Hypertension, pressor agents, and cardiovascular injury: Introduction

Progress

Cardiovascular VOL.

XVII,

Diseases JULY/AUGUST

NO. 1

Hypertension, Cardiovascular

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in CardiovascularDiseases,Vol.

XVII,

No. 1 (July/August),

1974

Pressor Agents, and Injury : Introduction pecially the renal arterioles. He also provides evidence for the amplifying effect hypertension has on the production of arteriosclerosis of larger vessels, especially the coronary carotids and vertebral arteries. And he cites a little-known but possibly highly relevant study of Oppenheimer and Esterly in which children with elevated bl.ood pressure, nephrotic syndrome, and marked hypercholesterolemia exhibited coronary arteriosclerosis at autopsy. A second group of nephrotic chilldren with normal blood pressure did not exhibit coronary atherosclerosis, despite equally marked hypercholesterolemia. This experiment of nature highlights the comparative roles of hypertension and hypercholesterolemia in producing coronary disease. Similar relationships are analyzed in considering the pathogenesis of cerebral hemorrhage and infarction. Finally, the author provides a basis for caution in comparing experimental models with human phenomena. In the third paper of the symposium, Dr. Frank Byrom summarizes his pioneering work relating experimental vascular injury in the brain to blood pressure elevation. Dr. Byrom made the first observation of areas of constriction and dilation in the arterioles of the retina and on the surface of the brain. His findings have been confirmed by other subsequent work involving other areas such as the gut mesentary. His work has drawn attention to the fixed anatomic site of the vascular constrictions, which always disappear and then reappear in concordance with blood pressure reductions and elevations, in the very same place. The hypothesis that the arteriolar lesions result from overstretching and failure of autoregulation is a most attractive one. This hypothesis has recently gained additional experimental support from studies in man3 With this hypothesis, it is possible to attribute the sequence of events observed in acute hypertensive situations to a sudden overstretching

HIS SYMPOSIUM compiles some current concepts on the roles of high blood pressure and of circulating pressor substances in the production of experimental and clinical cardiovascular injury. As reviewed by Sir George Pickering in his book High Blood Pressure, ’ it is quite clear that an increased blood pressure is associated with vascular damage in both man and animal models. Moreover, the data in hand strongly suggest that the degree of elevation of the blood pressure is directly related to the degree of vascular damage produced. While the entire vascular tree is susceptible, injuries to the coronary circulation, to the brain, and to the kidneys in particular are of special clinical relevance. In keeping with this relationship, certain clinical studies in recent years’ have established that lowering the arterial blood pressure, by whatever pharmacologic means, is clearly associated with a reduced predisposition to kidney disease, vascular damage in general, stroke, and congestive heart failure. The data thus far, however, do not provide definitive evidence that reducing blood pressure will prevent heart disease and myocardial infarction. In this symposium, certain aspects of this important problem are critically examined. In the first paper, Dr. William B. Kannel presents data from the almost unique Framingham Study. He reports that hypertension is the most potent and universal contributor to cardiovascular mortality, but that even so, its presence and its degree have a variable impact on cardiovascular damage, depending upon the presence or absence of other, albeit less strong, risk factors. The data summarized in this paper provide a basis for further study as well as for new approaches to epidemiologic control. In the second paper, Dr. Robert Heptinstall reviews the evidence for a key role hypertension plays in the damaging of small blood vessels, esProgress

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of weaker zones or branches as the arterial pressure rises above a critical level fast enough to outstrip the reserves of the vascular musculature. The paper by Dr. Haralambos Gavras and associates introduces yet another factor in experimental vascular injury. The authors assume that elevated blood pressure is a prime factor in producing cardiovascular injury but then examine the question of whether or not other factors affecting the volume or the vasoconstrictor tone of the circulation are also involved. The basis for this approach is supported by well-known observations in experimental hypertensions, which indicate that vascular damage is not necessarily closely related to the degree of blood pressure elevation. For example, mineralocorticoid hypertension may be associated with marked vascular damage, even though the blood pressure elevation may not be nearly as impressive as that observed in experimental renal hypertension with much less cardiovascular damage. Furthermore, congenital hypertension in animals may exhibit very severe hypertension with less vascular damage than either mineralocorticoid or experimental renal hypertension. Gavras and associates provide evidence for a role for renin, via angiotensin generation, in producing or amplifying vascular injury in hypertensive situations, and they also provide an explanation for the cardiovascular damage produced by excess mineralocorticoid hormones such as aldosterone, the latter occurring in the face of very low renin and angiotensin levels. Altogether, their data indicate two factors in hypertension and attendant vascular injury: a vasoconstrictor factor largely attributable to excess angiotensin II formation and a volume factor that is usually based on mineralocorticoid excess or renal damage. These observations appear to have important implications not only for further study but for analyzing, understanding, and treating human hypertensive situations. To complement the Gavras analysis, Drs. Donald J. Reis and Nobutaka Doba present an excellent review of the current state of our knowledge of the role of the nervous system in experimental hypertension. These authors define eight neural interdictions that can produce hypertension in the arteriolar tree. Of special interest is their identification of sites within the brain that govern and coordinate afferent and efferent signals for determining arterial pressure. The authors also review evidence that suggests that specific norepinephrinemediated pathways within the brain may be

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critical for determining peripheral sympathetic tone. Moreover, these sites may be at least partially governed by circulating angiotensin levels, and it may be that these sites comprise the site of action of certain effective antihypertensive drugs. Altogether, this review provides the very latest information on a possibly key, though still ill-defined, role of the brain in determining blood pressure. Dr. Jacob Haft considers the role of the catecholamine hormones in producing cardiovascular damage. His analysis is primarily concerned with the effect of excessive catecholamines on the coronary circulation. He presents evidence from his own laboratory and from others supporting the view that intravascular platelet aggregation is of prime etiologic importance in producing catecholamine-induced vascular injury. This relationship, he suggests, might be important in the induction of myocardial infarction when it follows catecholamine release of stress. He also reviews evidence suggesting that catecholamine-induced vascular injury could be related to the pathogenesis of atherosclerosis. In the paper by Dr. Hans R. Brunner and colleagues, the current state of our knowledge of the use of an exciting new pharmacologic approach to blood pressure control is reviewed. This involves a presentation and analysis of experiments using specific competitive inhibitors of angiotensin II activity. The two agents currently available are an octapeptide that blocks the action of angiotensin II and a nonapeptide that blocks the conversion of angiotensin I to angiotensin II by competitively interfering with converting enzyme. The experience with both agents is parallel. Thus, it is possible for the first time to define the contribution of angiotensin to blood pressure maintenance both in normal subjects and in the spectrum of hypertensive diseases. For the first time, a role for angiotensin in the causation of high renin and some normal renin forms of hypertension has been, as might have been hoped, clearly demonstrated with the use of these new agents. Moreover, with these drugs it has been possible to define a role for angiotensin II in the maintenance of normal blood pressure under circumstances of sodium depletion. When sodium is available in the diet, however, normal animals and man do not seem to call upon the renin-angiotensin system for vascular tone. In patients with high blood pressure, the use of these new agents makes it possible to wipe out the influence of the renin system, thereby exposing

INTRODUCTION

and quantitating the role of the second component in blood pressure control, that is, the sodium extracellular and intravascular fluid volume factor. The use of these agents, therefore, has provided experimental support for the recently proposed bipolar vasoconstrictor volume analysis4 of hypertensive states in general. In experimental renal hypertension, for example, the so-called one-kidney and two-kidney Goldblatt models can be entirely explained in these terms and their clinical counterparts as they exist in renal vascular hypertension and in patients with chronic renal disease can be identified. This identification in turn enables highly specific surgical or medical treatment. In the light of these experimental and clinical observations, the paper by Drs. Charles A. Chidsey and Thomas B. Gottlieb considers the pharmacologic basis for antihypertensive therapy with particular reference to the use of those vasodilator drugs that act primarily to dilate the arterial vascular bed. The authors present the view that combination therapy involving diuretics and betaadrenergic blocking drugs probably should precede the use of vasodilator agents. That is to say, arterial vasodilatation with beta-blocking drugs alone may be adequate, but even when this is not the case, the vasodilators provide another point of attack. The advantage is the provision of a mechanistically different therapeutic approach. However, the authors caution that despite the eminently satisfactory short-term results, a long-term evaluation of this approach with special reference to toxicity factors is required. The final paper of this symposium by Drs. Ray W. Gifford, Jr. and Edward Westbrook provides a probing analysis of the mechanisms involved in hypertensive encephalopathy in man and then reviews the known effective treatments. This paper nicely complements the experimental analysis of this problem, as presented herein by Dr. Byrom. The authors’ broad experience with this problem should prove most useful for clinicians. They stress the great importance of reducing blood pressure to normal or near normal as promptly as possible to avoid or attenuate the adverse affects of exceeding the limits of autoregulation of the cerebral circulation, limits known to be compromised in hypertensive subjects. The authors review the current “overregulation or arteriolar spasm theory” and the “breakthrough or failure of autoregulation theory.” They suggest that this dilemma will probably not

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be resolved in man until serial measurements of cerebral blood flow are available during evolu.tion of spontaneous encephalopathy in order to determine whether or not there is a phase of increased cerebral perfusion before symptoms appear. Whatever the case, rational treatment does not require resolution of this controversy. Taken altogether, then, this symposium deals critically with certain major aspects of the problem of hypertensive disease, pressor agents, and vascular damage. The problem is so broad that many other dimensions could have been considered. I-Iopefully, however, the symposium will provide useful information for both the investigator and the clinician. We are approaching an era in which not only arterial blood pressure can be measured in our patients, but also pressor-active or volume-active agents, such as renin and aldosterone. Soon, we may also be able to provide a meaningful lahoratory guide for nervous activity and add this to the analysis. The experience to date in our laboratory suggests that renin measurements, when related to the state of sodium balance (the so-called “renin sodium index”), can be extremely useful in classifying hypertensive patients and in getting a quantitative impression as to the relative presence or absence of vasoconstrictor and volume components.4 This information seems relevant not only for understanding but also for prognosis and treatment. Thus, low renin patients seem to be volume expanded, and they appear to be relatively protected from the development of either stroke or heart attack. From the treatment standpoint, high renin and normal renin patients are best treated with drugs like propranolol that act to curtail renin secretion. In contrast, low renin patients usually respond to diuretic therapy. Thus, simpler and more specific therapy with a single agent is now possible as a long-term commitment for an increasing fraction of all patients with essential hypertension. These observations may in fact be a wedge i.n the door, and hopefully we will soon be able to further subclassify hypertensive disorders and with more precision. The future holds great promise.

John H. Laragh, M.D. Professor of Clinical Medicine Columbia University New York, N. Y.

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REFERENCES 1. Pickering GW: High Blood Pressure (ed 2). London, Churchill, 1968 2. Freis ED: The treatment of hypertension. Why, when and how. Am J Med 52:664,1972 3. Lassen NA, Agnoli A: The upper limit of autoregulation of cerebral blood flow: On the pathogenesis of hyper-

tensive encephalopathy. Stand J Clin Lab Invest 30: 113115,1972 4. Laragh JH: Vasoconstriction-volume analysis for understanding and treating hypertension: The use of renin and aldosterone profiles. Am J Med 55:261, 1973