LESIONS IN HUMAN DISEASE ENTITIES WITH NORMAL BLOOD PRESSURE AND ACTIVATION OF THE RENIN-ANGIOTENSIN SYSTEM Clinical conditions characterized by the presence of normal blood pressure despite increased activity of the renin-angiotensin system are relevant to the problems under review. In Bartter’s syndrome, hyperreninemia, increased aldosterone secretion rate, hypokalemic alkalosis and normal blood pressure are prominent features [125]. There is a similar combination of findings in cases of familiar chloride diarrhea [126,127] and in chronic laxative abuse [128]. These various syndromes have so far not been fully understood with respect to pathologic physiology, and little is known about the functional state of the vasculature in these conditions. In Bartter’s syndrome, the possible importance of a primary vascular hyporesponsiveness to angiotensin has been considered [125]. It is interesting that several investigators have observed vascular lesions not unlike those seen in benign hypertensive disease in patients with this class of disorders. These lesions have been observed in small children and in adults who have been persistently normotensive throughout the period of observation [126-1331. The majority of studies have been based upon renal biopsies, but changes have also been described in periadrenal and muscular arteries. A perusal of these histologic observations reveals that the lesions are predominantly in the nature of muscular hypertropia of the media in small arteries, although endothelial hyperplasia or hyalinization has been described in a few cases. It seems pertinent to emphasize that fibrinoid necrosis of arterioles was not encountered. Pasternack [ 126,127] has considered the possibility that the hyperangiotensinemia found in these conditions might induce local or generalized arteriolar constriction and thereby initiate a series of events similar to those pertaining in states of

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hypertension. It is pertinent to note that hypertrophy of the arteriolar media, which is the dominant alteration of vascular morphology in these peculiar conditions, has generally been interpreted as a response to an increased work load, just like cardiac hypertrophy in hypertension [95]. The absence of high blood pressure could possibly be due to a low effective blood volume, at least in some of these disease entities. A more complete insight would probably require further histologic observations in conjunction with hemodynamic measurements, including determinations of the intravascular volume, cardiac output and calculated total peripheral resistance, in patients afflicted with these various disorders. FINAL COMMENTS This review has covered a series of complicated problems, and it should be quite evident to the reader at this point that several facets of the general theme are in need of further studies. For many of the questions at issue, the available answers are still conjectural. In this state of affairs an appropriate way to conclude this review would be to make an attempt at integrating the present knowledge on the causation of arterial lesions in hypertensive disease with particular reference to the possible participation of the renin-angiotensin system. Naturally, the hypothetic and temporary nature of such a statement must be realized. The evidence pointing to the influx of plasma proteins into the arteriolar wall as a decisive and initial event in the morphogenesis of malignant hypertensive arteriolar lesions is very strong indeed. This evaluation encompasses acute as well as more chronic states of hypertension. There is no information requiring the assumption of fundamental differences between the morphogenetic mechanisms of so-called benign hyaline arteriolar sclerosis on one hand and the fibrinoid arteriolar necrosis of malignant hypertension on the other, although there is, of course, a difference of tempo and degree [50,134]. In acute hypertension there is direct evidence, and in chronic hypertension there is a large body of more circumstantial evidence, that the penetration of plasmatic macromolecules into the arteriolar wall takes place within distended segments of the arteriolar bed whereas constricted segments are not affected. This abnormal permeability of dilated arteriolar segments could well be related to the increased wall tension. The tangential wall tension is determined by the product of the intraluminal pressure and the radius of the segment according to the Laplace equation [135]. Like-

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wise, stretching or deformation of the anatomic structures of the arterial wall has been clearly documented by several investigators, particularly as regards the endothelial cells, the interendothelial junctions and the internal elastic lamina. The mechanisms conducive to the emergence of focal dilatations, with intervening zones of intense constriction, along the course of small arteries have not been elucidated in a satisfactory way. A priori it might be expected that at least administration of a pressor drug would bring about a more uniform constriction. An uneven distribution of smooth muscle fibers along the length of the arterioles is one possible reason. The occurrence of arteriolar constriction-dilatation patterns has been well documented in acute and chronic experimental hypertension, but there is a deplorable paucity of information on the occurrence or absence of this peculiar phenomenon in hypertensive man. There is convincing evidence to show that high concentrations of angiotensin II can induce the acute emergence of this bizarre pattern of patchy dilatations and intervening constricted segments along the course of the small arteries. In chronic hypertension it is possible, and indeed probable, that activation of the renin-angiotensin system may directly cause the development of abnormal arteriolar reaction patterns or that the pressor action of angiotensin II may at least facilitate the development of such patterns during hypertensive states. It is, however, important to realize that similar abnormal vascular patterns can occur without participation of the renin system, as shown in hypertensive states induced by other pressor agents in nephrectomized animals. Furthermore, hypertension and necrotizing fibrinoid arteriolar necrosis can be produced in experimental animals by bilateral nephrectomy and appropriate manipulations of sodium balance. There is also a large number of observations indicating the development of severe hypertensive vascular lesions under experimental conditions associated with suppression of the renin system. Therefore, activation of the renin system is definitely not a necessary condition for the development of hypertensive vascular lesions. A multitude of important questions must be answered in order to achieve further progress in this

field, particularly as related to the understanding and management of hypertensive vascular disease in man. Suffice it here to mention two important areas of research. At this point it seems imperative to obtain further information on the fundamental relevance of the animal models to the disease in man. It is all important to know whether the arteriolar abnormalities leading to the development of acute hypertensive vascular disease in animals can be demonstrated in man. Furthermore, there is a great need to develop methods for assessing the state of activity of the renin-angiotensin system in kinetic terms. Attempts to achieve an approximative measurement of in vivo generation rates for angiotensin II represent one challenging approach. There is no doubt that kinetic and dynamic lines of thought will be needed in order to arrive at a more comprehensive understanding of the role of renin secretion in the pathogenesis of hypertension per se and to achieve further insight into the possible importance of the renin system for the development of vascular lesions. The writing of this review was occasioned by the recent proposition that activation of the renin system may be of fundamental importance to the development of cardiac and cerebral complications of hypertensive disease. Therefore, as a final note, it is appropriate to emphasize the diversity of vascular lesions observed in human hypertensive disease. It should be pointed out very distinctly that the central theme of this review has been the possible importance of the renin-angiotensin system in the development of the specific vascular disease at the arteriolar level observed in experimental and human hypertension. The precise relationships between these lesions of small arteries and arterioles on the one hand, and the vascular lesions leading to myocardial infarction or a cerebrovascular accident on the other hand, have not been fully clarified, although there are a number of observations demonstrating close connections between these various types of vascular disease. ACKNOWLEDGMENT I thank Doctors F. S. Goldby and L. J. Beilin and the Editor of Cardiovascular Research for their kind permission to reproduce the photomicrographs shown in Figure

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1969. Robertson AL, Khairallah PA: Effects of angiotensin II and some analogues on vascular permeability in the rabbit. Circ Res 31: 923, 1972. Robertson AL, Khairallah PA: Role of temporary endothelial cell contraction and circulating platelets in the initial stages of vascular disease. The “trap door” effect. Int Res Corn Syst 1: 15, 1973. Byrom FB: The Hypertensive Vascular Crisis. An Experimental Study, London, Heinemann Medical Books Ltd., 1969. Goldby FS, Beilin LJ: The evolution and healing of arteriolar damage in renal clip hypertension in the rat: An electron microscope study. Clin Sci 44: 5P, 1973. Abt K, Bruckner R: Netzhautgefasspasmen bei artifizieH hypertonischen Ratten. Ophthalmologica (Basel) 119: 17,195o. Byrom FB: The nature of malignancy in hypertensive disease. Evidence from the retina of the rat. Lancet 1: 516, 1963. Byrom FB: The caliber of the retinal arteries in hypertension. Amer Heart J 66: 727, 1963. Rodda R, Denny-Brown D: The cerebral arterioles in experimental hypertension. I. The nature of arteriolar constriction and its effects on the collateral circulation. Amer J Path 49: 53, 1966. Hill GS, Heptinstall RH: Steroid-induced hypertension in the rat. Amer J Path 52: 1, 1966. Giese J: The Pathogenesis of Hypertensive Vascular Disease, Copenhagen, Munksgaard, 1966. Schloss G: Die Histogenese und Pathogenese der Gefassveranderungen beim experimentellen renalen Drosselungshochdruck der Ratte. Schweiz Z Path ii: 109.1948. Pannier R: Le myocarde dans I’isch8mie r&ale experimentale. Rev Beige Path 21: 420, 1951. Wagener HP: Retinal arterial and arteriolar lesions associated with systemic vascular hypertension. Amer J Med Sci 241: 240,196l. Ashton N: The eye in malignant hypertension. Trans Amer Acad Ophthal Otolaryng 76: 17, 1972. Hill DW, Dollery CT: Calibre changes in retinal arterioles. Trans Ophthal Sot UK 63: 61, 1963. Page IH: Heart attacks: possible risk factor. Proc Nat Acad Sci USA 69: 1813.1972. Goldblatt H: Studies on experimental hypertension. VI I. The production of the malignant phase of hypertension. J Exp Med 67: 609, 1936. Soustek Z: Zur Morphologie der Quellungsnekrose (sogenannte fibrinoide Nekrose) der fibrinosen Durchtrankung und der fibrinoiden infiltration der Arteriolen. Zbl Allg Path 95: 509, 1956. Govan ADT: The pathogenesis of eclamptic lesions. Path Microbial (Basel) 24: 561, 1961. Lendrum AC, Fraser DS, Slidders W, Henderson R: Studies on the character and staining of fibrin. J Clin Path 15: 401, 1962. Kuhns G, Puchtler H, Sweat F: Histochemical evidence for plasma proteins in arteriolosclerosis. Anat Ret 142: 250,1962. Fennell RH, Reddy CRRM, Vazquez JJ: Progressive systemic sclerosis and malignant hypertension. Arch Path (Chicago) 72: 209, 1961. Paronetto F: lmmunocytochemical observations on the vascular necrosis and renal glomerular lesions of malignant nephrosclerosis. Amer J Path 46: 901, 1965. Montgomery P O’B, Muirhead EE: Similarities between the lesions in human malignant hypertension and in

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the hypertensive state of the nephrectomized dog. Amer J Path 29: 1147, 1953. Montgomery P O’B, Muirhead EE: A characterization of hyaline arteriolar sclerosis by histochemical procedures. Amer J Path 30: 521, 1954. Montgomery PO’B, Muirhead EE: A microspectroscopic study of arterioles in benign and malignant hypertension. Amer J Path 30: 1161, 1954. Muirhead EE, Booth E, Montgomery P O’B: Derivation of certain forms of “fibrinoid” from smooth muscle. Arch Path (Chicago) 63: 213, 1957. Sanerkin NG: Vascular lesions of malignant essential hypertension. J Path 103: 177, 1971. Ooneda G, Suto H, Matsuyama K, Sekiguchi M, Murata S: Autoradiographic studies on the morphogenesis of arterial fibrinoid degeneration using 13’l-labelled plasma protein and- 13’ I-labelled fibrinogen. Gunma J Med Sci 12: 26,1963. Kojimahara M: Healing and exacerbation of arterial lesions in rats with experimental hypertension, with special reference to effects of antihypertensive drugs on arterial lesions. Gunma J Med Sci 16: 1, 1967. Wiener J, Lattes RG, Meltzer BG, Spiro D: The cellular pathology of experimental hypertension. IV. Evidence for increased vascular permeability. Amer J Path 54: 187, 1969. Jellinek H, Nagy Z, Htittner I, Balint A, Kocze A, Kerenyi T: investigation of the permeability changes of the vascular wall in experimental malignant hypertension by means of a colloidal iron preparation. Brit J Exp Path 50: 13, 1969. Giacomelli F. Wiener J, Spiro D: The cellular pathology of experimental hypertension. V. increased permeability of cerebral arterial vessels. Amer J Path 59: 133, 1970. Giacomelli F, Juechter KB, Wiener J: The cellular pathology of experimental hypertension. VI. Alterations in retinal vasculature. Amer J Path 66: 61, 1972. Suzuki K, Ookawara S, Ooneda G: Increased permeability of the arteries in hypertensive rats. An electron microscope study. Exp Molec Path 15: 196, 1971. Hodge JV, Dollery CT: Retinal soft exudates. A clinical study by colour and fluorescence photography. Quart J Med 33: 117,1964. Jtitte A, Lemke L: lntravitalflrbung am Augenhintergrund mit Fluoreszein-natrium. Stuttgart, Ferdinand Enke Verlag, 1966. Wessing A: Fluoreszenzangiographie der Retina. Stuttgart, Georg Thieme Verlag, 1966. Traube L: Eine Hypothese ijber den Zusammenhang, in welchem die sogenannten uramischen Anfllle zur Erkrankung der Nieren stehen, Berlin, Gesammelte Beitrlge zur Pathologie und Physiologie, Band I I, I’Abt, 1871, p 551. Faarup P: Morphological aspects of the renin-angiotensin system. Thesis, Copenhagen, 1971. Brown JJ, Davies DL, Lever AF, Robertson JIS, Tree M: The estimation of renin in human plasma. Biothem J 93: 594,1964. Haas E, Gould AB, Goldblatt H: Estimation of endoge.nous renin in human blood. Lancet 1: 657, 1966. Giese J, Jorgensen M, Nielsen MD, Lund JO, Munck 0: Plasma renin concentration measured by use of radioimmunoassay for angiotensjn I. Stand J Clin Lab Invest 26: 355,197O. Boucher R, Veyrat R, de Champlain J, Genest J: New procedures for measurement of human plasma an-

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