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Biomedical subjects

J E Sealey

Publications and source records attributed to J E Sealey.

At least 109 records · Page 6Linked to original sources
PubMed1985

Cyclical secretion of prorenin during the menstrual cycle: synchronization with luteinizing hormone and progesterone.

Plasma prorenin, a high molecular weight precursor form of renin, (renin, EC 3.4.23.15; old number, EC 3.4.99.19), was measured three times weekly in normal young women during the menstrual cycle and was related to changes in luteinizing hormone, estradiol, and progesterone. In all subjects a stable baseline level of prorenin occurred during the follicular phase. Then, simultaneously or soon after the luteinizing hormone peak, plasma prorenin consistently increased about 2-fold. Baseline prorenin ranged from 18 to 40 ng per ml per hr, and peak prorenin ranged from 35 to 65 ng per ml per hr. The maximum increase in prorenin averaged 80%. Prorenin remained elevated during the mid-luteal phase of the menstrual cycle and returned to baseline during the late-luteal phase in coordination with the decrease in progesterone. The changes in prorenin were not synchronized with changes in active renin which was significantly increased only during the mid-luteal phase. These findings suggest that prorenin may be involved in reproductive physiology.

Enzyme Precursors↗
PubMed1985

Comparison of renal vein renin activity in hypertensive patients with stenosis of one or both renal arteries.

Renal vein renin measurements were compared in 64 hypertensive patients with arteriographically documented stenoses or complete occlusion of one or both renal arteries. The characteristic pattern of curable renovascular hypertension, i.e. increased increment of renin from the ischaemic kidney with contralateral suppression of renin secretion, was seen not only in patients with unilateral stenoses, but also in most patients with bilateral stenoses. Contralateral suppression was less marked in azotemic patients. The highest increments of renal vein renin were seen when the renal artery was completely occluded. The patterns were similar following acute or chronic administration of captopril, suggesting that angiotensin II is not responsible. Increased sodium delivery to the macula densa is postulated as a possible cause of contralateral suppression.

Angiotensin II↗
PubMed1984

Whole blood viscosity as a determinant of cardiac hypertrophy in systemic hypertension.

The relationships among blood pressure (BP), blood viscosity and echocardiographic left ventricular (LV) muscle mass were evaluated in 24 patients with essential hypertension and in 13 normotensive control subjects. LV mass was greater in the hypertensive patients than in the control subjects (225 +/- 69 vs 170 +/- 31 g, p less than 0.02) as was blood viscosity at a shear rate of 104 sec-1 (4.7 +/- 0.1 vs 4.3 +/- 0.2 cp, p less than 0.005). Among the hypertensive patients, LV mass was most closely related to viscosity at 104 sec-1 (r = 0.80, p less than 0.001), whereas only weak correlations were found between LV mass and systolic or diastolic BP (r = 0.45, p less than 0.05 for both). The 14 hypertensive patients with normal LV mass had viscosity similar to that in control subjects (4.5 +/- 0.3 vs 4.3 +/- 0.2 cp), whereas viscosity was consistently increased (5.0 +/- 0.4 cp, p less than 0.02) in hypertensive patients with LV hypertrophy. Thus, increased blood viscosity may be a determinant of or a response to hypertensive cardiac hypertrophy.

Adult↗
PubMed1984

Predictive value and changes of renin secretion in hypertensive patients with unilateral renovascular disease undergoing successful renal angioplasty.

Peripheral and renal vein renin activity was measured in 46 hypertensive patients with arteriographically diagnosed unilateral renal artery stenosis before and six months after technically successful renal angioplasty. The renin-sodium profile was high in 80 percent before angioplasty, fell in all patients, and became normal or low in 85 percent after angioplasty. Renal vein renin activity, which initially showed lateralization of renin secretion to the ischemic kidney with contralateral suppression, became normal. Renal vein renin activity was more reliable for predicting the therapeutic response when expressed as the increment of renin for each renal vein over the infrarenal vena caval value (sensitivity 74 percent, specificity 100 percent) than as the ratio between the two renal veins (sensitivity 62 percent, specificity 60 percent). The predictive value of renal vein renin activity is poor when plasma renin activity is stimulated by long-term administration of captopril. These data support the usefulness and define the limitations of peripheral and renal vein renin measurements in selecting patients for treatment by renal angioplasty.

Adult↗
PubMed1984

Ca-dependent hemodynamic and natriuretic effects of atrial extract in isolated rat kidney.

The effects of rat atrial tissue extract on renal hemodynamics and fluid and electrolyte excretion were investigated in the isolated perfused rat kidney (IK). IK were perfused at a constant effective perfusion pressure of about 90 mmHg. After control clearance periods (C), extracts of rat atria (AE) or ventricles (VE) were added to the perfusate and three 10-min experimental periods followed. AE, but not VE, significantly increased (P less than 0.001) renal vascular resistance (RVR) to 133 +/- 8% of C, GFR to 201 +/- 34%, filtration fraction to 245 +/- 41%, urine flow (V) to 675 +/- 131%, fractional excretion (FE) of H2O to 336 +/- 29%, absolute Na excretion (UNaV) to 1,259 +/- 290%, FENa to 642 +/- 129%, UKV to 2,226 +/- 1,237%, and FEK to 542 +/- 119%. Despite the marked natriuresis, since GFR doubled, Na reabsorption rose from 78.3 +/- 36.3 in C to 132 +/- 36.3 mueq/min after AE. The effects of AE were immediate and lasted to the end of the perfusion. The lower the initial control GFR, the larger was the AE-induced increase in GFR. Perfusion with low [Ca] (0.2 mM) or verapamil (10(-5) M) severely blunted the hemodynamic, diuretic, kaliuretic, and natriuretic effects of AE. AE decreased rather than increased the RVR when IK were perfused with vasoconstrictors such as angiotensin II, norepinephrine, or vasopressin. The results demonstrate that AE acts directly on the kidney, eliciting powerful Ca-dependent hemodynamic and natriuretic responses. The natriuresis induced by AE can be accounted for, at least in part, by its renal hemodynamic effects rather than by the presence of a putative tubular natriuretic factor. The hypothesis is advanced that AE contains a substance(s) which behaves as a functional agonist/antagonist of endogenous vasoconstrictors with a preferential site of action on the efferent arterioles of the renal vasculature.

Animals↗
PubMed1984

Characterization of inactive renin ("prorenin") from renin-secreting tumors of nonrenal origin. Similarity to inactive renin from kidney and normal plasma.

Inactive renin comprises well over half the total renin in normal human plasma. There is a direct relationship between active and inactive renin levels in normal and hypertensive populations, but the proportion of inactive renin varies inversely with the active renin level; as much as 98% of plasma renin is inactive in patients with low renin, whereas the proportion is consistently lower (usually 20-60%) in high-renin states. Two hypertensive patients with proven renin-secreting carcinomas of non-renal origin (pancreas and ovary) had high plasma active renin (119 and 138 ng/h per ml) and the highest inactive renin levels we have ever observed (5,200 and 14,300 ng/h per ml; normal range 3-50). The proportion of inactive renin (98-99%) far exceeded that found in other patients with high active renin levels. A third hypertensive patient with a probable renin-secreting ovarian carcinoma exhibited a similar pattern. Inactive renins isolated from plasma and tumors of these patients were biochemically similar to semipurified inactive renins from normal plasma or cadaver kidney. All were bound by Cibacron Blue-agarose, were not retained by pepstatin-Sepharose, and had greater apparent molecular weights (Mr) than the corresponding active forms. Plasma and tumor inactive renins from the three patients were similar in size (Mr 52,000-54,000), whereas normal plasma inactive renin had a slightly larger Mr than that from kidney (56,000 vs. 50,000). Inactive renin from each source was activated irreversibly by trypsin and reversibly by dialysis to pH 3.3 at 4 degrees C; the reversal process followed the kinetics of a first-order reaction in each instance. The trypsin-activated inactive renins were all identical to semipurified active renal renin in terms of pH optimum (pH 5.5-6.0) and kinetics with homologous angiotensinogen (Michaelis constants, 0.8-1.3 microM) and inhibition by pepstatin or by serial dilutions of renin-specific antibody. These results indicate that a markedly elevated plasma inactive renin level distinguishes patients with ectopic renin production from other high-renin hypertensive states. The co-production of inactive and active renin by extrarenal neoplasms provides strong presumptive evidence that inactive renin is a biosynthetic precursor of active renin. The unusually high proportion of inactive renin in plasma and tumor extracts from such patients is consistent with ineffective precursor processing by neoplastic tissue, suggesting that if activation of "prorenin" is involved in the normal regulation of active renin levels it more likely occurs in the tissue of origin (e.g., kidney) than in the circulation.

Adult↗
PubMed1983

Divalent cations in essential hypertension. Relations between serum ionized calcium, magnesium, and plasma renin activity.

We studied the relation of plasma renin activity to serum levels of ionized calcium and magnesium in 102 normotensive patients and in 98 patients with essential hypertension who were divided into low-renin, normal-renin, and high-renin groups. Serum magnesium levels were higher in patients with low-renin hypertension and lower in patients with high-renin hypertension than in those with normal-renin hypertension (P less than 0.025 for both comparisons) or in normotensive controls (P less than 0.005, P less than 0.05, respectively). In contrast, serum levels of ionized calcium were lower in patients with low-renin hypertension and higher in patients with high-renin hypertension than in those with normal-renin hypertension (P less than 0.001, P less than 0.05, respectively) or in normotensive controls (P less than 0.001, P less than 0.05, respectively). Altogether, the range of plasma renin activity in essential hypertension shows a continuous negative correlation with the serum magnesium level (r = -0.60, P less than 0.001) and a positive correlation with the serum ionized calcium level (r = 0.44, P less than 0.001). Accordingly, plasma renin activity in hypertension may reflect or contribute to changes in calcium and magnesium fluxes across cell membranes.

Calcium↗
PubMed1983

Suppression of the renin-angiotensin system by intravenous digoxin in chronic congestive heart failure.

Recent studies have demonstrated that therapy with digitalis preparations may be of inconsistent benefit in the treatment of chronic congestive heart failure. One explanation may be a varying effect on vasoconstrictor hormones, as digoxin has been shown to suppress plasma renin activity in normal and hypertensive persons. Therefore, the effect of short-term digoxin administration on plasma renin activity and plasma aldosterone in six patients with compensated, severe, chronic congestive heart failure was evaluated. Intravenous administration of digoxin (0.50 mg) resulted in a reduction of plasma renin activity from 4.3 +/- 0.9 to 2.0 +/- 0.9 ng/ml per hour and plasma aldosterone from 34 +/- 16 to 14 +/- 6 ng/dl (both p less than 0.05). Maximal response occurred at three hours after administration, with return to baseline by seven hours. Therefore, evaluation of the role of digitalis in chronic heart failure requires consideration of its direct or indirect effect on angiotensin-mediated vasoconstriction and aldosterone-mediated sodium retention, as well as other neurohormonal mechanisms of vasoconstriction.

Adult↗
PubMed1983

Prorenin in plasma and kidney.

Circulating prorenin is an enzymatically inactive form of renin, also present in kidney, which can be activated in vitro. Its biochemical properties and physiological behavior suggest that it may be a biosynthetic precursor of active renin. However, in contrast to typical prohormones, the normal plasma concentrations of prorenin are much higher than the active hormone. The purposes and functions of prorenin are unclear. It may have no further role after its secretion into the circulation. On the other hand, it may be a transport form of renin that can enter or exit cells more easily than the active form. It is also possible that the activity of the renin-angiotensin system may be regulated by the conversion of prorenin to renin in the kidney (which may be under beta-adrenergic control) or at other possible sites. Irreversible activation of prorenin appears to be a proteolytic process. In addition, acidification causes reversible activation, perhaps through a change in molecular conformation. Such reversible activation might occur in vivo by unknown mechanisms. Future studies are needed to define the biochemical processes by which increased physiological demand for renin is translated into the production of more active enzyme.

Adrenergic beta-Antagonists↗
PubMed1982

Renin subgroups in essential hypertension.

A nomogram based on the relationship between plasma renin activity and urinary sodium excretion in normal subjects has been used to classify 956 patients with essential hypertension into low, medium and high renin subgroups. Patients with low renin hypertension (27 percent of all patients) were older (P less than 0.001) than patients with medium or normal renin hypertension. They also contained more women (P less than 0.01) and had higher systolic blood pressures than patients with medium renin hypertension. Creatinine clearance, albumin concentration and hematocrit were lower in low renin patients than in patients with medium renin activity. Serum potassium levels were lower, but urinary potassium excretion was higher in low renin patients. Most of the differences in clinical and biochemical parameters could be explained by the differences in age and male:female ratio between the subgroups. Despite lower renin values, aldosterone excretions were similar between the subgroups. Differences in renin activity and differences in aldosterone-renin ratio could not be explained by differences in age, duration of hypertension and sex ratios. Patients with low renin hypertension showed evidence of increased adrenal sensitivity to angiotensin II-induced aldosterone secretion. Patients with high renin hypertension (11 percent of all patients) were younger than patients with medium or normal renin hypertension. Other differences in biochemical characteristics between these renin subgroups included a slightly higher albumin concentration and hematocrit in patients with high renin levels. These differences and the difference in renin activity between patients with high and patients with medium renin essential hypertension could not be explained by differences in age and/or sex ratio between the two subgroups. Despite the higher renin activity, aldosterone excretion was similar between the high and medium renin subgroups. Therefore, patients in the high renin subgroup are characterized by signs of volume contraction and by a relative unresponsiveness of the adrenal gland to angiotensin II-induced aldosterone secretion. The possible role of these differences in the sensitivity of the adrenal gland in sustaining hypertension has yet to be defined.

Aldosterone↗
PubMed1982

Apparent molecular size difference between plasma and renal inactive renins.

Partially-purified inactive renins from human plasma and kidney seem to be identical in most respects except for apparent molecular size. To evaluate this difference, we determined apparent molecular weights by gel filtration with internal radiolabeled standards, using trypsin activation in the presence of benzamidine and albumin to provide reproducible detection. While there was a suggestion of a shoulder in the 50,000-dalton region of the plasma inactive renin peak, the major form (56,000) was consistently larger than that of renal inactive renin (50,000), confirming our previous observation. Since both renal and plasma inactive renins appear to be glycoproteins, based on their ability to bind to concanavalin A-Sepharose, it is possible that differences in carbohydrate composition might contribute to this discrepancy in gel filtration behavior. The striking similarity of these substances in all other respects, including inhibition of the activated forms by monospecific antirenin antibodies, makes it unlikely that they differ in primary structure.

Cold Temperature↗
PubMed1982

Quantitation of inactive renin in human and dog plasma: techniques for activation.

For human samples quantitation of inactive renin can be carried out by incubation with trypsin under defined conditions, followed by RIA of the activated renin. For dog samples we were unable to obtain evidence for the presence of inactive renin in the plasma by using trypsin, acid or cold to activate. Increases in angiotensin generation did occur with trypsin and acid but they both changed renin substrate such that the rate of angiotensin generation by exogenous renin was increased at pH 7.4, but not at pH 5.7; also following trypsin or acid treatment angiotensin I was cleaved from renin substrate by a plasma acid protease that normally does not cleave renin substrate in plasma. Therefore, for dog samples, it is important to demonstrate that an increase in the rate of angiotensin generation is indeed due to activation of inactive renin and not to changes in pH optimum of renin with angiotensinogen or to the effect of another enzyme.

Animals↗
PubMed1982

The renin system for understanding human hypertension: evidence for blood pressure control by a bipolar vasoconstriction-volume mechanism. Prorenin as a determinant of renin secretion.

A body of evidence indicates that all hypertensive phenomena ranging from mild disorders to fulminant malignant hypertension can be profitably analyzed by assessing the relative contribution of two final determinants of the arterial blood pressure--the degree of arteriolar vasoconstriction and size of the volume filling the arterial tree. The latter function is largely determined by the state of sodium balance. Renin-sodium profiling and separate testing with specific pharmacologic probes are the basic tools for quantifying these factors in individual patients. This bidimensional analysis of blood pressure phenomena has considerable practical value for identifying and treating curable renovascular and adrenocortical forms. Beyond this, the analysis provides pathophysiologic information of practical value for characterizing and treating individual patients in the whole spectrum of human hypertensive diseases including essential hypertension. This new analytical scaffold also identifies key physiologic questions for future research. About 90 percent of the circulating renin occurs in an inactive form as a possible prorenin, which could be an important regulatory point for renin release. In response to stimuli prorenin rises and falls with active renin. Beta blockade may lower active renin by blocking the conversion process. At the physiological level the activation and/or release of renin appears to be primarily determined by sodium-volume changes perceived by a distal tubular mechanism.

Adult↗
PubMed1982

Changes in active and inactive renin throughout normal pregnancy.

Active and inactive renin were measured sequentially in 16 women throughout pregnancy and again post-partum. By 12 weeks, inactive renin was elevated 14-fold and fell slightly thereafter. By 12 weeks, active renin was 3.5-fold elevated. It continued to rise in 8 patients (Group A) until term, it remained stable in 6 (Group B) and in 2 it was quite variable. Between 12 and 32 weeks PRA and plasma aldosterone increased in Group A from 7.0 to 17.1 ng/ml/hr, and 20.0 to 95.7 ng/dl respectively and both were unchanged in Group B (6.5 to 8.1 ng/ml/hr and 26.5 to 24.6 ng/dl respectively). Inactive renin was higher in Group B than in Group A at 12 weeks (224 v 126 ng/ml/hr) but fell thereafter to the same stable but elevated level. Group A were younger (24 +/- 1.8 S.E. v. 30 +/- 2.2 years). These studies demonstrate that active and inactive renin increase early in pregnancy and remain elevated thereafter. In certain younger subjects, further increases in active renin and aldosterone sometimes occur and appear necessary for the maintenance of normal blood pressure.

Enzyme Activation↗
PubMed1982

Cultured juxtaglomerular cells cause hypertension by secreting angiotensin.

Cultured JGC contain renin, angiotensin I, angiotensin I-converting enzyme, angiotensin II, and, by implication, the entire RAS. JGC, as transplants, appear to secrete angiotensin II/III directly into the bloodstream to cause hypertension when the renal mass is reduced. There are two main phases of the hypertensive state, an angiotensin-dependent developmental phase and a non-angiotensin-dependent maintenance phase. This model may be useful in attempts to evaluate pro-hypertensive actions of angiotensin other than those due to direct systemic vasoconstriction. Certain of these actions appear to be intrarenal and include the stimulation of sodium reabsorption, a decrease in renopapillary blood flow, the stimulation of prostaglandin synthesis, and a constraint on the antihypertensive function of the RIC.

Angiotensin II↗
PubMed1982

The vasoconstriction-volume spectrum in normotension and in the pathogenesis of hypertension.

A body of evidence has been reviewed indicating that all hypertensive phenomena ranging from mild disorders to fulminant malignant hypertension can be profitably analyzed by assessing the relative contribution of two final determinants of the arterial blood pressure--the vasoconstriction and volume components. Renin-sodium profiling and the separate application of specific pharmacologic probes provide the basic tools for identifying the relative contribution of the two components. For an equal degree of hypertension, volume forms appear to exhibit better organ flow than the more vasoconstricted forms. This bidimensional analysis has provided new understanding of the pathophysiological mechanisms of the spectrum of human hypertensive diseases of practical value for the evaluation, diagnosis, and treatment of individual patients. Beyond this, the analytical scaffold identifies some key questions for future research.

Aldosterone↗
PubMed1981

Direct relationship between blood pressure and blood viscosity in normal and hypertensive subjects. Role of fibrinogen and concentration.

Blood pressure and components of blood viscosity were measured in 49 normal subjects and in 49 untreated patients with essential hypertension. Blood viscosity values measured at six different shear rates were significantly correlated with blood pressure (r = 0.432 to 0.505, p less than 0.001). Blood viscosity was higher in hypertensive patients. This was due to both higher plasma viscosity (1.29 +/- 0.08 standard deviation versus 1.24 +/- 0.05 centipoise (cPs), p less than 0.001) and increased hematocrit values (44.4 +/- 4 percent versus 41.5 +/- 3 percent, p less than 0.005). When blood viscosity was evaluated in subgroups of normal and hypertensive subjects with matched hematocrit values, it remained higher in the hypertensive patients, and the relationship between blood pressure and viscosity was still significant. Regardless of the hematocrit value, fibrinogen levels were elevated in hypertensive patients (p less than 0.006) and, in association with the increased globulin concentration, fibrinogen was largely responsible for the increased plasma viscosity in hypertensive patients. Since the viscosity of defibrinated blood was similar in normal and hypertensive subjects with matched hematocrit values, the elevated fibrinogen level also affected whole blood viscosity. Defibrinated blood viscosity and arterial pressures were not correlated. These studies demonstrate a direct correlation between blood pressure and blood viscosity among normotensive and hypertensive subjects. This relationship is, in part, due to the rheologic effects of an elevated fibrinogen level and to an increased hematocrit value. The basis for hyperfibrinogenemia in hypertensive patients is unclear.

Adult↗