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Biomedical subjects

J E Sealey

Publications and source records attributed to J E Sealey.

180 records · Page 10Linked to original sources
PubMedDate not supplied

Changes in glomerulotubular dimensions, single nephron glomerular filtration rates and the renin-angiotensin system in hypothyroid rats.

Glomerular diameters (GD) and lengths of attached proximal convoluted tubules (TPL) were measured in nephrons dissected from the superficial (S), intermediate and juxtamedullary (JM) cortex (7-15 each) of acid-macerated kidneys of weight-matched (E) euthyroid and (H) hypothyroid (2-6 months after radioiodine treatment or thyroidectomy) male Sherman-Wistar rats. Incoordination of growth in H rats was evident in a more marked retardation in kidney than in total body growth. A similar incoordination of microstructural growth was evident in maintenance or GD within normal limits with respect to body weight while attached TPL fell 23% on the average below control values relative to body weight. These changes affected the total nephron population uniformly. As a result, GD/TPL in all nephrons increased significantly (p less than 0.01), by 27% in S and by 29% in JM nephrons. The glomerulotubular dimensional imbalance was associated with a marked and uniformly distributed reduction in single nephron glomerular filtration rate (ferrocyanide method), by 36% in S and JM nephrons. Plasma renin activity fell within normal limits while plasma renin substrate was decreased to 56% of control values. These findings are construed as evidence that growth retardation in hypothyroid rats affects the parenchyma of the kidney (and perhaps other viscera) more than the vasculature.

Angiotensin II↗
PubMedDate not supplied

Regional distribution of the angiotensinogens in human placentae.

Angiotensinogen is the substrate for the enzyme renin. In addition to the well-characterized low molecular weight forms of angiotensinogen, a high molecular weight form (HMrA) comprises about 15 per cent of the total angiotensinogen in plasma of pregnant women. In the current study the different forms of angiotensinogen were quantitated in different regions of the placenta. The highest concentration of total angiotensinogen was found in the chorion laeve followed by the amnion. It was found that HMrA was the major form of angiotensinogen in all regions of the placenta, accounting for 72, 67, 63, and 59 per cent of the total angiotensinogen in the chorion laeve, chorion plate, amnion, and chorion frondosum, respectively. There was a significant correlation between the distribution of total renin and HMrA. This data in conjugation with previous data indicate that HMrA should be considered a significant component of the renin angiotensin system in the human pregnant state. It is suggested that HMrA may be a component of a tissue specific renin angiotensin system that occurs in the placenta.

Amnion↗
PubMedDate not supplied

Purification, sequencing and synthesis of natriuretic and vasoactive rat atrial peptide.

Mammalian atria contain potent natriuretic and diuretic substances which exist in high- and low-molecular-weight forms and which appear to be associated with atrium-specific granules. The natriuretic effect of atrial extract is largely accountable for by its renal haemodynamic effects; atrial extracts also antagonize hormone- and non-hormone-induced contraction of the isolated rabbit aorta and isolated rat kidney vasculature. We have completely purified a low-molecular-weight natriuretic and vasoactive substance from rat atria and characterized it as a 24-amino acid peptide. Synthetic peptide, produced by solid-phase synthesis, mimics biological effects of crude atrial extract and purified peptide; its activity is enhanced by slow oxidation, suggesting a disulphide (Cys 4-Cys 20) configuration for the native peptide. If secreted into blood, this atrial natriuretic peptide (' auriculin B') could be a novel peptide hormone of considerable importance to renal and cardiovascular homeostasis.

Amino Acid Sequence↗
PubMedDate not supplied

Low and high renin essential hypertension: a comparison of clinical and biochemical characteristics.

Based on a renin-sodium nomogram, patients with essential hypertension can be divided into low, normal and high renin subgroups. To define more clearly the clinical and biochemical characteristics of the two extreme groups, data of 83 patients with low renin essential hypertension were compared with those from 42 patients with high renin essential hypertension. In a further analysis, data or 27 age-and sex-matched patients from these two groups were compared with data from 27 matched subjects from a normotensive control group. Compared with high renin patients, low renin patients more frequently are female, older, and have higher systolic blood pressures and pulse pressures. The latter two characteristics are age-related. The similarity of duration of hypertension in both groups and the lack of correlation between age and plasma renin activity suggest that low renin hypertension is a separate entity rather than just a later phase of the same disease. Patients with low renin hypertension had better renal function than high renin patients or normotensive control subjects. High renin patients showed signs of hemoconcentration: hemoglobin, hematocrit, and total protein were higher than in low renin patients and normotensive controls. A significant difference between the slopes of the regression lines relating renin activity and sodium excretion for the two renin subgroups indicates that renin release in low renin patients is less sensitive to alterations in sodium balance. Both groups of patients had similarly elevated aldosterone levels, suggesting an increased sensitivity of aldosterone secretion to angiotensin II in low renin hypertensives. The relationship between aldosterone and potassium excretion was similar in both groups, indicating a comparable mineralocorticoid sensitivity.

Adult↗
PubMedDate not supplied

Use of first-dose response or plasma renin activity to predict the long-term effect of captopril: identification of triphasic pattern of blood pressure response.

A triphasic pattern of blood pressure response was observed in 13 of 26 patients treated with captopril. Pressure fell after the first dose in all but 3 patients, reaching a minimum by 90 min. Over the next several days, pressure either remained at this level (n = 13) or returned towards control levels (n = 13) even with increased dosage. Blood pressure then fell gradually, usually reaching a level by 10 days that was equal to or slightly lower than that after the first dose. The secondary rise in blood pressure was more frequent and pronounced in patients who had larger initial responses and higher renin levels. The transient increase in pressure could not be explained by failure of blockade of the renin system, since aldosterone excretion was maximally suppressed by the second day of treatment. The data indicate that both the blood pressure response to the first dose and the renin level can be used to predict the long-term response to captopril.

Aldosterone↗
PubMedDate not supplied

The substitutive role of ACTH in supporting aldosterone response to head-up tilt during acute renin suppression in patients with essential hypertension.

The relative contribution of the renin-angiotensin system, adenocorticotrophic hormone (ACTH) and plasma electrolytes in the response of plasma aldosterone to 30 minutes of 65 degrees head-up tilt was assessed in 10 essential hypertensive patients. Studies were carried out before and during acute blockade of renin release by propranolol, ACTH suppression by dexamethasone and combined renin and ACTH blockade. In control studies orthostasis induced significant increases only in plasma renin activity and aldosterone. In contrast, when the renin response to tilt was acutely suppressed by propranolol administration, the aldosterone response was nonetheless maintained but now appeared to be under ACTH control, since concurrent increases in cortisol were observed. During ACTH suppression aldosterone increased during tilt and so did renin. However, during combined ACTH and renin blockade aldosterone failed to increase during tilt. These studies suggest that the aldosterone secretory response to head-up tilt is normally mediated by the renin-angiotensin system but, when the renin response is suppressed, an ACTH response is elicited which assumes a backup role. However, when these two systems are blocked other factors appear unable to respond during tilt to support a normal aldosterone response.

Adrenergic beta-Antagonists↗
PubMedDate not supplied

Detection and isolation of inactive, large molecular weight renin in human kidney and plasma.

Estimation of apparent molecular weight (mw) of inactive renin by gel filtration of human plasma was found to be inaccurate when "acid activation" or "cryoactivation" was used for detection; recoveries were only 5% to 20%. Trypsin activation produced greater recoveries, but the apparent elution volume of inactive renin varied with the concentration of trypsin used; the presence of trypsin inhibitors increased trypsin requirements to 100 to 200 micrograms/ml in the 60,000 dalton region, while low protein concentration in the 50,000 dalton region resulted in destruction of renin by as little as 10 microgram/ml trypsin. A composite trypsin-activated inactive renin peak corresponded to a mw of 56,000 +/- 1500 daltons (104% to 120% recovery), while active plasma renin was 48,000 +/- 2000 daltons. When this prorenin-like substance was isolated by affinity chromatography, it was found to be completely inactive. It was also nearly free of trypsin inhibitors, so that a single trypsin concentration correctly identified and confirmed the elution characteristics of inactive renin peak following gel filtration. The apparent mw of trypsin-activated inactive renin was slightly lower (52,000 daltons) than that of inactive renin. Human renal cortex was also found to contain a trypsin-activable form of renin. Like plasma inactive renin, it could be isolated by chromatography on Cibacron blue-agarose (Affi-Gel blue). It was found to be completely inactive following passage over a pepstatin affinity column. This inactive renal renin, as well as a similar substance in perfusate of normal human kidney, had a mw of 49,500 +/- 1000, while active renal renin was 39,500 +/- 500. Trypsin-activated inactive renal renin had a mw of 46,500 +/- 500; its pH optimum was identical with that of active renal renin, and it no longer bound to Cibacron blue-agarose. We conclude that both human plasma and kidney contain an inactive, prorenin-like substance that can be detected reliably by trypsin activation. There appear to be slight differences in the apparent mw of plasma renins and kidney renin, but the similarity of other characteristics suggests that the inactive, prorenin-like substances in renal cortex, renal perfusate, and plasma may be one and the same substance.

Chromatography, Gel↗
PubMedDate not supplied

Plasma and platelet vasopressin in essential hypertension and congestive heart failure.

In this study we found that, in 31 normal subjects, close to 90% of circulating arginine vasopressin (AVP), measured by radioimmunoassay, was associated with platelets. By using routine methods of centrifugation, which do not completely separate platelets, the normal range of plasma vasopressin was higher by twofold than the normal range in platelet-free plasma prepared by differential centrifugation, which was 1.4 +/- 1.0 sd pg/ml. Platelet vasopressin was 12.9 +/- 5.7 pg/ml. Patients with congestive heart failure had, on average, an elevated platelet-free plasma AVP, as did two patients with thrombocytopenia and one with thrombocytosis. Patients with essential hypertension had slightly high levels of platelet-free plasma AVP and demonstrated an abnormal inverse relationship between platelet-free plasma AVP and serum osmolality. Immunoreactive platelet vasopressin was slightly low in patients with essential hypertension and was subnormal in patients with congestive heart failure. These studies demonstrate that platelets normally present in centrifuged plasma cause an overestimation of the plasma vasopressin levels. Until the physiological meaning of plasma and platelet-bound AVP is understood, studies of circulating vasopressin should probably assess both plasma and platelet AVP levels.

Arginine Vasopressin↗
PubMedDate not supplied

Atrial natriuretic factor inhibits angiotensin-, norepinephrine-, and potassium-induced vascular contractility.

We have previously shown that the natriuretic effect of rat atrial extract (AE) may be due, perhaps entirely, to its powerful renal hemodynamic actions. The present study was undertaken to test the hypothesis that mammalian atria contain a substance that behaves as a functional antagonist of endogenous vasoconstrictors, by examining the direct effects of AE and extensively purified atrial "natriuretic" factor on the contractile response of rabbit aortic rings to angiotensin II (AII), norepinephrine (NE), and K+-induced depolarization. Dose-response curves to AII and NE (i.e., change in tension vs log hormone concentration) were determined in the absence or presence of boiled AE or ventricular extracts (VE). Increasing concentrations of boiled AE caused a progressive right-ward shift of the AII and NE dose-response curves, whereas VE was without effect. A similar inhibitory effect was produced after extensive purification of atrial natriuretic factor by gel filtration and reversed-phase high performance liquid chromatography (HPLC). It appeared that this factor antagonized AII-induced contractility to a greater degree than that of NE. Moreover, the partially purified factor also inhibited the contraction induced by depolarization with 15 mM KCl in a concentration-dependent manner. These studies show that a substance present in the atria, but not ventricles, blocks both hormone- (receptor) and depolarization- (nonreceptor) induced vasoconstriction in aortic rings. Moreover, this antagonism is retained following extensive purification of an atrial factor that induces natriuresis in the intact rat and isolated rat kidney, suggesting that both the vasoactive and natriuretic properties of AE may reside in a single substance.(ABSTRACT TRUNCATED AT 250 WORDS)

Angiotensin II↗
PubMedDate not supplied

Kidney is the only source of human plasma renin in 45-kb human renin transgenic mice.

Prorenin is expressed in certain extrarenal tissues, but normally only the kidneys process prorenin to renin and secrete renin into the circulation. Although transgenic animal lines containing the human renin (hREN) structural gene with either 0.9-kb or 3-kb 5'-flanking DNA express the transgene appropriately in renal juxtaglomerular cells and secrete hREN into the circulation, the source of the circulating renin is not known. In the present study, we observed that 13-kb hREN transgenic mice that contain the structural gene and 0.9-kb 5'-flanking DNA express hREN mRNA in many unusual tissues. We also observed that circulating hREN levels in 13-kb hREN mice increased after bilateral nephrectomy. These results suggested that the hREN gene is expressed at inappropriate locations where prorenin might be processed to renin. To determine if more distal sequences flanking the hREN gene might contribute to cell and tissue specificity, we used a 45-kb hREN genomic fragment that contained the structural gene and about 25-kb 5'- and 8-kb 3'-flanking DNA sequences to generate 3 separate transgenic lines that contained the intact transgene sequences. Ribonuclease protection assays revealed a much narrower tissue distribution of hREN expression than in the 13-kb hREN transgenic mice. In each 45-kb hREN line, hREN mRNA was present only in the kidney, adrenal, lung, eye, ovary, and brain. Moreover, 24 hours after nephrectomy, human plasma renin fell to very low levels, indistinguishable from those of nontransgenic littermates, indicating that their circulating hREN is of renal origin. These studies suggest that sequences flanking the structural gene, missing from previous hREN transgenic lines, suppress renin gene expression at inappropriate extrarenal sites where cellular proteases, to which prorenin is not normally exposed, could convert prorenin to renin, resulting in abnormal secretion of renin into the plasma.

Animals↗
PubMedDate not supplied

Biochemical similarity of partially purified inactive renins from human plasma and kidney.

Inactive renin was partially purified from 4.5 liters of human plasma (502-fold, specific activity 0.8 X 10(-3) Goldblatt units/mg protein) and from 207 g renal cortex (103-fold, 52 X 10(-3) Goldblatt units/mg). In contrast to active renin, inactive renin from each source bound to Cibacron blue-agarose and was unable to bind to pepstatin-Sepharose. Both plasma and renal inactive renin had weaker affinity for anion-exchange resins than the active form, both bound to concanavalin A-Sepharose and were eluted with carbohydrate, and both bound tightly to hydrophobic gels. Each substance could be isolated in a completely inactive form during small-scale pilot studies, but "spontaneous" activation did occur, to a limited degree, during large-scale purification; this was possibly due to a plasma serine protease that fractionated with inactive renin during the initial purification steps. Both plasma and renal inactive renin were activated irreversibly by trypsin. Following activation, each substance lost it ability to bind to Cibacron blue-agarose. Each could be activated fully by acidification at 4 degrees C, but this activation was reversed during subsequent incubation at higher temperature and pH. There was no evidence of acid protease activity in either preparation. Activated inactive renin from both plasma and kidney were identical to partially-purified active renal renin in terms of pH optimum (pH 5.5-6.0) and reaction kinetics (Km 0.8-1.3 microM) with homologous angiotensinogen, noncompetitive inhibition by pepstatin (ki 2.5-3.5 microM), and an identical inhibition profile by monospecific antirenin antibodies. These results suggest that inactive renin from plasma and kidney may be the same substance and that their activated forms are similar to the endogenously produced active enzyme, consistent with the possibility that inactive renin is a precursor of circulating active renin.

Chromatography, Affinity↗