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Biomedical subjects

J E Sealey

Publications and source records attributed to J E Sealey.

At least 145 records · Page 8Linked to original sources
PubMed1978

Studies of plasma aldosterone in anephric people: evidence for the fundamental role of the renin system in maintaining aldosterone secretion.

When plasma aldosterone (PA) was measured in 32 predialysis samples from 18 anephric subjects more than 3 months postnephrectomy, all but two values were subnormal, 16 measurements were undetectable, i.e. below 0.35 ng/100 ml, and PA averaged only 1.7 ng/100 ml +/- 0.5 (SE) in the remaining 16. In contrast, PA averaged 29.7 +/- 5.6 ng/100 ml in 12 dialysis patients with kidneys. Plasma renin activity was undetectable in 15 assays of anephric subjects and averaged 0.5 +/- 0.1 ng/ml/h in the remaining 17. However, these latter measurements appeared to be an artifact caused by the presence of plasma prorenin. Serum potassium fell during dialysis and appeared responsible for the concurrent 75% fall in PA observed in six nephric patients (delta 14 ng/100 ml), and in three anephric patients (delta 3.3 ng/100 ml) with low but measurable PA values. Overt hyperkalemia was required for potassium to stimulate aldosterone into the normal range in anephric subjects. The angiotensin II analog, saralasin, also increased PA slightly in five studies. Renin and PA fell after nephrectomy and increased after transplantation. Decreases and increases in renin always preceded those of aldosterone. Usually it took several weeks for aldosterone to fall to undetectable levels and several days to return to normal levels after renal transplantation. These observations suggest that the baseline plasma level of angiotensin determines both the baseline level of aldosterone secretion and its capacity to respond either to more angiotensin or to other stimuli. In the absence of renin, the adrenal almost loses its capacity to generate aldosterone. The data support the view that the renin system plays a fundamental role in maintaining aldosterone secretion in man.

Aldosterone↗
PubMed1977

Plasma renin and "prorenin" in essential hypertension during sodium depletion, beta-blockade, and reduced arterial pressure.

An inactive form of renin is activated by incubating human plasma at -5 degrees C. The relative proportions of active renin and this cryoactivatable "prorenin" in plasmas of untreated hypertensive patients varied widely. However, prorenin increased in parallel with active renin after sodium deprivation or diuretic therapy in 36 patients; the increases were similar whether or not blood-pressure fell. In contrast, propranolol administration in 22 patients lowered active renin in all, but it increased prorenin by 98% in 15 in whom systolic pressure fell. In the other 7 blood-pressure did not change, and beta-blockade produced a fall in total renin (active renin plus prorenin) while prorenin was unchanged. For all 22 there was an inverse relationship between propranolol-induced changes in plasma-prorenin and systolic pressure (r=-0-77, P less than 0-001). The fraction of active plasma-renin fell during propranolol administration from 43% to 18%, regardless of the blood-pressure response. Clonidine produced similar changes in 10 patients. Thus, sodium depletion stimulates total renin release, while propranolol and clonidine produce divergent responses of active renin and prorenin, the changes in prorenin depending on the changes induced in blood-pressure. These observations suggest that propranolol may block intrarenal conversion of prorenin to active renin while also suppressing total renin release. But the latter effect may be offset by concurrent baroreceptor-mediated release of total renin (mostly prorenin) when blood-pressure is lowered.

Adult↗
PubMed1977

Possible role of renin in hypertension as suggested by renin-sodium profiling and inhibition of converting enzyme.

To block renin activity, a nonapeptide converting-enzyme inhibitor was given to 65 seated hypertensive patients. Depressor responses occurred only when control plasma renin activity exceeded 2 ng of angiotensin I per milliliter per hour and correlated directly in amplitude with control plasma renin activity and with induced increments in activity (P less than 0.001 for both). Depressor responses, like renin activity, were characteristic for renin subgroups as defined by renin-sodium profiling. Before and after sodium deprivation, the nonapeptide reduced diastolic pressure in all patients with high renin (by 17.3 and 19.8 per cent) and most patients with normal renin (by 9.1 and 17.7 per cent). Low-renin patients remained unresponsive. This enzyme blockade may cause bradykinin accumulation. But if, as seems likely, depressor responses are due to blockade of angiotensin II formation, the results indicate that, irrespective of sodium balance, measurements of plasma renin activity reflect its contribution to blood-pressure maintenance. The results suggest broad participation of the renin system in common forms of hypertension.

Angiotensin II↗
PubMed1977

The immediate pressor response to saralasin: a measure of the degree of angiotensin II vascular receptor vacancy.

(1) An immediate pressor response so saralasin, 10 microgram/kg/min, occurred in 52 of 57 (91%) hypertensive patients. (2) We propose that the amplitude of the immediate pressor response functions as an in vivo measure of the number of initially vacan angiotensin II vascular receptors. (3) The immediate pressor response to saralasin forecasts the subsequent sustained response, both of which are related to the renin-sodium profile. (4) The dual blood pressure responses to saralasin, immediate and sustained, make this drug useful for the pharmacological identification of high, normal, and low renin hypertensive patients as they are presently classified. (5) The ability of saralasin to elevate the BP immediately in most hypertensive patients shows the need for caution in its use. It is a safe drug from this standpoint if very small infusions (0.01-0.10 microgram/kg/min) are first tried in hypertensive patients whose PRA is unknown.

Angiotensin II↗
PubMed1977

Systemic hypertension associated with coronary artery bypass surgery. Predisposing factors, hemodynamic characteristics, humoral profile, and treatment.

Systemic hypertension occurs in more than one third of patients having coronary artery bypass graft (CABG) operations. This report describes our studies in 100 consecutive patients undergoing CABG. We found that certain preoperative clinical, angiographic, and biochemical factors predispose to the development of perioperative hypertension. These included a well-documented history of hypertension, an elevated blood pressure the day prior to operation, greater than 50 percent obstruction of the left main coronary artery, and increased levels of dopamine beta hydroxylase (DBH). The hemodynamic pattern of perioperative hypertension was that of an increased systemic vascular resistance which was associated with increased levels of plasma catecholamines and plasma renin activity (PRA). Nitroprusside was shown to be effective in managing CABG hypertension, although other, more specific therapy may be preferable.

Adult↗
PubMed1977

Plasma prorenin in normal, hypertensive, and anephric subjects and its effect on renin measurements.

We have previously shown that a cryoactivatable inactive form of renin, which we have tentatively termed prorenin, occurs in human plasma. Plasma prorenin is measured by subtracting the endogenous plasma renin activity (PRA) from the total renin activity measured after cryoactivation. Cryoactivation is accomplished by shaking plasma at -5 degrees C for 4 days. Circulating prorenin averaged 5.6 +/- 0.8 (SE) ng/ml per hour in a group of 30 normal subjects and 5.1 +/- 1.0 ng/ml per hour in 25 hypertensive subjects during random sodium intake. In these two groups, prorenin ranged from zero to 36 times the endogenous renin level, averaging 2.5-fold in normal subjects and 3.4-fold in hypertensive subjects. During sodium deprivation prorenin more than doubled in 12 hypertensive subjects from a mean of 2.8 to 6.3 ng/ml per hour. In 25 anephric subjects, circulating prorenin was slightly lower than in normal subjects, averaging 3.4 +/- 0.9 ng/ml per hour (P less than 0.05). In contrast to our findings in nephric subjects, the low level of PRA measured in anephric subjects ((0.26 +/- 0.04 ng/ml per hour) was almost always a constant fraction of the measured prorenin. This led to the demonstration that prorenin can be inadvertently activated by chilling blood during processing for renin measurement and this often accounts for the small amount of renin measured in plasmas from anephric subjects. The error in routine PRA measurements due to inadvertent activation averaged +48% in anephric subjects and +17% in those with kidneys. Evaluation of the effect of processing bloods at room temperature revealed that net angiotensin I accumulation is less than 2% of that generated during incubation and can be ignored. Accordingly, to avoid the inadvertent activation of prorenin which can at times lead to a sizable and variable overestimation of PRA we recommend collecting and processing blood samples at room temperature and then storage of plasma completely frozen until the time for analysis.

Adolescent↗
PubMed1976

Renin and aldosterone suppression in the antihypertensive action of clonidine.

In 18 hypertensive patients receiving a constant (100 mEq/day) sodium diet, treatment with clonidine (0.3 mg/day for 5 days) decreased blood pressure in 11 patients with high and normal renin levels and 7 with low renin levels. The high and normal renin group had early and rapid reductions in blood pressure and plasma renin activity. In contrast, the low renin group had a more gradual hypotensive response and only a small absolute decrease in plasma renin. For all patients, pretreatment renin levels were related to the initial decrease in blood pressure but not to the reductions measured after 5 days. Thus, two mechanisms of action of clonidine are possible, one related to acute inhibition of the renin-angiotensin system in patients with high and normal renin levels and another that is independent of renin mechanisms and occurs in all hypertensive patients. In six additional patients with high renin levels induced by prior sodium depletion (10 mEq/day sodium diet), clonidine did not reduce blood pressure or renin, thus indicating that the suppressive action of this agent on renin pressor mechanisms occurs only in patients whose elevated renin levels are intrinsic to hypertension and unrelated to sodium depletion. Of the 18 patients receiving a normal sodium diet, 13 were classified as responding to treatment (decrease in both systolic and diastolic pressures of at least 10%). The five nonresponders had greater weight gain and higher values for aldosterone excretion. For all patients, there was a significant correlation between decrements in blood pressure and in aldosterone, suggesting that the countervailing effects of fluid accumulation on blood pressure in nonresponding patients resulted from a failure of aldosterone to be suppressed. Changes in aldosterone, in turn, correlated significantly with changes in renin. Thus, the antirenin effect of clonidine enhances its antihypertensive action not only by acutely ablating renin-angiotensin pressor mechanisms, but also by inhibiting aldosterone production and thereby minimizing longer-term reactive volume retention during treatment.

Adult↗
PubMed1976

Usefulness and limitations of saralasin, a partial competitive agonist of angioten II, for evaluating the renin and sodium factors in hypertensive patients.

Saralasin was infused into 52 untreated hypertensive patients. Immediate, transient pressor responses occurred in 94 per cent followed by a more gradual sustained change in blood pressure reaching an apogee in about 20 minutes. Most (86 per cent) patients with high renin values had sustained depressor responses irrespective of sodium balance. In contrast, during a normal sodium intake, the drug produced a neutral (45 per cent) or mildly pressor (50 per cent) response in patients with normal renin and pressor responses in patients with low renin values. Sodium depletion abolished pressor responses and resulted in depressor responses in 64 per cent of the patients with normal renin values. The pretreatment angiotensin level appeared to determine direction and amplitude of the response to saralasin, since increases and decreases in diastolic pressure exhibited a highly significant relationship to the control renin lever (r = 0.80, p less than 0.001). Above a neutral range of control renin values, from 2 to 7 ng Al/ml/hour, depressor responses were the rule, and below it pressor responses were consistent. Sodium balance also appeared to determine the amplitude of the response. In a subset of patients with similar renin values (range 1.4 to 2.2 ngAl/ml/hour), the induced pressor responses correlated directly with the 24-hour sodium excretion (p less than 0.05). For all patients, the induced pressure change also was related to the rate of sodium excretion (r = 0.53, p less than 0.001). The data suggest that saralasin behaves as a partial competitive agonist of angiotensin II. For this reason, saralasin testing provided only a rough physiologic validation for renin profiling. Thus, depressor responses expose most patients with high renin values. Neutral responses occur in many patients with normal renin and intermediate renin values. But pressor responses occur in subjects with either low or normal renin levels and they may reflect sodium and volume excess associated with a partial or relative absence of renin. Accordingly, due to its partial agonism, saralasin testing under-estimates the renin factor. Hence, the drug cannot be used to identify or exclude renin involvement in the blood pressure in the large majority of hypertensive patients who do not exhibit depressor responses. For them an agent devoid of agonism is required. Moreover, prior sodium depletion as a device to increase the frequency of depressor responses to saralasin does not measure intrinsic renin dependency of the blood pressure but rather the reactivity of the system to sodium depletion.

Angiotensin II↗
PubMed1976

Plasma prorenin: cryoactivation and relationship to renin substrate in normal subjects.

We previously demonstrated an inactive form of renin, termed prorenin, in the plasma of normal, hypertensive and anephric patients. Prorenin activity can be determined in plasma from the total renin activity after activation, minus the prior endogenous plasma renin activity. In the present study, conditions for cryoactivation of prorenin have been defined. Plasma prorenin is slowly converted to active renin-like material at -5 degrees C at pH 7.4. Activation takes four days and does not occur at pH 5.0. The degree of activation increases above pH 5 and is greatest between pH 7 and pH 9. Thus, almost no cryoactivation of prorenin occurs at the pH optimum for renin (5.7) in contrast to maximum activation at pH 7.4. No activation has been observed in the frozen state, but it does occur with decreasing rapidity at temperatures from -5 degress to +4 degress C. Since blood samples obtained for the determination of plasma renin activity are routinely chilled upon collection by most laboratories, some activatin of prorenin most likely occurs in all routine renin assays. The pH optimum of the enzymatic reaction of the activated prorenin in plasma is 5.8, the same as for renal renin, and the shape of the pH optimum curve is similar to that of renal renin added to human plasma. In a group of 23 normal subjects with plasma renin activity of 3.5 +/- 2.9 (SD), the activated prorenin increment was found to be significantly higher, 6.3 +/- 5.0 (SD) ng/ml/hour. Unlike plasma renin activity, prorenin activity in these normal subjects was directly related to the concentration of renin substrate (p less than 0.001). When the actual "concentration" of prorenin was calculated using renal renin as the reference standard, a direct relationship was also found between the concentration of prorenin and renin substrate (p less than 0.01). The observed relationship between prorenin and renin substrate concentrations might be a consequence of their regulation by common factors.

Angiotensin II↗
PubMed1976

Estimating renin participation in hypertension: superiority of converting enzyme inhibitor over saralasin.

This study was designed to examine more closely the differences in blood pressure responses in hypertensive patients to two agents which block the renin-angiotensin system. Accordingly, 39 seated patients received under the same conditions both saralasin, an octapeptide competitive antagonist of angiotensin II, and the nonapeptide converting enzyme inhibitor, SQ20881, which blocks the generation of angiotensin II from angiotensin I. A second component of the study involved administration of these agents in 10 addtional studies in anephric subjects. Although both agents produced maximal responses in blood pressure that correlated well with each other (p less than 0.001) and with the pretreatment plasma renin levels (p less than 0.001), analysis of the results by renin subgroups revealed significant differences. Thus, both drugs lowered the diastolic pressures of patients with high renin levels, but but converting enzyme inhibitor produced changes of greater amplitude (p less than 0.05). In contrast, saralasin was consistently pressor in both patients with low renin levels and anephric patients in whom converting enzyme blockade preduced no significant changes in blood pressure. Another impressive disparity in the responses to the two agents occurred in the group with normal renin levels in whom saralasin produced either neutral or pressor responses (mean change was +2.0 +/- 1.5 standard error of the mean (SEM) per cent control diastolic pressure) whereas the converting enzyme inhibitor consistently induced depressor responses (mean change was -10.2 +/- 1.2 per cent, p less than 0.001). Altogether, the results suggest that converting enzyme inhibitor tests for angiotensin II-dependent blood pressure with more sensitivity than the partial agonist saralasin. Moreover, it is unlikely that the differences between the responses to the two agents were due to bradykinin accumulation, since depressor responses to converting enzyme inhibitor were not observed in the patients with low renin levels and the anephric patients.

Adolescent↗
PubMed1976

Lowering of blood pressure, plasma renin substrate, cholesterol and triglyceride by portacaval anastomosis in rats fed on a 60% sucrose/5% lard diet.

1. Portacaval anastomosis was carried out in ten rats fed on a 60% sucrose/5% lard diet, which induced moderate hypertriglyceridaemia, mild hypercholesterolaemia and normotension. 2. Plasma triglyceride was decreased to 45% of concentrations observed in ten pair-weighed control rats. 3. Plasma cholesterol concentrations were reduced to 58%, renin substrate to 70% and aortic blood pressure to 80% of control values by portacaval shunt surgery. 4. Individual blood pressures were directly related to plasma renin substrate concentrations.

Animals↗
PubMed1975

Hypertension and unilateral parenchymal renal disease. Evidence for abnormal vasoconstriction-volume interaction.

Hypertension was not renin-dependent in the majority of 62 hypertensive patients with seemingly unilateral renal parenchymal disease, as indicated by plasma renin activity: low in 14 (23%), normal in 40 (56%), and high in only 8 (13%). By a weighted scoring system for analysis of differential renal-vein and peripheral renin levels, 70% (16 of 23) of these patients did not give scores predictive of cure by nephrectomy. Thus, occult bilateral disease reflected by attendant volume expansion and consequent reactive renin suppression may explain the well-known disappointing cure rate after uninephrectomy in this group. Since unilateral hypersecretion of renin with a completely normal contralateral kidney is rare in this group, abnormal renal-vein and peripheral renin values should be a prerequisite for advising nephrectomy, especially when the suspected kidney shows considerable excretory function.

Adolescent↗
PubMed1975

The renin axis and vasoconstriction volume analysis for understanding and treating renovascular and renal hypertension.

Information defining the renin-angiotension-aldosterone axis as a control system concurrently regulating salt balance and blood pressure has been applied to reexamine the role of renin in experimental and clinical forms of renovascular and renal hypertension, and thence to develop criteria for differentiating these entities. Experimentally, there are two models of renovascular hypertension; one is characterized by excess renin with reduced sodium (vasoconstrictor form) and the other by excess sodium with reduced renin (volume form). But with sodium depletion, the volume form converts to a vasoconstrictor form illustrating how the two factors coordinate to maintain blood pressure. In man, renovascular and renal hypertensions appear to be sustained by the same two mechanisms. Studies in man show that, in the absence of unilateral disease, the supine renal venous renin level in each kidney is consistently 24 percent higher than the peripheral level. Because of this constant relationship, the peripheral renin level is a measure of the renal secretion rate. Our studies indicate the curable unilateral renovascular hypertension is, in fact, renin-dependent vasoconstrictor hypertension. Three criteria, derived from four renin measurements, identify this situation: (1) Hypersecretion of renin is reflected by a high peripheral level when indexed against sodium excretion. (2) Lateralization of renin secretion with contralateral suppression rules out occult bilateral disease. It is indicated by V-A equal 0 from the uninvolved kidney. (3) (V-A)/A greater than 48 per cent from the ipsilateral kidney supports unilateralization. With data derived from patients with essential hypertension as a reference, the degree to which (V-A)/A is greater than 0.48 can be used to estimate the degree of renal ischemia, using Fick's principle. Corroborative evidence to support these three criteria can be developed from the blood pressure response to angiotensin blocking drugs or to antirenin therapy with propranolol. Clinical analysis validates these criteria to identify curable hypertension from unilateral renovascular or parenchymal disease. In patients with either occult or overt bilateral renal disease, the volume factor often predominates and is expressed by some suppression of plasma renin levels. Continued

Aldosterone↗
PubMed1975

Radioimmunoassay of plasma renin activity.

Plasma renin activity is quantitated by measuring the rate of angiotensin generation during incubation of plasma renin with endogenous renin substrate. The angiotensin is quantitated by radioimmunoassay. Our studies indicate that the incubation step is best carried out in undiluted plasma at the pH optimum for renin (pH 5.7) in the presence of EDTA, neomycin, and DFP or PMSF. By using these conditions, incubation of low-renin samples can be prolonged for up to 18 hr, because angiotensinases and converting enzyme are completely inhibited. Accuracy is enhanced by prolongation of the incubation time, which results in more angiotensin and eliminates the need for blank subtraction. Incubation at pH 7.4 is disadvantageous because of lower rates of generation of angiotensin 1, because of the inability to maintain pH constant without addition of strong buffer, and because the incubation step cannot be prolonged beyond 3 hr. Dilution of plasma is undesirable because it results in a slower reaction rate due to dilution of both enzyme and substrate, and it is not possible to correct for the effect of substrate dilution. The radioimmunoassay of angiotensin I presents few unusual problems. The volume of plasma assayed should be 20 muI or less. If blank subtraction is used, antibodies should be screened to determine the extent to which they bind nonspecific substances in plasma, and then to ascertain whether the blank is entirely additive when angiotensin is added to it. Assay sensitivity is an important issue, since approximately 30 percent of patients with essential hypertension have subnormal plasma renin activity. In a study of three different commercial kits we found that many low-renin samples were undetectable and major fractions could not be discriminated with precision or consistency from normal renin samples. However, the incubation conditions can be easily modified, so that an 18-hr incubation can be utilized and then low-renin samples can be detected with the same degree of accuracy as those with normal plasma renin activity.

Angiotensin II↗
PubMed1975

"Prorenin" in human plasma?

An increase in plasma renin activity was demonstrated in plasma from normal subjects and most patients with essential hypertension after prolonged storage of the plasma at -20 degrees C. No change in renin substrate concentration was observed after storage for 12 months, and the rate of angiotensin generation during incubation with a fixed amount of added human renin was not increased. It therefore seems unlikely that the observed increase in renin activity was due to changes in plasma activators or inhibitors. The data are consistent with the activation of an inactive form of renin, tentatively called "prorenin" in normal subjects averaged from 1 to 2 ng/ml/hr, and did not change during sodium deprivation. However, three of four patients studied who had low-renin essential hypertension secreted abnormally large amounts of "prorenin" in response to sodium depletion. In these patients, subsequent sodium administration was associated with a return of "prorenin" to baseline levels.

Angiotensin II↗