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Biomedical subjects

J D Barrett

Publications and source records attributed to J D Barrett.

At least 55 records · Page 3Linked to original sources
PubMed1981

Activation of rat plasma renin.

Three distinct molecular weight species of active renin, with apparent molecular weights of more than 150,000, 65,000, and 43,000 are present in the plasma of conscious rats. After acute in vivo renin stimulation (ether anesthesia and hemorrhage), however, only the low molecular weight form could be detected. If, on the other hand, when diabutal was given and the duration of anesthesia was extended to 1 h to allow the active plasma renin level to return toward control, two species of renin were observed (greater than 150,000 and 43,000). Acid dialysis (pH 3.3) of normal plasma resulted in a significant increase in renin concentration, confirming the presence of an inactive renin (prorenin) in this species. Acid dialysis was shown to induce a decrease in the relative proportion of the high molecular weight form of the enzyme (greater than 150,000), with a concomitant increase in the 43,000 molecular weight species. Dialysis to pH 1.5 of plasma from 30-h nephrectomized rats to inactivate renin and destroy renin substrate resulted in the generation of an acid-stable factor which, when added to normal rat plasma, caused renin activation at pH 7.4. This renin- and renin substrate-free dialysate (pH 1.5) did not, however, alter the rate of angiotensin I generation when added to plasma samples devoid of inactive renin. Activation of renin in normal plasma could also be induced at pH 7.4 by the addition of plasma from nephrectomized rats which had previously been dialyzed to pH 3.3. These results indicate that the activation of renin by acid dialysis is not directly mediated by acid conditions and confirm the existence of an endogenous plasma factor which, after acid dialysis, is capable of converting inactive to active renin.

Angiotensin I↗
PubMed1981

Dopaminergic modulation of renin release.

The effect of metoclopramide, a procainamide derivative with dopamine antagonistic properties, and L-dopa on plasma renin activity (PRA) was studied in adult rats. Following an intravenous bolus of metoclopramide (200 microgram/kg) to the American Wistar rat there was a significant (p less than 0.05) elevation in PRA at 10 min and a maximum response at 30 min. There was a significant depression (p less than 0.05) in PRA at 15 through 40 min following an intravenous bolus of L-dopa (30 mg/kg). Pre-administration of L-dopa delayed and blunted the PRA response to metoclopramide. However, the PRA response to this dopamine antagonist was not altered by beta blockade with propranolol and alpha blockade with phentolamine. Administration of metoclopramide resulted in considerably greater (p less than 0.01) PRA responses in spontaneously hypertensive rats than in Wistar Kyoto (WKY) normotensive controls. Administration of L-dopa resulted in similar suppression of PRA in the two groups. These results indicate that there is a dopaminergic inhibitory control mechanism for renin secretion. Dopaminergic control of renin release appears to be altered in the spontaneously hypertensive rat.

Animals↗
PubMed1980

Angiotensin II, plasma renin and sodium depletion as determinants of blood pressure response to saralasin in essential hypertension.

To evaluate the role of the renin-angiotensin system and sodium depletion in the hypotensive response to 1-sarcosine-8-alanine-angiotensin II (saralasin), 15 male patients with essential hypertension were studied on a diet containing 120 mEq of sodium and 100 mEq of potassium per day. After a 5-day control period, all subjects had a mild pressor response to the saralasin infusion (p less than 0.01). After 5 days of the diuretic metolazone (5 mg/day), eight of the 15 patients had a vasodepressor response; these responders had a significantly greater increase in plasma renin activity and angiotensin II concentrations than did the non-responders. Sodium deficit differed markedly (p less than 0.001) between the two groups (361 +/- 121 mEq (SD) vs 52 +/- 26 mEq sodium, respectively). The addition of spironolactone (400 mg/day) for 5 days resulted in saralasin responsiveness in all but two patients, both of whom had small sodium deficits. Thus, variability in the natriuretic response to diuretics may affect saralasin testing and limit its clinical utility.

Adult↗
PubMed1979

In vitro inhibition of renin by human des-angiotensin I renin substrate.

Human des-angiotensin I renin substrate, a cleavage product of the renin reaction, was generated in plasma and from semipurified renin substrate by exhaustive incubation with renin and was quantitated by a direct RIA. An increase in the Michaelis-Menten constant of the renin-substrate reaction, from 2000 to 5000 ng angiotensin I equivalents of renin substrate/ml, with no change in maximal velocity was observed upon addition of this semipurified protein to plasma. It is suggested that this phenomenon of competitive inhibition of the renin reaction by des-angiotensin I renin substrate accounts for discrepancies in the determination of renin substrate concentration and possibly has physiological significance for feedback inhibition of angiotensin I generation.

Angiotensin I↗
PubMed1978

Partial characterization of aortic renin in the spontaneously hypertensive rat and its interrelationship with plasma renin, blood pressure and sodium balance.

1. A renin-like enzyme in aortic tissue of the spontaneously hypertensive rat was found to be a freely dissociable enzyme (saline homogenization) with an affinity for the renin inhibitor pepstatin. At neutral pH values, the enzyme was active in homologous plasma to produce angiotensin I, and therefore distinct from pseudorenin and cathepsin D. The arterial enzyme and semi-purified renal renin could not be distinguished on the basis of Km values by using homologous renin substrate 2. An inverse relationship between the aortic renin content of the spontaneously hypertensive rat and the progressive increase of systolic blood pressure was observed with age. In contrast to this strain of rat, aortic renin of the normotensive WKY strain did not decline with age. 3. Plasma renin concentration and the aortic renin content of the spontaneously hypertensive rat showed divergent changes in response to a blood pressure fall associated with acute diuretic therapy, chronic administration of hydrallazine and in some animals in response to chronic administration of propranolol. 4. A low sodium diet elevated both plasma and aortic renin and retarded the progressive increase of blood pressure in the spontaneously hypertensive rat. A high sodium diet accelerated the progress of hypertension with no effect on aortic or plasma renin. 5. Antihypertensive therapy (1--6 weeks), resulting in a lowering of conscious systolic blood pressure of the spontaneously hypertensive rat, consistently led to a decrease in aortic renin content.

Angiotensin I↗
PubMed1978

Multiple forms of human plasma renin substrate.

The objective of this investigation was to determine whether heterogeneity of plasma renin substrate could be observed in states of steroid excess and various forms of hypertensive disease. In states of stimulated renin substrate production by estrogens or glucocorticoids, multiple forms of renin substrate were apparent when stimulation was excessive. Stimulation of substrate production caused by uremia associated with hypertension showed similar results. None, or only trace quantities of the additional forms of renin substrate were evident in subjects with normal or suppressed levels of plasma renin substrate. The additional forms of renin substrate could be distinguished from the normal form on the basis of cross-reactivity with a specific antiserum to the normal form, electrophoretic mobility, and kinetic rate constants. Differences in rate constants of the various forms of plasma renin substrate may account for the altered rate of the renin reaction associated with several states of hypertension. In plasma of patients with renovascular hypertension, significant quantities of a protein which cross-reacted with the antiserum but could not generate angiotensin I were observed.

Angiotensinogen↗
PubMed1977

A direct radioimmunoassay for human renin substrate and identification of multiple substrate types in plasma.

Plasma renin substrate, a widely measured parameter of the renin reaction, is quantitated indirectly by the measurement of liberated angiotensin I upon exhaustive incubation of plasma with added renin. To overcome methodological problems of this assay system, we have developed a direct radioimmunoassay for this plasma protein using renin substrate purified from pooled plasma of normotensive subjects as the antigen. Comparison of substrate quantitated by the two assay systems (direct and indirect) indicates a 1:1 correlation with the exception of certain subjects with elevated substrate levels induced by estrogen therapy. To study the possibility of multiple substrate forms, we have made a comparison of substrate quantitated by both radioimmunoassays in conjunction with electrophoresis of plasma on polyacrylamide gel. One major form of substrate with a retardation factor (Rf) = 0.60 was found in normotensive and essential hypertensive subjects which gave a 1:1 correspondence on quantitation by the two methods. In contrast, six of 16 women on oral contraceptives demonstrated three forms of substrate (Rf = 0.16, 0.35, and 0.60) on electrophoresis. Substrate with Rf = 0.16 and 0.35 did not cross-react with the antiserum prepared against substrate from normotensive subjects, implying structural differences in these proteins.

Angiotensinogen↗
PubMed1977

Antihypertensive and renin angiotensin effects of metolazone with and without propranolol.

Renin angiotensin system parameters and blood pressure (B.P.) were followed monthly in patients with essential hypertension on metolazone, 5 mg daily for three months and with added propranolol, 40 to 160 mg, for the subsequent three months. On metolazone alone at three months, sitting B.P. declined from 166/108 +/- 14/11 mm Hg to 145/98 +/- 14/9 mm Hg (P less than 0.005). Plasma renin activity (PRA) increased from 3.9 +/- ng/ml/hr to 10.4 +/- 8.6 ng/ml/hr (P less than 0.005); plasma angiotensinogen did not change. Venous blood angiotensin I and II levels (pg/ml) rose initially but returned toward control values. A significant decline in plasma renin substrate reactivity (PRSr) in index occurred. Propranolol addition caused further lowering of only systolic B.P. and predominantly in the standing position, more marked at one month (40 mg) than at three months (160 mg). No significant further changes were observed in any of the measured parameters of renin angiotensin system, except for a rise in PRSr index concomitant with B.P. elevation at three months. Metolazone-induced changes in B.P. showed significant correlations at three months with changes in PRSr index. It is concluded that during chronic metolazone administration, the overall activity of the renin angiotensin system was diminished or unchanged. Propranolol did not inhibit metolazone stimulated PRA but did cause further decline in B.P. in the first two months, unrelated to renin angiotensin system.

Angiotensin II↗
PubMed1977

Extraction and measurement of circulating angiotensins I and II.

We describe a method for simultaneous extraction of angiotensins I and II from human blood. Blood was diluted with 10 volumes of isotonic saline containing ammonium ethylenediaminetetraacetate, and the angiotensin peptides were extracted by cation-exchange chromatography. The dilution effectively inhibits in vitro production of angiotensin I, conversion of angiotensin I to angiotensin II, and degradation of the peptides. Analytical recovery of exogenous angiotensin I or II added to whole blood in physiological concentrations was essentially complete. The extraction procedure removes blood and plasma components that interfere with radioimmunoassay of angiotensin, thus eliminating the need to correct for nonspecific interference. Circulating angiotensins I and II, measured in patients with essential hypertension before and after a week of diuretic administration, increased in parallel with plasma renin activity.

Angiotensin II↗
PubMed1976

Purification and partial characterization of human angiotensinogen.

Renin substrate was initially extracted from human plasma by (NH4)2SO4 followed by chromatography on Sephadex G-150, DEAE cellulose, calcium phosphate gel, isoelectric focusing and preparative polyacrylamide gel electrophoresis. On the basis of one mol of angiotensin per mol of substrate, the purity of the preparation is in excess of 95%. On analytical polyacrylamide gel electrophoresis in the presence of 1% sodium dodecyl sulfate or 8 M urea, the protein appears homogenous. In addition, the purified protein shows only one preciptin line against anti-normal human serum on either Ouchterlony immunodiffision or immunoelectrophoresis. The biological activity appears similar to "native" renin substrate since the Km is the same as that reported for the renin reaction in whole plasma. The molecular weight was determined as 110 000 by gel filtration and polyacrylamide gel electrophoresis; amino acid analysis of the human substrate differs from that reported for hog, especially in the Asp, Glu and Gly composition.

Amino Acids↗
PubMed1976

Dissociation of blood angiotensin II and plasma renin activity during chronic treatment in essential hypertension.

1. Plasma renin activity and circulating amounts of blood angiotensin II were measured in twenty-six patients with uncomplicated essential hypertension. 2. Measurements were made during a control period and at 1, 4, 9 and 14 weeks of diuretic treatment with metolazone or hydrochlorothiazide. 3. Linear regression analysis indicated a progressive change in the relation of plasma renin activity and blood angiotensin II. 4. During chronic diuretic therapy (beyond 14 weeks) blood angiotensin II had stabilized to low and relatively fixed values across a wide range of plasma renin activities.

Angiotensin II↗
PubMed1975

Marked elevation of plasma renin activity during post diuretic sodium conservation in furosemide stimulated subjects.

Plasma renin activity (PRA) was measured in 3 subjects during control period, after 3 days of oral furosemide (40 mg B.I.D.) and on the 2nd, 3rd and 5th days post diuresis. PRA, ng of angiotensin per ml plasma per 3-hour incubation was 8, 0.4 ng during the control period and rose to 51, 6 and 16 respectively. During the post diuretic phase, PRA rose to 99 in the first and 49 in the second subject. Urinary sodium was drastically reduced during this period. By 5th post diuretic day PRA returned to normal values. Striking elevations of PRA during intense sodium conservation are in accord with a concept of reduced Na load to macula densa stimulating renin release.

Aged↗