Rationale and Methods for the Treatment of Early Essential Hypertension* EDWARD D. FREIS, M.D. Chief. Medical SerzGce. Vetera?zs Administratiozz Hospital. Washi?zgton, D.C. G IVEN a reasonable amount of knowledge and common sense the treatment for un- complicated hypertension today can be made rela- tively effective, simple and safe. This recent ad- vance necessitates a critical review of old attitudes and opinions, for it is now possible to reduce blood pressure in many mild and moderate cases with little or no discomfort to the patient. Has therapy been perfected? No, far from it. But it is now possible to achieve better control more easily in a higher precentage of patients than was POS- sible in the past. THl: QLJr;STION OF EARLY TREATMENT Should this development alter present attitudes toward the management of the early, mild cases? Until now general policy has been to treat the un- complicated, early cases symptomatically and "con- servatively," reserving antihypertensive therapy for patients with more advanced disease. This nihilis- tic approach was justified when we could offer only drastic surgery, stringent diets or "tricky" hypotensive drugs. But is it justified today? Therapeutic philosophy in many diseases carries with it a tradition from the past. In the case of hypertension this tradition from older times is one of therapeutic nihilism. The administration of the unsatisfactory therapeutic agents available 20 years ago was rightly looked upon as bordering on char- I&nism. Our elders' attitude can be sensed in the very name "essential" hypertension suggesting that the elevated blood pressure was a compensation and was necessary in some way for the patient's welfare. Rightly or wrongly, a negativistic attitude per- sists in many quarters today. These critics point out that a controlled study over a period of suffi- cient time to determine the value of blood pressure reduction has not been carried out. But, such J study would involve a collaborative effort of sev- eral hospitals and a time period of five to ten years or more. Such a study is, in fact, in progress in the Veterans Administration, but it will be man) years before definitive proof becomes available that antihypertensive agents prolong life or prevent complications in the milder cases. Are we justified in doing nothing about early hypertension while awaiting for final proof? Let us examine the argue- ment from another aspect. Antihypertensive therapy is based on a rationale here described. It is granted that we do not know. and hence, cannot remove the ultimate cause of essential hypertension, Therefore, we cannot cure. But to an increasing degree from year to year as more effective agents are developed we can con- trol the hypertension. If the level of blood pres- sure can be controlled at normotensive or near]) normotensive levels, then the organic progression. such as cardiac hypertrophy and vascular degenern- tive changes, will not occur. If this argument is valid it should be possible to demonstrate that elevation of blood pressure in the arterial tree, ,be/, se, produces the organic damage. tn brief, we must ask the question Re@in/rd jm JOLrRNAL OF THE NATIONAL ILIEDICAL ASSOCIATION November, 1958, Vol. 50. No. 6, pp. 405-412 106 JOURNAL OF THE NATIONAL MEDICAL ASSOCIATION NOVEMBER, 1955 whether the cardiac, renal and vascular damage in hypertension is due to ,the hydraulic effect of the elevated pressure, or is associated rather with some unknown toxic factor acting to damage the walls of arteries and arterioles. ARTlXRIOLOSCLt:ROSIS IN HYPERTENSION Fart of the answer to this question lies in determining whether the characteristic arteriolar lesions precede or follow the hypertension. In the past it was thought that thickening of the internal layer of the arterioles was a primary process and that the resultant narrowing produced the hyper- tension. This impression was gained from autopsy examination in patients dying in the advanced stages of hypertensive disorders. However, it is now known that although the proliferation of the intima is a constant finding in cases of long standing or rapidly advancing hypertension it is not seen early in the course of benign essential hypertension. The absence of organic arteriolar changes in the early cases has been shown in renal biopsies by Castleman and Smithwick' and in muscle biopsies by Evelyn'. In early hypertension there is no observable pathological change in the arterioles. There is rather a functional constriction, a narrowing due to spasm as can be seen in the fundi, but not intimal proliferation and fibrosis. Byron1 has shown in the meningeal arterioles of hypertensive rats that the spasm is rel,ieved when the blood pressure is reduced". If the organic arteriolar changes follow rather than precede the hypertension it is possible that they may be produced by the hypertension or the long continued spasm associated `therewith. A clue to this question was supplied by Wilson and Byrom in their experiments on the hypertension produced by constricting a renal artery in the rat4. Distal to the clamp there was not only a decrease in blood flow but also in blood pressure. Because of the constriction a severe hypertension developed in the animal's body, except, in the kidney pro- tected by the arterial constriction. It was significant that the animals who died of malignant hypertension exhibited at autopsy arteriolosclerotic and necrotic lesions in certain visceral organs including the kidney opposite to the clamp, but not in the kidney on the same side as the clamp. Obviously, if there were any toxic substance circulating in the blood which produced the organic arteriolar changes it could affect both kidneys since the blood supply was only diminished and was not cut off completely. However, the pressure distal to the clamp was sharply reduced due to the arterial coarctation. Thus, it seems reasonable to conclude that the arterioles showing organic degenerative changes did so because they were subjected to a high head of blood pressure, whereas in the area where the pressure was low the arteriolar changes could not develop. These observations in the rat have been con- firmed in man. Blahd reported a case of malignant hypertension which at autopsy was found to be associated with a thrombosis of one main branch of a renal artery:. Sufficient blood supply was received from other branches so that infarction did not occur. Typical arteriolosclerotic and arteriolonecrotic lesions were present in both kidneys escept in the area supplied by the throm- bosed artery. Brust and Ferris presented a series of patients with hypertension due to unilateral renal disease". They emphasized the fact that in the patients with "Goldblatt kidney" degenerative arteriolar lesions were limited to the areas exposed to high blood pressures and were not found in the areas distal to coarcted arteries. Thus, in man also, arteriolosclerosis does not seem to be a primary process but seems rather to be a reaction to an abnormal elevation of arterial pressure. ATHEROSCLI:ROSIS IN H-x'PERTENSlON However, many hypertensive patients die or are disabled not from arteriolosclerosis but by athero- sclerosis of larger arteries, coronary and cerebral. What can be said about the cause and effect relationship between hypertension and athero- sclerosis of large vessels? First, it should be pointed out that there is a higher incidence of coronary and cerebral atherosclerosis in the hypertensive than in the normotensive population. The incidence of cerebral thrombosis is so obviously higher in hypertensives that it needs no further comment. In regard to coronary atherosclerosis, studies by Goldstein and his coworkers' showed that the incidence of myocardial infarction was four to five times higher in hypertensi\.es than in normo- tensive males and 21 times higher in hypertensive than in normotensive females. In the carefully controlled Framingham Study on coronary athero- sclerosis, hypertension was found to ha1.e a high statistical correlation. Thus, there is good evidence that coronary as well as cerebral atherosclerosis is much more prevelant in hypertensive than in normotensive individuals. Something is present in hypertensi\,es which accelerates the atherosclerotic process. Is the ac- celeration also due to the elevated pressure, per. se: or to some other mysterious factor, some unknown circulating noxious agent associated with the hypertensive process? In this regard it is pertinent to discuss the autopsy observations made in patients who h.ld longstanding pulmonary hypertension due to certain forms of congenital heart disease. These were patients who survived to young adult life with conditions such as patent ductus arterio- sus with right to left shunt or with large intra- ventricular septal defects or a single common ventricle. In these patients the pulmonary arterial pressure was markedly elevated for many years approaching the systemic pressure. At autopsy, extensive atherosclerosis usually was found not of systemic arteries, but of the pulmonary arteries. It seems highly significant that the athero- sclerosis occurs so frequently in areas subjected to abnormally high pressure and avoids areas of low pressure, sparing the pulmonary arteries in sys- temic hypertension and the systemic arteries in pulmonary hypertension. Not long ago we saw a young man at autopsy who died following repair of a coarctation of the aorta. He was hypertensive only in the area above the coarctation. That portion of the aorta subjected to high pressure was covered with early placques, whereas below ,the coarctation in the area of lower pressure not a single placque could be found. These various observ-ations have impressed me that high pressure within a vessel is one of the factors favoring the deposition of lipids in the intima of arteries. However, I do not wish to imply that hypertension causes atherosclerosis, but r.lther that the hydraulic effect of a high pressure within an artery accelerates the atherosclerotic ]lrocess. OTHER ORGANIC COMPLICATIONS Another major cause of death and disability in hypertension is congestive heart failure. Few can deny that for the left ventricle to maintain a normal output in the face of an in&eased peri- pheral resistance it must hypertrophy and dilate. This process of compensation has its limits, how- ever, beyond which the output begins to fall off and failure develops. It also has been amp11 demonstrated in such patients that when the systemic pressure is reduced by anti-hypertensi1.e agents the failure is ameliorated and the dilatation if not the hypertrophy may regress. It also is reasonable to believe that the com- plication of cerebrovascular hemorrhage. which is so common in hypertensive as compared to normo- tensive individuals, may well be associated with the presence o'f high pressure within the cerebral arterial system. Thus, if one looks at the evidence available to- day and attempts to form an unbiased judgement as to whether hypertension is merely a meaninp- less symptom or the principle cause of the disa- bling and fatal organic complications, he will find far more evidence to indicate the latter than the former. BLOOD PRESSURE AND LONGI:.VI11 If you believe that hypertension is a meaningless symptom you are led straight to therapeutic nihil- ism. But, if you say that the high pressure existing within the arterial tree is the major factor in pro- ducing organic cardiovascular damage you will be led to treatment aimed at reduction of the elevated levels. In addition, you will treat early, before the damage has occurred. We cannot expect to be ver) successful in dissolving atherosclerotic placques or in restoring scarred arterioles; yet many physicians will treat only these advanced cases, choosing to be more "conservative" with the younger, benign es- sential hypertensives. They argue that the benign cases live out a normal or nearly normal life span anyway. So why bother? But do they? Perera found in his studies of hypertension that when the disease begins in the thirties the life span from onset to death averages about 20 years". In 1940 the life insurance com- panies pooled their data to determine the relation- ship between blood pressure levels and life expec- tancy". Their figures were based on the follow-up of hundreds of phousands of insured individuals. They demonstrated a smooth curve relationship be- tween the level of blood pressure and longevity. the higher the pressure the poorer the outlook. Also worthy of note is that the values, particularly in regard to systolic pressure, pay no attention to 408 JOURNAL OF THE NATIONAL MEDICAL ASSOCIATION I~OVEMBER. 1958 the normal range. For example, the average indi- vidual with a systolic of 115 can look forward to a longer life span than the one with a pressure of 135. The studies by the life insurance companies throw serious doubt on the argument that hyper- tension is a benign process. It is, rather, the excep- tional cases, usually females with labile blood pressures, that stand out in the physician's mind. These labile, middle aged, females impress us over- ly much and should be differentiated from males and from all young adult hypertensives with more persistent elevations of diastolic pressure. The lat- ter, in my opinion, should be treated before they develop irreversible organic changes, when they are still called early and "benign." METHODS OF TREATMENT In general, the earlier the hypertension the easier it is to control the blood pressure. The treatment of severe hypertension is a job for the specialist who has had considerable experience with such problems. Therefore, the subsequent discussion will be devoted to the management of mild, moderate and early hypertension, since it is here that general practitioners and internists, as opposed to the hypertensive specialist, can make their most valu- able contribution. A great number of agents acting at many differ- ent sites in the body have been found to have anti- hypertensive effects. Some of these are not practical for general use. The important agents for the pres- ent purposes are chlorothiazi'de (Diuril) which acts on the kidney increasing the excretion of salt; hydralazine (Apresoline) which seems to have sev- eral sites of action, a peripheral action directly on arterioles, a central action in the higher autonomic centers and possibly also a very mild adrenergic blocking action; Rauwolfia, including its acti1.e Jkaloid, reserpine, which seems to act in the area of the hypothalamus and which also antagonizes serotonin; and the ganglionic blocking agents which inhibit the transmission of impulses throughout all antonomic ganglia. CHLOROTHIAZIDE (DIURIL) Chlorothiazide seems to represent a most valu- .lble addition to the treatment of hypertensive pa- tients. It is easy to administer and seems to be relatively free of discomforting side effects. While only moderately effective as an antihypertensive agent in its own right, it demonstrates a remark- able ability to enhance the antihypertensive activity of other agents, particularly the ganglionic block- ing drugs and hydralazine. Chlorothiazide produces considerable salt deple- tion even in nonedematous individualsi". In bal- ance studies on a nonedematous hypertensiv,e pa- tient the intake of sodium and chloride was main- tained at 70 mEq per day. Following chlorothia- zide (joo mg. three times daily) sodium and chloride excretion increased markedly and potas- sium to a lesser extent. The excess loss of chloride and sodium (representing depletion of body stores) averaged about 350 mEq. during the first 18 hours. This was accompanied by a decreze in blood pressure. Despite continuation of chlorothia- zide, the excess salt and po'tassium excretion ta- pered off after the first 48 hours and after 1iv.e days came into balance with the intake. Accompanying the increased excretion of elec- trolyte, there was a depletion of extracellular fluid space as reflected in a decrease in sodium, sulf.tte, or SCN spaces, plasma volume, body weight and an increase in the hematocri't. As yet, unpublished observations from our laboratory suggest that the antihypertensive effect of chlorothiazide is depen- dent upon the plasma volume depletion and cm be abolished by giving 500 ml. of Dextran. Serum concentrations of sodium and chloride fell only slightly, if at all, except in unusual patients with severe renal or cardiac damage. Electrocardio- graphic changes suggesting electrolyte depletion have not been seen except in `the unusual c.tses mentioned. Serum potassium levels. however, fell quite frequently. This has become troublesome in patients with congestive heart failure who are .11- ready in a potassium depleted state". Unfortun.ltc- ly, relatively small degrees of K loss will markedly reduce the threshold of sensitivity to digitalis. Therefore, anorexia, nausea and arrhythmias due to digitalis, plus slight hypokalemia have been the most common side effects of chlorothi.tzide12. The optimal dose of chlorothiazide in hyperten- sion is 500 mg. twice daily. This amount is usu~~lly required to maintain the antihypertensive effect; it must be given daily and not intermittently as in the treatment of edematous states. There is little ad- vantage and somewhat more danger in giving more than this amoun't. We have made .t point of .td- ministering the first dose on arising and the sec- ond on retiring. Since patients eat their main meal .It night the s.dt losing effects of the morning dose will be dissipated by evening permitting the pa- tient to ,lbsorb and distribute the ingested potas- Gum prior to the last dose at bedtime. It has not been necessary to use potassium supplements except in the patients taking digitalis. In most hyperten- Gve cardi,q digitalis can be discontinued after the blood pressure has been reduced and the edema cle,ired. The pdticnt achieves an enhanced antihyperten- ,ive effect from chlorothiazide if he observes at least moderate salt restriction in his diet. When the s.dt intake was raised from four to a range of 1 1 to 25 grams per day, the blood pressure rose scrmewh.lt despite continuation of chlorothiazide .md only fell again when the salt in'take was re- Jucetl. This provides additional evidence to indi- c.lte that the antihypertensive effect of chlorothia- Lide is associated with its salt depleting action. The Lultihypertcnsivc effect of the drug can be im- proved by restricting, at least moderately, the salt content of the diet. This does not limply rigid re- btriction which most patients would not obser1.e .myway, but, r,lther, a moderate restriction such as .ivoidanc-e of heavily salted foods and elimination IIf the salt shaker at the table. The reduction of mean blood pressure on chlor- Irthiazide Jane in hospitalized hypertensive pa- tients averaged 16 per cent. However, when chlor- ~~:hiz.ide was added to other antihypertensive ,kgents the reduction from pretreatment levels ap- proached 30 per cent. Chlorothinzide was added to the treatment regi- men of 73 ambulatory hypertensive patients". These had been carefully followed, most of them t.tking their blood pressures at home for one month to three years prior to chlorothiazide ther- ~13);. A variety of treatments had been used: pan- ,qlionic blocking agents wimth or without rescrpine .md/or hydral.lzine, veratrum alone or in combina- tion and reserpine alone or with hydralazine. Most of these were patients with moderately severe hy- pertension. Only ooe had malignan't hypertension. A few had quite mild hypertension. Immediately before chlorothLlzide, the reduction of blood pres- \urc for the entire group averaged I 1 per cent from pretreatment levels. Following the addition cli chlorothiazide, the reduction .lver.lped 27 per cent. This additional reduction occurred despite the fact that the ganglionic blocking agents were discontinued in 19 of the 32 cases taking these drugs and their dosages reduced in the remainder. Usually, however, hydralazine was continued or substituted. It is important to bear in mind the enhancement of the activity of the ganglionic blocking agents by chlorothiazidc. It was essential to reduce the dosage of blocking agent to half the prior effective dose when chlorothiazide was instituted. Other- wise, the patients may develop severe postural hypotension and collapse. After reducing the dos- age of the blocking agent in half, it was possible to raise or lower the dosage as indicated after the chlorothiazide had been instituted in order to trb- tain optimal resul,ts. I believe that home blood pressure rwordings are essenti`ll in using this po- tent combination. By the same token, patients who have had surgical sympathectomy for hypertension in the past were unusudly responsive to chloro- thiazide. The discovery of chlorothiazide has returned hydralazine (Apresoline) to prominence since the two make an effective combination in many pa- tients even though small, dnd hence, safe doses of hydralazine can be used. The combination is well tolerated. The acute side effects of hydralazine dre LIIKOI~I- fortable at times, but not serious. The drug pro- duces an increase in cardiac output at the some time that it reduces blood pressures. This effect on the heart which is most pronounced in the first few days of treatment produces the acute effects of palpitation and dyspnea on slight exertion. Angina if present may be aggravated. Hydralazine pro- duces arteriolar dilitation, including the cerebral \~~sels, which can resulmt in severe headache. This effect also is seen only in the early stages of treat- ment. These acute side effects rarely occur if chlor- othiazide is given concomittantly with the hydrala- zine and if the hydralazine is instituted gradually and in low dosage. One can usually begin with a dose of 25 mg. three times daily and increase grad- ually, if necessary, to a level of 50 mg. three times daily. Thus, if two precautions are observed: first, to use hydralazine not alone but in combination \vith chlorothiazide and second, to begin with a t IO JOL`KNAL OF THE NATIOKAL MEDICAL ASSOCIATIOK ~voVEMB!3, 195h small dose and gradually increase, the acute side cffccts seldom need occur. The chronic side effects wh'ich are potentiali) quite serious consist of hypersensitivity reactions, the most important being a syndrome resembling disseminated lupus with L. E. cells demonstrablc- in the peripheral blood. This reaction characteris- tically occurs in patients taking high dosages for long periods of time. It rarely if ever occurs when the dosage is kept below 200 mg per day. For this reason the drug can be considered to be quite safe if the daily dosage does not exceed 150 mg. per day. P'ortunately, this level of dosage, and even rmallcr in many early hypertensives, has been quite effective in controlling blood pressure in the less severe cases when combined with chlorothi`l- zide. In general, the less hydralazine required the hct ter. RAI'WOLFIA ANI) RESERPINI: li.~u~olfi~~ and its most active alkaloid, rcserpine, hale been so widely used by almost all physicians [or the treatment of hypertension that they rcquiri- little comment. Ordinarily, this is not as effectilc- an antihypertensiyc agent as the two just diF- cussed. Its advantages are a simple dosage schrd- ulc (we use 0.3 n-g. of reserpine twice daily for two weeks, followed by a maintainence dose of O. I to 0.25 mg daily), Some patients are unable t-o endure taking the drug because it produces .I disturbing lethargy, loss of drive and vague de- pression. Others are quite happy with the emo- tion.11 change it produces. Some patients are trou- bled with nasal stuffiness, particularly at night. which may be difficult to control, although, anti- histaminics sometimes are helpful as is reduction of maintainance dosage. The drug apparently pro- duces hyperemia of the nasal mucosa which can le:ld to prolonged and severe @axis in occd- \ion.J patients. The most serious side effect is a severe depres- sion coming on insidiously usually after months of therapy. Some suicides have occurred as a result of this depression. The higher the maintainence dose the more likely are such depressions, and for this reason, the maintenance dose should be kept as low `1s possible, that is about 0.1 to 0.25 mg. reser- pine daily. It is interesting that the more intellec- tual and sensitive individuals are most prone to de\ elop these serious mental depressions following Rauwolha. I have seen it develop frequently in physicians, teachers and clergymen and ha1.e a- most never seen it in the clinic `type patient. At any rate, the Rauwolfia alkaloids are not the benign tranquilizing agents in all patients that they are reported to be. They are, however, useful in many patients with mild and moderate hyperten- sion providing the physician watches his patient', reactions with alertness and sympathy and keeps his maintainencc dosages low. OAN(,L[ONIC BLOCKIN<; A(iIlNI: Chlorothiazide also has influenced fa\.or,tbl!- rreatment with the ganglionic blocking agents. but at the same time has reduced the number of case\ in which they may be required. However, by lolvcr- ing the dosage requirement of the blocking agent chlorothiazide permits one to obtain a sizeablc rc'- duction of blood pressure with fewer side effect5 of ganglionic blockade. Of the various prepar,l- tions available, chlorisondamine (Ecolid), mec,l- myalmine (Inv-ersine) and pentolinium tartrate (Ansolysen) seem to be about equally cffectivc-. The important practical points in regard to ad- ministering these agents are as follows: Little more need be said about the ganplionic blocking agents despite their great important-e in the treatment of severe hypertension, since t;ht purpose of this paper is to emphasize, primarily, the management of early hypertension. In these- less resistant patients they may not be required, or, if required, the dosages can be kept fairly Ion. making them easier to use, providing one observes the precautions mentioned above. HOME RECORDIN(;S OF BLOOD PRESSL:Rt< It is necessary to emphasize the point about home blood pressures. Many hypertensive patients ex- hibit falsely high pressures in the doctor's office Antihypertensive agents primarily effect basal blood pressure and ore not as effective in combatting the transient pressor responses produces by apprehen- >ion. Reliance on falsely high office pressures leads to overdosage and resultant severe side effects. To use the antihypertensive agents effectively a record of day to day and diurnal fluctuations of basal blood pressure is essential. Many physicians fear the adverse psychological effects of home pressure recordings. But we and others who have utilized this method have not found that the frequent recording of blood pres- \ures disturbs the average patient any more than it disturbs J diabetic to check his urine for sugar. li under treGltment you seem to be making no progress with your patient on the basis of office blood pressures there is no reason why you should not take advantage of the more reliable data that home pressures can afford. I'RO(,RAM FOR hIANAGlN(; EARLY HYPERl'ENSION The following represents a simple program which should produce significant reduction of blood pressure in the majority of cases of less .ldvanced hypertension. It is aimed at the preven- tion of organic damage in early asym#ptomatic pa- tients. To begin with, the patient should buy, or if he cannot afford it, can be loaned a blood pres- jure apparatus to make a record at home of pres- sures taken before and after work for one or two weeks prior to any therapy. Then, salt should be rcstricttd moderately and chlorothiazide 500 mg. .&~inistered on arising and at bedtime for another tine or two weeks. If the blood pressure is not .Iclequately controlled hydralazine (Apresoline), is .~ddcd 25 mg. three times daily on arising, at 2:OO P.M. and at bedtime for one week and if neces- \.Lry it can be increased to 50 mg. per dose. If the blood pressure still is not controlled adequately rescrpine 0.i mp. daily is added reducing after two weeks to 0.1 to 0.25 mg. daily at bedtime. If \uccessful, and after several months, one may at- tempt a gradual withdrawal of all medications c-xccpt chlorothiazide, withdrawing reserpine first, .md if the blood pressure does not rise withdraw- ing hydralazine. It often is possible in the earlier c.lses to nGnt.Gn ,I reduction with less medication than waq necessary origin.llly to obtain the reduc- :ion. If ,111 the mc.lsures described ,tbo\,c fail to IOW~I the home blood pressure level, either Inversine in ,I dose of 1.25 mg. after breakfast, at 2:00 P.M. Jnd at bedtime, or Ecolid 10 mg. or Ansolysen 10 mg. may be tried. While this is being done, chlor- othiazide and maintainance dosage of reserpine should be maintained. The dosage of the gangli- onic agent may then be raised by gradual incre- ments until the blood pressure falls or side effects become troublesome. If the latter occurs, refer the patient to a physician who specializes in the treat- ment of complicated hypertensive patients. How- ever, this should seldom be necessary. If the blood pressure is controlled, it often is possible to gradu- ally reduce and then discontinue the blocking drug after four to eight months, substituting hydralatine again. Apparently, the early cases often become easier to manage after a prolonged period of blood pressure control. As patients become older or more .kdvanccd along the road of organic damage, less can bc achieved and the patients are more difficult to man- age. The aged patient with advanced arterioscler- osis and primarily systolic hypertension probably should not be treated vigorously. Also, the very severe cases with fixed high levels of diastolic pressure and extensive renal damage may be be- yond help. It seems probably that the pitiful cases of accelerated hypertension need rarely occur if the family physicians institute adequate treatment while the patients are still in the benign phase. CONCLUSIONS The advent in the last six years of a series of antihypeftensive agents for controlling elevated blood pressure has altered our approach to the management of essential hypertension. AS more effective and better tolerated agents have appeared, the opportunity has presented itself of treating early, benign, hypertension more definitively than we could in the past. This places a new responsi- bility in the hands of the family physician who first sees such patients. For those who take the trouble to apply the simple techniques required, the rewards and satisfactions can be extremely gratifying. I.ITCKATI'RC CITITD 412 JOURNAL OF THE XATIOXAL MEDICAL ASSOCIATION NOVFX~HER. 1958 2. EV~TLY&. K. A.: Pathogenesis, clinicopathological correlation and treatment of hypertension. McGill M. J., 16: 185, 1947. 3. BYROM, F. B.: The pathogenesis of hypertcnsilt c-ncephalopathy and its relation to the malignant phase of hypertension. Lancet, 2: 201. 1954. 4. WII.SOX. C., and F. B. &ROM: The vicious circle in chronic Bright's disease-Experimental evidence from the hypertensive rat. Quart. J. Med.. 10: hi, 1941. 5. ULAHD. W. H.. R. M.snc~rs md D. M. WASSER- MAN: A case of malignant hypertension secondar) to renal ixhemia, Arm. Int. Med., 37:179. 1952. 0. HRUST. A. A., and E. B. FERRIS: The diagnostic ,ipproach to hypertension due to unilateral kidne) discax. Ann. Int. Med., 47: 1049, 1957. 7. GOLDSTITIX;. F. and W. K. JENSON, J. M. WALD- RON nnd G. F. D~JNCAN: The relationship hthwcn hypertc-nsion and coronary occlusion. Ann. Int. Med.. 446, 8. PERERA. G. A.: The life history of 100 paticnb with hypertensive vascular disease. Am. Heart 1.. 42: 421, 1951. 9. Actuarial Society of America and the Association of Life Insurance Medical Directors: Blood prc-ssurc- study. 1939, Actuarial Society of American and the Association of Life Insurantc Medical Director). New York. 1940. IO. FREIS. E. D. and A. WANKO, J. M. WILSON and A. E. PARRISH: Chlorothiazide in hypcrtwsive and n:~rmotcn ive patitnts. Ann. N. Y. Atad. Scirncc\. 71: 450, 1958. I 1. JXRI. I>. T. and A. J. Boyr.~, D. E. CHANDLER ancl G. B. MYERS: Electrolyte studies in heart failure I. Cellular factors in the pathogtnrsis of the wlcm~ of congestive heart failure. CircuLiticm, 1 I : 61 i 1955. 12. FREIS, E. D.: The use' of chlorothiat.idc- in the treatment of hypertension. Angiology. In Pre\s. Press of Charles C. ~Corchami Co., S. 1.. C