Review

The Role of Renin Substrate in Hypertension

DAVID B. GORDON, P H . D .

SUMMARY A positive correlation between blood pressure and renin substrate concentration isfound in a wide variety of conditions in human beings and in animal experiments. The evidenceconcerning this relationship is reviewed and the exceptions are discussed. The frequent positivecorrelation between renin substrate and elevated blood pressure suggests that increased renin sub-strate concentration may be a causal factor in hypertension. (Hypertension 5: 353-362, 1983)

KEY WORDS • angiotensinogen * renin substrate • blood pressureliver disease • estrogens • captopril • pregnancy

RECENTLY, Gardes et al.1 reported that intra-vascular injections of antiserum to renin sub-strate cause a prompt fall of blood pressure in

rats. This suggests that renin substrate may play a rolein maintenance of normal blood pressure. Numerousother studies have indicated a possible relation be-tween elevated renin substrate and elevated blood pres-sure. A review of the literature concerning the relationof plasma renin substrate concentration and the level ofblood pressure reveals a frequent positive correlationbetween these two entities. The results of my revieware presented here according to the following outline:

1. Role of the liver in hypertensionA. Clinical observations of liver diseaseB. Experimental injury to the liver

2. Hypertension in high plasma renin substratestatesA. PregnancyB. Women taking oral contraceptives or es-

trogensC. Patients with Cushing's syndrome and pa-

tients treated with glucocorticoidsD. Men given di-ethylstilbestrol (DES)

3. Hypertension with associated elevation of plas-ma renin substrateA. Essential hypertensionB. Malignant hypertensionC. Experimental and spontaneous hypertension

From the Veterans Administration Medical Center, Livermore,California.

Address for reprints: David B. Gordon, Ph.D., Veterans Admin-istration Medical Center, Livermore, California 94550.

Received May 26, 1982; revision accepted October 11, 1982.

Low blood pressure or low vascular resistanceassociated with low plasma renin substrateA. Cirrhosis of the liverB. Bartter's syndromeC. Adrenal insufficiency

Effect of therapy on plasma renin substrate

Role of the Liver in HypertensionClinical Observations of Liver Disease

Since the beginning of this century, various clinicalinvestigators have noted that a low blood pressure ischaracteristic of cirrhosis of the liver,2 that low bloodpressures occur in acute infectious hepatitis,3 and thathypertensive patients may have an acute as well asprolonged fall in blood pressure following an attack ofacute infectious hepatitis.4

Raaschou,3 a Danish physician, in 1954 summa-rized this early work and presented the results of hisown study of a series of 102 women autopsied afterdying of chronic hepatitis (subchronic yellow atrophyof the liver). These were compared with a controlgroup of 93 women of similar age who died fromdiseases unrelated to the liver. He used three criteria ofarterial hypertension: 1) incidence of cerebral hemor-rhage; 2) evidence of cardiac hypertrophy; and 3)known elevations of blood pressure. Based on thesecriteria, he found that the frequency of arterial hyper-tension is considerably lower in patients with severehepatic disease than in patients without liver disease.He hypothesized that severe impairment of liver func-

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tion prevents arterial hypertension or can eliminatealready existing hypertension.

In the United States, the leading investigator of therelationship between liver disease and blood pressurehas been Hubert F. Loyke. He published a series ofstudies beginning in 19556 with a report on blood pres-sure in over 500 patients with cirrhosis of the liver. Theage distribution of this group was broad, with an aver-age of about 55 years. Of these patients, only 60 haddiastolic blood pressures over 90 mm Hg (based onblood pressure measurement at the time of hospitaladmission). Of the 60, in 14 cases there was coexistingrenaJ disease and in 13 cases there was some kind ofdistressing or painful stimulus at the time of admissionwith subsequently lower blood pressure readings.Eliminating these cases left 33 patients (out of 470)with coexistent hypertension and cirrhosis, or 7% ofthe population studied. This is definitely less thanwould be expected in a similar group of otherwisenormal individuals without liver disease, but Loykedid not include a group of noncirrhotic hospital pa-tients as controls. He made three additional importantobservations: 1) in the cirrhotic patients as a groupthere was no progressive rise in blood pressure withage, the mean value remaining close to 134/80; 2) in afew patients with preexisting hypertension, there was afall in blood pressure, often to normal, as the liverfailure progressed; and 3) in these cases there was a"reversal" of the plasma albumin:globulin ratio coin-cident with the deterioration of liver function. Loykepublished the results of subsequent clinical studies,7'8

which expanded and confirmed his original publica-tion and presented the hypothesis that remission ofhypertension in liver disease may depend on somealteration of plasma proteins, either a deficiency in aparticular protein that is necessary for maintaining hy-pertension or the production of an abnormal proteinthat blocks the hypertensive mechanism. Loyke alsowent on to perform some interesting experimentalstudies, which are described in the following section.

Experimental Injury to the LiverThe earliest reports of remission of hypertension

produced by experimental liver damage are those ofPage et al.9 and Davis et al.10- " Page et al., as early as1941, reported that oral administration of a mixture ofalcohol and carbon tetrachloride to five renal hyperten-sive dogs sometimes caused a fall in arterial bloodpressure (data are presented only for three dogs, two ofwhom showed a fall from hypertensive to normoten-sive levels). They also showed that these dogs had areduction in plasma renin substrate concentration asjudged by the rather crude means of measurement,which was the only one available to them at this earlydate. Davis and coworkers in 194910 and 1951"showed that partial occlusion of the portal vein in renalhypertensive dogs resulted in a significant fall in bloodpressure. They did not measure renin substrate. In1953 Raaschou and Trautner12 reported that obstruc-

tion of the common bile duct in dogs with hypertensiondue to bilateral constriction of the renal arteries re-duced arterial pressure to, or nearly to, normal levels.They found, as Davis had previously reported, thatsome degree of hepatic injury was necessary for remis-sion of hypertension to occur. They did not measurerenin substrate.

In 1966, Schwartz et al.'3 showed that the operationof "portacaval transposition" (end-to-end portacavalanastomosis combined with above kidney end-to-endcavaportal shunt) reversed or prevented hypertensiondue to renal artery constriction in dogs. In 1969,Schwartz et al.14 reported that the same operation pre-vented or corrected hypertension in dogs subjected tounilateral radiation nephritis. Renin substrate was notmeasured in either experiment.

Recently, there has been a revival of interest in theeffect of portacaval anastomosis (not transposition) onblood pressure in experimental animals. In 1976, Ed-wards et al.13 found that this operation significantlylowered blood pressure in normotensive rats on a spe-cial high fat diet. Edwards et al. did measure reninsubstrate concentration and found a significant 30%decrease. Furthermore, the fall in blood pressure andthe decrease in renin substrate were significantly corre-lated.

Other than the early experiments of Page, the firstuse of hepatotoxic chemical agents to assess theireffect on experimental hypertension was carried out byLoyke and coworkers. In 1960, Loyke et al.16 reportedthat semiweekly subcutaneous injections of carbon tet-rachloride, CC14, into renal hypertensive rats resultedin a marked fall of blood pressure. In subsequentyears, Loyke continued his investigation of the effectof chlorinated hydrocarbons on hypertension in ratsand found that methylene chloride, CH2C12, and chlo-roform, CHC13, as well as carbon tetrachloride, wereeffective blood pressure lowering agents, even in mild-ly hepatotoxic doses."1 '8 Loyke also investigated thepossible mechanism of the blood pressure loweringaction of liver damage.19"21 In one of these studies19

plasma renin substrate was measured and no decreasewas found. In experiments done some 7 years later,17

however, Loyke reported a marked decrease in reninsubstrate concentration in renal hypertensive rats inwhich blood pressures were lowered by biweekly sub-cutaneous injections of chloroform, CHC13.

More recently Douglas et al.22 reported that methy-lene chloride injected daily for 5 days into spontaneoushypertensive rats resulted in a significant fall in bloodpressure. They measured plasma renin activity andfound it slightly but not statistically significantly re-duced in the treated hypertensive rats. They did notmeasure renin substrate concentration.

From the preceding reports one may conclude thatexperimental damage to the liver, by a variety ofmeans, is able to reduce or eliminate several types ofexperimental hypertension. The mechanism of this ac-tion remains to be elucidated; the hypothesis that a fallin renin substrate level is responsible is supported bysome, but not all, of the available evidence.

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Hypertension in High Plasma ReninSubstrate States

It is well known that, in several different clinical andnatural conditions, human beings with elevated levelsof renin substrate show a tendency toward or actuallydo have hypertension. It is equally well known that, inmost of these conditions, the majority of people withelevated renin substrate do not have high blood pres-sure. If some explanation for this lack of correlationwere available, it would help to clarify the relationshipbetween renin substrate and arterial pressure. The fol-lowing are specific examples of the positive correla-tion between high renin substrate and high blood pres-sure and an attempt to explain the frequent observationthat high renin substrate levels may coexist with nor-mal blood pressure.

PregnancyIn most women, blood pressure goes down during

pregnancy, usually with some tendency to return toprepregnancy levels during the third trimester.23 How-ever, in a significant proportion of pregnancies, theblood pressure rises to hypertensive levels during thethird trimester. Chesley24 has emphasized the impor-tance of distinguishing between true preeclampsia andother forms of gestational hypertension. Preeclampsiahas several distinguishing characteristics: it occurs pri-marily in nulliparas; it involves proteinuria and a char-acteristic glomerular lesion; and apparently has a fa-milial or genetic basis. Gestational hypertension otherthan preeclampsia may be, according to Chesley: 1)latent hypertension revealed by pregnancy; 2) chronicglomerulonephritis or other renal disease; or 3) essen-tial hypertension or renal hypertension which hasabated during the first part of pregnancy but whichreappears during the last part. In general there is, inearly pregnancy, a tendency toward lowering of bloodpressure and, in late pregnancy, a tendency towardelevation of blood pressure.

What is the basis of the decrease in blood pressureduring early or midpregnancy? There is no conclusiveanswer but there is considerable evidence to supporttwo or three possible mechanisms. One is estrogen-induced vasodilation. During pregnancy there is a de-creased vascular resistance and corresponding in-creased blood flow in various parts of the body,23

including hands and feet,26 uterus,27 kidneys,28 andskin.29 There is also a vasodilation and increased dis-tensibility of veins.30 This widespread vascular relax-ation may be due to the action of the increased levels ofestrogens that occur during pregnancy. Estrogens havebeen shown, when administered to animals or humans,to cause prompt vasodilator effects on vessels of thelimbs, nasal mucosa, ears, and uterus.23-31 There issome evidence that progesterone may have a similarvasodilator influence but it appears that estrogens aremore potent in this action.32

A diminished responsiveness to the pressor effect ofangiotensin is another important vascular alteration

during human pregnancy. It has been shown by severalinvestigators33"33 that, during normal human pregnan-cy, a greater amount of angiotensin II is required toproduce the same rise in blood pressure, as comparedto nonpregnant women. This diminished responsive-ness may be specific for angiotensin, although thereare conflicting reports as to responsiveness to va-sopressin and to norepinephrine in nonpregnant vspregnant women.3*

Chesley37 and Gant et al.35 made the important ob-servation that women with pregnancy-induced hyper-tension do not have the usual pregnancy-associatedrefractoriness to the pressor effect of angiotensin. Fur-thermore, Gant et al. showed that this change actuallyprecedes the development of hypertension. After thedevelopment of reduced responsiveness to angiotensinin early pregnancy, sensitivity to angiotensin graduallyincreases, starting about the 22nd week of pregnancyand reaches or surpasses the nonpregnant level of sen-sitivity during the last 1 or 2 months of pregnancy, atwhich time hypertension may occur. Everett et al.38

have recently investigated the mechanism of the loss ofsensitivity to angiotensin in pregnant women and havefound that it apparently involves prostaglandins, sinceindomethacin or aspirin (prostaglandin-synthetase in-hibitors) restore sensitivity to the nonpregnant level.They also found that a metabolite of progesterone (5a-dihydroprogesterone), but not progesterone itself, re-stores vascular refractoriness to angiotensin in womenwith mild pregnancy-induced hypertension.39 In addi-tion , they reported that theophy lline (an inhibitor of theenzyme phosphodiesterase) has a similar effect in suchwomen. Their tentative conclusion is that the mecha-nism of refractoriness to angiotensin in normal preg-nant women involves a localized prostaglandin orprostaglandin-like action mediated by cyclic nucleo-tides and that progesterone or one of its metabolitesinfluences the synthesis or catabolism of locally pro-duced prostaglandins.

Thus, there appear to be two basic mechanisms un-derlying vasodilation and lowered blood pressure dur-ing pregnancy, one mediated by estrogens and possi-bly representing a direct effect of estrogens on bloodvessels, the other mediated by progesterone acting in-directly by affecting prostaglandin synthesis at the vas-cular level.

What about the mechanism underlying the increaseof blood pressure in late pregnancy? An increased con-centration of renin substrate might be expected to pro-mote vasoconstriction and to elevate blood pressure.All pregnant women have a substantial and progressiveincrease in renin substrate concentration during preg-nancy, the highest levels occurring during the thirdtrimester.40"42 Presumably, during normotensive preg-nancy the vasodilator mechanisms just described ade-quately compensate for the vasoconstrictor influenceof renin substrate, especially during early pregnancy.In particular, reduced responsiveness to angiotensinwould diminish the vasoconstrictor effect of increasedangiotensin levels resulting from increased renin sub-strate. However, if this refractoriness is progressively

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diminished, as occurs in some pregnant women, and asthe concentration of renin substrate progressively in-creases, there will be a greater and greater tendency tovasoconstriction and elevation of blood pressure. Inlate pregnancy, if both influences (increased sensitiv-ity and increased concentration) are sufficiently exag-gerated, frank hypertension would be expected tooccur.

The evidence supporting a role for renin substrate ingestational hypertension may be summarized as fol-lows: 1) in pregnancy renin substrate increases and insome pregnant women hypertension develops; 2) thehighest levels of renin substrate occur late in pregnan-cy, which is also when hypertension, if it occurs at all,will be present; 3) hypertension is more likely to occurin women who regain sensitivity to angiotensin, whichwould make them more responsive to the vasoconstric-tor action of renin substrate; and 4) the fact that mostwomen have high levels of renin substrate during preg-nancy but do not become hypertensive can be account-ed for by the presence of potent vasodilator influencesthroughout pregnancy, presumably resulting from in-creased plasma levels of estrogens and progesterone.

Women Taking Oral Contraceptives or EstrogensThe relationship between blood pressure and renin

substrate concentration in women taking oral contra-ceptives is quite similar to that in pregnancy, althoughthere are some important differences. Only a smallpercentage of women who take estrogen-containingoral contraceptives develop a significant degree of hy-pertension,43-44 although most of them, according toFisch, et al.,45 have some small elevation of both sys-tolic and diastolic blood pressure. However, all wom-en who take such oral contraceptives do have elevatedlevels of renin substrate. The question again arises:Why do some women become hypertensive, whilemost do not?

There has been some speculation about this ques-tion, mostly centered about what happens to renin con-centration in these women when renin substrate con-centration rises. Skinner et al.4* showed, in 1969, thatin normal women taking oral contraceptives, reninsubstrate concentration increases and renin concentra-tion decreases. They also found increased renin sub-strate levels in six hypertensive women taking oralcontraceptives (average for hypertensives, 4.77 /i.g/ml; average for normotensives, 3.4 /u.g/ml). They pro-posed that "suppressed renin secretion is a normalresponse to elevated substrate and that inadequate sup-pression might account for the hypertensive effect oforal contraceptives."

In 1970, Saruta et al.47 supported this hypothesis in amore extensive study. They gave oral contraceptives to56 initially normotensive women for a period of 18 to30 weeks. During this period 10 of these women devel-oped mild to moderate hypertension. Plasma renin ac-tivity, plasma renin concentration, and renin substrateconcentration were measured. Comparisons weremade between the group that remained normotensiveand the group that became hypertensive. Higher con-

centrations of renin substrate were found in the hyper-tensive group, but the difference was statistically sig-nificant only at the 6-week interval. However, plasmarenin concentration was statistically and consistentlydifferent in the two groups, being higher than the con-trol (pretreatment) value in the hypertensive group andslightly lower than the control value in the normoten-sive group. Thus, Saruta et al. not only did not find adecrease in renin concentration in the women whobecame hypertensive, but found an actual increase.

However, this result is contrary to that found byother investigators. Beckerhoff, et al.,48 in 1972, re-ported just the opposite result; in women who werehypertensive while taking oral contraceptives, plasmarenin concentration was not only reduced (compared tothe normal mean value) but was reduced to a lowervalue than that found in normotensive women takingoral contraceptives. Thus, hypertension in these wom-en could not be due to a failure of suppression of renin.The reason for the discrepancy between the results ofSaruta et al. and those of Beckerhoff et al. is not clear.There were significant differences in the techniqueused to measure renin concentration.49 A more likelyexplanation is that in the study reported by Saruta etal., the women were taking oral contraceptives for ashorter time (values measured at approximately 4-week intervals from the start of oral contraceptive ther-apy up to 18 to 30 weeks) whereas in the Beckerhoffstudy "the onset of hypertension was first noted be-tween 3 and 36 months after the medication was start-ed," and, presumably, the study was begun somemonths after hypertension was established in these pa-tients. Further support for this notion is given by Sar-uta et al., who added some results of more prolongedstudy to their paper and stated: "With continuation oforal contraceptives through 52 weeks, renin substrateremains elevated and constant, whereas renin activityand concentration tend to decrease an average of 20%in both women who remain normotensive and in thosewho become hypertensive."

It has also been shown that estrogen use by postmen-opausal women is associated with a significantly in-creased occurrence of hypertension.30 Pfeffer foundthat the incidence of hypertension is 1.6 to 2 timesgreater in women who take estrogens than in women ofthe same age who do not. Almost half (47%) of thewomen below age 70 in his study who used estrogenswere hypertensive, while of the comparable group whodid not take estrogens, some 29% were hypertensive.In the age group 70-79 years, the corresponding fig-ures were 39% hypertension in estrogen users and 19%in nonusers.

Surprisingly, there is very little published data onrenin substrate levels in women taking estrogens forother than contraceptive purposes. In 1971, Crane etal.5' reported increased plasma renin substrate levels ina few women with hypertension due to taking conju-gated estrogens (Premarin). We found a high level inone such patient tested in my laboratory. When shestopped taking estrogens, her blood pressure returnedto normal. Crane and Harris32 found that conjugated

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estrogens (1.25 mg daily) caused a significant progres-sive rise in renin substrate concentration in 10 womenof premenopausal age (21 to 49 yrs) and also in 10women of postmenopausal age (42-64 yrs).

In summary, young women who take estrogen-con-taining oral contraceptives and older women who takeestrogens for relief of postmenopausal symptoms havean increased incidence of hypertension. They alsohave, without exception, increased plasma levels ofrenin substrate. Whether the latter is the cause of theformer remains to be proven. Since the increase inrenin substrate due to estrogen intake is universal andthe elevated blood pressure is exceptional, it remainsto be explained why all of the estrogen-treated womendo not become hypertensive or, conversely, what isspecial about the women who do. A possible clue tothe latter is the finding by Ahluwalia et al.53 that hyper-tensive users of oral contraceptives have significantlyhigher plasma estrogen levels than normotensive usersof the same medication. Apparently in some womenthe metabolism of estrogens is different from that ofmost other women and, presumably, the ones whoattain the highest plasma concentration of estrogensare the ones who are likely to develop hypertension.

treated patients may be related to increased arterialpressure, although other possible pathogenetic mecha-nisms, such as an increased tendency to thrombosis,are not excluded. By analogy, the finding by Pfeffer50

seems very relevant, that the increased incidence ofstroke in older women taking estrogens could be en-tirely related to their increased blood pressure.

Do men given DES for treatment of prostatic cancerhave elevated levels of renin substrate? In male ratsgiven DES, renin substrate levels are elevated.59-60 Inwomen given DES, renin substrate levels are elevat-ed,52 and in men given other estrogens, renin substratelevels are elevated.52 For some reason (as far as Iknow) no study has been published showing that mengiven DES have elevated levels of renin substrate. Yet,in fact, they do, as we have found in some preliminaryexperiments in my laboratory (Gordon DB et al., un-published data).

More studies are obviously needed, but it appearslikely from the available evidence that: 1) men givenDES have an increased incidence of hypertension; 2)that this may contribute to the increased mortalityfound in such men; and 3) that increased levels of reninsubstrate, if sought, will be found.

Patients with Cushing's Syndrome and Patients Treatedwith Glucocorticoids

Krakoff54 has shown that in patients with Cushing'ssyndrome and in patients given large doses of gluco-corticoids there is a significant increase in the concen-tration of renin substrate in the plasma. It is wellknown that in both conditions there is a high incidenceof hypertension. Krakoff et al.55 have suggested thatthe elevated levels of plasma renin substrate may playa role in the pathogenesis of hypertension in theseconditions.

Men Given Di-ethylstilbestrol (DES)The use of DES for treatment of prostatic cancer in

men has been shown to be a beneficial procedure inthat it reduces morbidity and mortality due to the can-cer itself. However, in a large controlled study involv-ing over 2000 patients, a comparison of patients givenplacebos with those receiving 5 mg of DES dailyshowed that the mortality rate was higher in the DES-treated group.5* Although deaths from prostatic cancerwere reduced, the number of deaths from other causes,especially heart failure and cerebrovascular accident,increased disproportionately, so that the overall mor-tality was greater, not less, in the treated group. In asubsequent study57 it was shown that smaller doses ofDES caused fewer cardiovascular deaths, while stillpermitting some reduction of mortality due to the pros-tatic cancer. As a result of these findings, the approvedtherapy with DES is now limited to 1 mg daily.

Surprisingly, in the studies cited above, the status ofblood pressure in the patients was not reported. Only abrief reference to blood pressure levels in DES-treatedpatients has been published by Byar.58 It is possiblethat some or all of the increased mortality in the DES-

Hypertension with Associated Elevation ofPlasma Renin Substrate

In the preceding section, evidence was consideredthat indicates that in various situations in which reninsubstrate levels are increased, hypertension is alsopresent, not invariably, but in a greater or lesser pro-portion of the population involved. In this section, theevidence will be examined concerning renin substrateconcentration in a few situations in which, by defini-tion, all the individuals concerned have elevated bloodpressure, namely, essential hypertension and malig-nant hypertension in humans and experimental andspontaneous hypertension in animals.

Essential HypertensionWalker et al.,6' showed that in a large group of

individuals with essential hypertension, or with nor-mal blood pressure, there is a good correlation betweenblood pressure level and renin substrate concentration.This must mean that those with essential hypertensionhave, on the average, higher levels of renin substratethan those with normal blood pressure and, in fact, inanother paper Walker et al.62 reported that those sub-jects who had diastolic blood pressures greater than 90mm Hg did have a significantly higher plasma reninsubstrate concentration than those subjects with bloodpressures below 90. However, other studies, whileconcurring that there is a somewhat higher level ofrenin substrate in patients with essential hypertension,reported a within-group variability so large that thedifference was not statistically significant.63 An excep-tion is the result reported by Gould and Green64 whofound a modest, but highly significant difference in

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renin substrate concentration in males with essentialhypertension compared to normotensive males. In ourown studies of renin substrate in men with essentialhypertension (Gordon DB et ah, unpublished data) wefound some with the same concentration as normoten-sive men and others with considerable increases,reaching two times the mean value of normotensives insome cases. Essential hypertensive patients can besubdivided into two categories, those with normal orslightly above normal levels of renin substrate andthose with elevated levels. This concept, it seems tome, is a reasonable one and might have heuristic value.In those patients with significantly elevated levels ofrenin substrate, say 1500 to 2000 ng/ml, the elevatedrenin substrate together with adequate vascular respon-siveness may be the cause of the hypertension.

Malignant HypertensionSince Helmer's report*5 in 1964, all investigators

have found that the majority of patients with malignanthypertension have elevated levels of plasma renin sub-strate.64- 66-67 Most such patients also have very highlevels of plasma renin activity and plasma renin con-centration. The two groups (high renin and high sub-strate) may not, in fact probably do not, completelycoincide. It is likely that renin, in high concentration inplasma, consumes renin substrate at such a high ratethat the concentration of renin substrate in plasma isdiminished, in spite of a high rate of production by theliver. Schultze and Oelkers68 have published evidenceto support this concept. They found in one patient withsevere malignant renovascular hypertension that, be-fore antihypertensive therapy, plasma renin activitywas extremely high (149 ng/ml/hr) while plasma reninsubstrate was below their normal range. After a fewdays' treatment with methyldopa, plasma renin activ-ity had fallen considerably (to 48 ng/ml/hr) but wasstiH far above the normal range, and plasma reninsubstrate had increased significantly. Subsequent re-moval of the ischemic kidney resulted in a prompt fallof plasma renin activity and of blood pressure, fol-lowed by a much slower, modest rise of plasma reninsubstrate.

There are two conflicting effects of plasma renin onplasma renin substrate concentration. On the one hand,as described above, increased renin concentration re-duces renin substrate concentration because of morerapid conversion to angiotensin I. On the other hand,as has been shown by several investigators69"72 in-creased levels of renin and of angiotensin stimulate theproduction of renin substrate by the liver. Rosset etah66 found that there is usually an inverse relationshipbetween plasma renin activity and plasma renin sub-strate in normal humans, but that in malignant hyper-tension this relationship does not hold; both plasmarenin activity and the renin substrate may be greatlyelevated.

Experimental and Spontaneous HypertensionSurprisingly little work has been done in this area.

Some investigators have found an increased level of

plasma renin substrate in rats with spontaneous hyper-tension73- 74 while others have not.75 In rats with hyper-tension due to constriction of one renal artery (oneclip, two kidney) elevated plasma renin substrate hasalso been reported.75 Many years ago Kohlstaedt etah76 reported an increase in renin substrate in the plas-ma of dogs with experimental renal hypertension, butthis result was dismissed as some kind of artifact byBraun-Menendez et ah77 who found no change in dogswith chronic experimental renal hypertension andwithout renal insufficiency.

Low Blood Pressure or Low Vascular ResistanceAssociated with Low Plasma Renin Substrate

Cirrhosis of the LiverAs previously described, in patients with severe cir-

rhosis of the liver there is usually no elevation of bloodpressure, in spite of a significantly increased concen-tration of plasma renin. There may be a normal bloodpressure with decreased peripheral vascular resistanceand increased cardiac output78 or there may be a franklowering of blood pressure.79 Evidently a potent vaso-dilator influence exists in cirrhosis. There is also amoderate to severe diminution of plasma renin sub-strate concentration, depending on the degree of im-pairment of hepatic function.80"82 The lowered reninsubstrate concentration may be the cause of the wide-spread vasodilation. Since, in severe cirrhosis, thereare many abnormalities of plasma components, theremay be vasodilator effects due to other chemical orhormonal changes. Nevertheless, cirrhosis of the liver,especially in its severe stages, is a good example of acorrelation between decreased renin substrate concen-tration and decreased vascular resistance.

Bartter's SyndromeBartter's syndrome is a complex syndrome charac-

terized by low to normal blood pressure, decreasedsensitivity to angiotensin, increased plasma levels ofrenin and aldosterone, and excessive excretion of po-tassium by the kidneys resulting in hypokalemia andweakness. It is, as is liver cirrhosis, one of those clini-cal entities in which high plasma renin activity andnormal blood pressure coexist. We have measuredrenin substrate in three women and two men with Bart-ter's syndrome (Gordon DB et ah, unpublished data).The three women had normal levels of renin substratebut the two men had clearly decreased concentrations.Tree83 has reported very low values of plasma reninsubstrate in two children who either had Bartter's syn-drome or some condition closely resembling it, includ-ing hypotension, hypokalemia, and extremely highplasma renin levels.

Adrenal InsufficiencyIn adrenal insufficiency, both clinical, as in Addi-

son's disease, and experimental, as in animals subject-

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ed to bilateral adrenalectomy, there are many distur-bances of normal physiological function, including atendency to abnormally low blood pressure. The latteris primarily due to renal loss of sodium and the conse-quent depletion of salt and water from the body withdehydration and hypovolemia. However, other effectsof lack of adrenal cortical hormones on the cardiovas-cular system are probably involved, and some part ofthese may be due to a decrease in plasma renin sub-strate concentration.

In adrenalectomized animals84"*6 and in human be-ings with severe adrenal insufficiency, i.e., with Ad-dison's disease,87 there is a profound decrease in theconcentration of renin substrate in plasma. The degreeof diminution of plasma renin substrate has beenshown to be proportional to the degree of reduction ofplasma cortisol in untreated Addisonian patients.87 Atthe same time that renin substrate is reduced, reninconcentration is greatly increased, but blood pressureis not elevated and is usually below normal. Stockigt etal.87 noted that their most severely hypotensive Addi-sonian patient was the one who had the lowest concen-tration of renin substrate and the highest concentrationof renin. The low renin substrate may be responsible,at least in part, for the low blood pressure in adrenalinsufficiency.

Effect of Therapy on Plasma Renin SubstrateIf the concentration of renin substrate in plasma is an

important determinant of blood pressure level, it isreasonable to suppose that some therapeutic agents thatare effective in lowering blood pressure in hyperten-sive patients may lower the concentration of renin sub-strate. This possibility has not been extensively inves-tigated. Two of the most widely used therapeuticmodalities for treating high blood pressure in humansare restriction of sodium intake and the use of sodium-depleting diuretic agents. Rosset and coworkers88 haveshown that in normal men salt depletion by restrictionof sodium in the diet results in a decrease in plasmarenin substrate and also an increase in plasma reninactivity. Similar observations have been made in salt-depleted rats,8589 although not all investigators havefound such a decrease. Rosset and Veyrat88 found that,with certain notable exceptions such as malignant hy-pertension, there is in general an inverse relation be-tween plasma renin activity and renin substrate in nor-mal humans and in some pathological conditions, too.Because increased renin concentration will increasethe rate of utilization of renin substrate, one wouldexpect plasma renin substrate to be decreased when-ever plasma renin concentration is increased, that is,unless the rate of renin substrate production by theliver increases enough to balance or overbalance theincreased utilization. The fact that angiotensin II stim-ulates synthesis and release of renin substrate by theliver71-72 complicates this relationship, since any in-crease of plasma renin concentration would be expect-

ed to provoke both increased destruction and increasedproduction of renin substrate. Herrmann et al.89 haveadmirably clarified this situation by showing that alarge increase in angiotensin II concentration in plasma(produced by a continuous intravenous infusion) doesresult in a significant increase in renin substrate outputby rat liver slices, whereas a modest increase, such asoccurs in sodium-deficient rats, does not result in anyincrease in renin substrate output. In such salt-defi-cient rats, increased utilization is not balanced by in-creased output, and renin substrate concentration inplasma falls.

With this information in mind, one can presume thatantihypertensive diuretics that provoke an increase inplasma renin activity or plasma renin concentrationwould also cause some reduction in plasma renin sub-strate concentration. Actual measurements of plasmarenin substrate are needed to verify this presumption.In fact, most antihypertensive diuretics, such as thethiazides, do cause an increase in plasma renin activityand renin concentration.90-91

Whether other antihypertensive drugs that are notdiuretics may have some more direct action on the liverand cause a lowering of plasma renin substrate largelyremains to be investigated. There is one antihyperten-sive drug, captopril, which, while presumably not act-ing directly on the liver, does have a significant effecton plasma renin substrate.

Captopril (2 D-methyl-3 mercapto propanoyl-L-proline) is an inhibitor of converting enzyme. It can begiven orally, and in adequate doses it prevents theconversion of angiotensin I to angiotensin II and thusblocks the vasoconstrictor action of the renin-angio-tensin system. The mechanism of the blood pressurelowering action of captopril was originally attributedto this specific blocking action. This was supported bythe findings that its blood pressure lowering effect inhuman beings is proportional to the level of plasmarenin activity prior to drug therapy92 and that the rise inplasma renin activity induced by the drug is also pro-portional to the extent of the fall in blood pressure.93

However, while this mechanism of action is generallyaccepted, considerable controversy has arisen aboutthe possibility that captopril may have some other ac-tion that also tends to lower blood pressure. Captopril,while most effective in high renin states, also is effec-tive in lowering blood pressure in essential hyperten-sion and even, in some circumstances, in nephrecto-mized dogs,94 rats,93 and human beings.96 On the otherhand, it usually does not lower blood pressure inanephric human beings,97 nephrectomized rats,98 orrabbits.99 Antonaccio and Asaad100 have recently sum-marized this controversial topic.

Another interesting observation is that captopril plushydrochlorothiazide may be more effective in loweringblood pressure in spontaneous hypertensive rats101 andin hypertensive humans102 than captopril alone, in spiteof the fact that captopril alone completely blocks theconversion of angiotensin I to angiotensin II. In theexperiments on rats, Chan et al.101 showed that thegreater hypotensive effect of hydrochlorothiazide plus

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captopril could not be attributed to loss of electrolytesand water since it was equally pronounced in rats withligated ureters and, presumably, nonfiltering kidneys.The clue to explaining this otherwise puzzling obser-vation is the fact that the two drugs together cause agreater increase in plasma renin level than either oneacting alone. According to the discussion presentedabove, this would make the combination of two drugsmore effective in lowering plasma renin substrate con-centration. The question is — Does it?

Rasmussen et al.103 have reported that this is precise-ly what occurs. They studied nine patients with severeor malignant hypertension whose blood pressure wasnot adequately controlled by a combination of antihy-pertensive drugs. After stopping the previous therapy,they began therapy with captopril in increasing dosesup to 450 mg daily, then added hydrochlorothiazide(100 mg/day), and after at least a month added pro-pranolol as a third antihypertensive agent. Plasma con-centrations of renin, renin substrate, angiotensin I andangiotensin II, as well as plasma renin activity, weremeasured. They found that captopril alone caused asignificant decrease in plasma renin substrate (from amean value of 2151 ng/ml to 1693 ng/ml) and thatcaptopril plus hydrochlorothiazide caused a greater de-crease (to 990 ng/ml). Correspondingly, plasma reninconcentration rose somewhat with captopril alone butmuch more with both drugs together. Addition of pro-pranolol to the other two agents partially reversed thesechanges; plasma renin concentration decreased some-what and plasma renin substrate increased accord-ingly.

These results strongly support the concept, de-scribed above, that increases in plasma renin concen-tration will tend to reduce plasma renin substrate con-centration. Whether the fall in plasma renin substrate isresponsible for the fall in blood pressure is unproven.

ConclusionsThe evidence presented shows that in a wide variety

of circumstances there is a positive correlation be-tween arterial blood pressure and the concentration ofrenin substrate in plasma. When renin substrate rises,blood pressure goes up; when renin substrate falls or isbrought down, blood pressure also goes down. Thereare several obvious exceptions but usually some rea-sonably acceptable explanation can be found. The bulkof the evidence supports the hypothesis that renin sub-strate may play an important role in hypertension, andthat high renin substrate levels, together with adequatevascular responsiveness, may be a cause of elevatedblood pressure. The strength of the hypothesis rests onthe wide range of circumstances in which it seems toapply. Its weakness is in the lack of a uniformly posi-tive correlation. Probably the main value of the hy-pothesis rests on the fact that it is straightforward andeasily testable. It is to be hoped that its considerationwill lead to additional experiments on the role of reninsubstrate in hypertension.

AddendumSince submission of this manuscript, a paper by Tewksbury DA

and Dart RA entitled "High Molecular Weight AngiotensinogenLevels in Hypertensive Pregnant Women" was published in Hyper-tension (4: 729, 1982). They reported that a high molecular weightfraction of angiotensinogen (renin substrate) is present in higherconcentrations in hypertensive than in normotensive pregnant wom-en. This study provides a significant new approach to the questionof the relationship of renin substrate to high blood pressure inpregnancy.

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