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Biomedical subjects

S A Atlas

Publications and source records attributed to S A Atlas.

At least 91 records · Page 5Linked to original sources
PubMed1983

Converting enzyme inhibition to identify and treat renin-mediated or sodium-volume related forms of increased peripheral resistance in hypertension and in congestive heart failure.

Ten years of experience with three different converting enzyme inhibitors (CEI; teprotide, captopril and enalapril) in over 300 hypertensive patients reveals that CEI act largely to block renin-angiotensin mediated vasoconstriction. Thus, their effectiveness or lack of it is predicted by the baseline plasma renin measurement. Accordingly, responses to these pharmacological agents can be used to identify and quantify renin-mediated vasoconstriction in the spectrum of hypertensive diseases. The converse is also generally true. Patients failing to respond to CEI exhibit low renin values and their increased peripheral resistance appears related to other mechanisms, possibly involving a subtle increase in total body sodium. Thus, low renin states such as low-renin essential hypertension, primary aldosteronism, and anephric man exhibit little or no response to CEI. The relationship between the renin system activity and effectiveness of CEI reflects a specific interference with a particular pathogenic mechanism which is further supported by the fact that two other types of renin system inhibitors (beta-blockers and saralasin) are similarly effective or ineffective according to the operant renin profile also by studies in patients with congestive heart failure without hypertension in whom the same relationships can be demonstrated. Like hypertensives, heart failure patients exhibit a broad spectrum of renin activity values, and their pretreatment renin levels predict the responses to CEI. We have also found that plasma renin values in heart failure are dependent on sodium intake. When salt is administered, renin falls and patients then become unresponsive to CEI.(ABSTRACT TRUNCATED AT 250 WORDS)

Angiotensin-Converting Enzyme Inhibitors↗
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

Long-term efficacy of captopril in renovascular and essential hypertension.

Captopril was used in primary and long-term treatment of 40 treatment-resistant hypertensive patients. Of these, 21 had renovascular hypertension, seven unilateral and fourteen bilateral, and 19 had essential hypertension, 10 with high-renin and 9 with normal-renin profiles. All patients were off treatment when started on captopril therapy and were treated for at least 12 months, on the average for more than 2 years. The strategy of systematic drug withdrawal used to find the lowest effective dose of captopril led to average doses of 150 to 300 mg/day. A diuretic agent was added in 17 of the 40 patients when diastolic pressure remained greater than 105 mm Hg and a beta-adrenergic blocking agent was added for tachycardia or additional pressure control in 16 patients. Captopril alone was effective in 14 of the 40 patients. In all groups, mean supine and standing blood pressure levels were maintained at less than 140/90 mm Hg without evidence of decreased effectiveness over time. Control and treatment systolic pressures were higher in patients older than 50 years. For patients of all ages, systolic but not diastolic pressure during captopril treatment was higher in the supine position than standing. Plasma renin activity remained significantly elevated over time and aldosterone excretion usually decreased despite concurrent diuretic therapy. Captopril alone or in combination with a diuretic or beta-adrenergic blocking agent is effective in long-term treatment of drug-resistant renovascular and essential hypertension.

Adult↗
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↗
PubMed1981

Relationship between plasma renin and cortisol in hypertensive patients.

1. Plasma cortisol at 08.00 hours was significantly higher (P less than 0.005) in patients with high-renin essential or renovascular hypertension (22.6 +/- 1.6 microgram/100 ml) than in patients with normal-renin (15.4 +/- 1.2) or low-renin (11.9 +/- 1.2) forms of hypertension. 2. Plasma cortisol at 12.00 or 16.00 hours did not differ significantly among the three groups; thus the diurnal swing in plasma cortisol was steepest in patients with high plasma renin. 3. Among all patients studied, there was a direct relationship between 08.00 hours plasma cortisol and ambulatory plasma renin activity (r = 0.65, P less than 0.001). 4. In patients with high-renin values, 08.00 hours plasma cortisol fell by 39 +/- 6% after 10 days treatment with the converting enzyme inhibitor captopril. No consistent decreases were observed in the normal- or low-renin groups. 5. We conclude that the renin--angiotensin system may interact with the pituitary--adrenal axis to influence circulating levels of cortisol. This effect might conceivably contribute to the pathogenesis of certain high-renin states.

Circadian Rhythm↗
PubMed1981

Acute and chronic treatment of severe and malignant hypertension with the oral angiotensin-converting enzyme inhibitor captopril.

The patients with severe and 10 with accelerated or malignant hypertension were treated with the angiotensin-converting enzyme inhibitor captopril. Captopril acutely reduced blood pressure in all patients except two who had suppressed plasma renin activity. Four patients with encephalopathy showed immediate improvement after the first dose. Two patients could be withdrawn from nitroprusside infusion upon administration of captopril. Nineteen of 20 patients have remained on captopril for 12-32 months. Blood pressure is controlled in 18 and improved in two. Eleven required addition of diuretic and one addition of clonidine. The maximal antihypertensive effect of captopril with or without diuretics was evident after 3 months of continuous therapy and was associated with elevated plasma renin levels, normal aldosterone excretion and preservation of renal function. Captopril was well-tolerated, but produced occasional rash, loss of taste and proteinuria. We conclude that captopril, alone or in combination with other drugs, is effective in both the acute and long-term management of severe and malignant hypertension.

Acute Disease↗
PubMed1981

Effect of captopril and aprotinin on inactive renin.

Inactive renin (prorenin) was measured in plasma from untreated hypertensive patients after acute (60 min) administration of the angiotensin I converting enzyme inhibitor captopril, after 4 weeks of treatment with captopril, and after an acute infusion of the protease inhibitor aprotinin. Inactive renin was unchanged during acute captopril therapy despite a 4-fold increase in active renin. In contrast, after 4 weeks of treatment with captopril, inactive renin had increased 2-fold and active renin was also elevated, but to a greater degree (6-fold). Active renin was significantly suppressed by the aprotinin infusion, to about 25%, but the inactive plasma renin level was apparently unchanged. These studies demonstrate that the time course of the responses of active and inactive plasma renins are different; the inactive renin level seems to change more slowly than does active renin in response to the same stimulus. The results also show that a neutral serine protease inhibitor can rapidly reduce the circulating level of active renin. This observation is consistent with the possibility, but does not prove it, that a kallikrein-like enzyme normally activating prorenin was inhibited by aprotinin.

Aprotinin↗
PubMed1981

Contact activation of human plasma prorenin in vitro.

Acid activation of plasma prorenin occurs during dialysis to pH 3.3. and also during subsequent dialysis to pH 7.4. The latter, alkaline phase, involves Hageman factor-dependent formation of kallikrein, which in turn activates prorenin. The present study evaluates whether prorenin activation always occurs whenever kallikrein is activated in plasma. TAME esterase activity was used as a measure of plasma kallikrein activity an increase was observed during the alkaline phase of acid activation of prorenin. TAME esterase activity was absent when Hageman factor- or prekallikrein-deficient plasmas were similarly assayed and prorenin was not activated. Kaolin treatment of normal plasma rapidly increased TAME esterase activity at both 25 degrees and -4 degrees C, but no prorenin activation occurred. Similar changes in TAME esterase activity were observed in acid-treated plasma, in which setting prorenin was activated. No change in TAME esterase or renin activity occurred after addition of kaolin to acid-treated plasma deficient in Hageman factor; however, both enzymatic activities increased slightly in acidified prekallikrein-deficient plasma. Mixtures of these deficient plasmas exhibited normal kaolin activation of both TAME esterase and prorenin after acidification. Thus both Hageman factor and prekallikrein are needed for optimal contact activation of prorenin. These results demonstrate that prorenin activation does not always occur when active kallikrein is present in plasma. Prior acidification appears to be a prerequisite. Acidified prorenin may be more susceptible to cleavage; alternatively, competing substrates and/or inhibitors of kallikrein may be destroyed at acid pH, thereby permitting kallikrein to activate prorenin. Under normal conditions, activation of the plasma kallikrein-kinin system appears unlikely to result in activation of prorenin in vivo.

Dialysis↗
PubMed1980

Proteinuria during long-term captopril therapy.

Proteinuria developed in six of 81 hypertensive patients given captopril for at least four months (protein excretion, greater than 200 mg/24 hr). Two had previously elevated protein excretion. In all patients the increased protein excretion occurred by the fourth month of treatment. It subsided in four after two to nine months, despite continued therapy. In two of the four, proteinuria cleared completely within seven months after onset, while in the other two it subsided to the range of 600 mg/24 hr. However, in the remaining two patients proteinuria persisted during captopril therapy and was associated with hypoalbuminemia and hypercholesterolemia. Renal biopsy specimens showed mild membranous nephropathy in two patients, one of whom had a remittance of proteinuria during continued captopril treatment.

Adult↗
PubMed1980

An inactive, prorenin-like substance in human kidney and plasma.

1. Plasma prorenin (inactive renin), which accounts for about 70% of the total renin in human plasma, was almost completely separated from active renin by affinity chromatography on Cibacron blue F3G-A-agarose. The slight residual renin activity present in the prorenin peak can be removed on concanavalin A-Sepharose, demonstrating that prorenin is completely inactive. 2. The renin activity of both human renal cortical extract and renal perfusate increased after incubation with trypsin. This trypsin-activable renin accounted for 15 and 40% of the total renin in extract and perfusate respectively. 3. Trypsin-activable renin from both renal extract and renal perfusate was, like plasma prorenin, almost completely separated from active renin on Cibacron blue F3G-A-agarose. After additional chromatographic steps, the trypsin-activable renin from renal cortical extract was found to be completely inactive. 4. We conclude that human kidney contains, and is able to release, a trypsin-activable renin that resembles plasma prorenin. It may differ from many of the 60 000 molecular-weight forms of renin previously identified in renal extracts, since these possess considerable intrinsic renin activity and probably represent a complex of renin with a binding protein.

Angiotensin I↗
PubMed1980

Genetic differences in phenytoin pharmacokinetics. In vivo clearance and in vitro metabolism among inbred strains of mice.

Plasma phenytoin elimination rates were examined among twelve inbred strains of mice. Two populations are identified--the 'fast metabolizers' (BALB/cN, C57BL/6N, C57BL/6J, AKR/N, AKR/J and C3H/HeN) having almost exactly twice as rapid an elimination rate as the 'slow metabolizers' (CL/FR, CBA/J, DBA/2N, STAR/N, SJL/N, DBA/2J and RF/N). The difference in elimination rate between C57BL/6J and DBA/2J cannot be accounted for by dissimilarities in volume of distribution. The phenytoin elimination rate in the (C57BL/6J)(DBA/2J)F1 heterozygote is expressed as an additive trait. A good correlation exists between phenytoin elimination rates in vivo and phenytoin metabolism by liver microsomes in vitro, as determined by a newly described assay using high-performance liquid chromatography. 3-Methylcholanthrene pretreatment does not enhance phenytoin elimination or metabolism. The cytochrome P-450-mediated monoxygenase metabolism of phenytoin is not associated with the Ah locus or with coat color among progeny of the (C57BL/6N)(DBA/2N) F1 x DBA/2N backcross. Phenobarbital pretreatment enhances phenytoin elimination and metabolism in both a fast metabolizer (C57BL/6N) and a slow metabolizer (DBA/2N) strain. Phenobarbital pretreatment probably also induces non-P-450 enzymes, such as those which form the phenytoin dihydrodiol and the glucuronide and glutathione conjugates, in addition to inducing one or more forms of P-450 that oxygenate phenytoin. These data probably reflect allelic differences in a structural gene encoding for one (or more) form(s) of control cytochrome P-450 that metabolizes phenytoin, rather than allelic differences in a regulatory gene. The marked sensitivity of inbred mouse strains CL/FR and A/J and the marked resistance of STAR/N, Swiss-Webster, and C57BL/6 to phenytoin-induced cleft lip and/or palate cannot be explained by genetic differences in phenytoin elimination rates or liver microsomal metabolism in vitro, as measured by the methods described in this report.

Animals↗