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Biomedical subjects

J D Barrett

Publications and source records attributed to J D Barrett.

At least 37 records · Page 2Linked to original sources
PubMed1987

Stimulation of brain and aortic renin substrate by central administration of steroids in the rat.

The influence of central and peripheral injections of dexamethasone and 17 beta-oestradiol on plasma, brain and aortic renin substrate was studied in the rat. Whereas intraperitoneal or intravenous injection of these steroids raised renin substrate in plasma, brain and the aorta, intraventricular injection raised it only in the brain and aorta. Bilateral nephrectomy produced results equivalent to those observed following intraperitoneal administration of steroids. Dissociation of the plasma and tissue renin-substrate levels in response to central administration of steroids indicates local synthesis of this protein, possibly under central control.

Angiotensinogen↗
PubMed1987

Tryptic generation of an angiotensin binding substance.

Following trypsin treatment of rat or human plasma, the level of angiotensin I, generated by renin, can be significantly underestimated by radioimmunoassay due to tryptic generation of an angiotensin binding substance. The precursor of the binding substance (void volume-AcA 44 gel) was converted by trypsin to 45K. Analogous to PRC methodology, known concentrations of angiotensin I were added to control and trypsin treated human plasma after the renin incubation step to determine the influence of the binding substance on the measured levels of generated angiotensin I. Using this technique, renin levels in trypsin exposed plasma were approximately two fold higher than when measured by single point conventional assay. If plasma levels of the binding precursor change in response to renin stimulation or suppression, its activation during the trypsin treatment step of the renin assay may explain the relative lack of change of inactive renin observed following numerous in vivo maneuvers.

Angiotensin I↗
PubMed1986

Renin substrate and the renin-angiotensin system in hog tissues.

The individual components of the renin-angiotensin system has been identified in numerous tissues. In this study we have examined whether a functional renin-angiotensin system is operative in several hog tissues including brain, aorta, and liver. The contribution of tissue renin substrate to the rate of local angiotensin generation was also assessed. Electrophoretic differences in plasma and tissue renin substrates, indicating structural differences, were employed as an index of independence of the tissue system from that of the peripheral circulation. Our results indicate that all tissues studied had the potential to locally generate angiotensin and that renin substrate limited to rate of the renin reaction in these tissues. Electrophoretic parameters, polyacrylamide gel electrophoresis, and isoelectric focusing suggest that the tissue renin systems are of local origin. The potential magnitude of local angiotensin production is such that tissue renin-angiotensin systems may significantly contribute to the control and regulation of blood pressure and other regulatory mechanisms influenced by angiotensin.

Angiotensin I↗
PubMed1986

The influence of acute stress on active and inactive renin in the rat.

The purpose of this study was to determine the influence acute stress on the plasma levels of active and inactive renin in the rat. Active and inactive plasma renins were measured in calm unanesthetized normal Wistar rats (indwelling catheter) and compared to values obtained after handling, anesthesia and decapitation. All maneuvers resulted in an increase of active renin. Only anesthesia significantly reduced inactive renin. It is concluded that acute stress can significantly change the ratio of active and inactive renins in rat plasma. These changes must be taken into consideration when the influence of "physiological or pharmacological" alterations of these enzymes are under investigation.

Acute Disease↗
PubMed1985

Studies of renin activation and regulation of aldosterone and 18-hydroxycorticosterone biosynthesis in hyporeninemic hypoaldosteronism.

In an attempt to evaluate deficiencies of renin activation and adrenal zona glomerulosa biosynthesis in hyporeninemic hypoaldosteronism (HH), we studied active and inactive renin (AR and IR, respectively) responses to the dopamine antagonist metoclopramide, furosemide, and graded dose infusion of ACTH in 10 HH patients and 6 normal subjects. In HH patients, AR levels, but not IR levels, were decreased relative to normal values. While normal subjects had an AR response to metoclopramide, the HH patients did not. The AR response to furosemide in HH patients was markedly diminished compared to that in normal subjects. Plasma cortisol and corticosterone levels were in the normal range, but the zona glomerulosa products 18-hydroxycorticosterone (18-OHB) and aldosterone (Aldo) were low in HH patients. Plasma 18-OHB and Aldo responses to metoclopramide and furosemide were diminished, but cortisol and 18-OHB responses to ACTH were normal in the HH patients. Our observation that 18-OHB and Aldo responses to metoclopramide were diminished refutes the possibility that excessive adrenal zona glomerulosa dopaminergic activity could account for reduced biosynthesis of 18-OHB and Aldo in HH patients. Our results appear most consistent with the concept that the primary etiological factor in the HH syndrome is impairment of renal activation of renin.

18-Hydroxycorticosterone↗
PubMed1984

Heterogeneity of renin substrate released from hepatocytes and in brain extracts.

Renin substrate was characterized in incubation medium of isolated hepatocytes, plasma, and brain extracts of the rat by isoelectric focusing and polyacrylamide gel electrophoresis. The isoelectric focusing (IEF) profile of renin substrate released into incubation medium of rat hepatocytes demonstrated two peaks with isoelectric points (pI) of 4.1 (minor peak) and 4.6 (major peak). Extracts of normal rat brain also showed two forms (pI 4.6 major form, and pI 5.1 minor form). In contrast, normal rat plasma contained a single broad peak of substrate with pI 4.5. On polyacrylamide gel electrophoresis (PAGE), the hepatocytes medium and brain extracts contained forms of substrate with reduced mobility as compared to the plasma form. Intraperitoneal injection of 17 beta estradiol (1 mg) or bilateral nephrectomy significantly elevated renin substrate levels in plasma and increased its release from hepatocytes, however, no change in the IEF or PAGE profiles was evident. There was no remarkable change of substrate concentration in the brain following these treatments. Molecular weights of renin substrate were 60,000-65,000 from all preparations. It remains to be established whether the different forms of renin substrate from hepatocytes represent precursor forms of circulating plasma substrate. The presence of distinct forms of brain renin substrate and the lack of an increase in brain renin substrate following nephrectomy or estrogen treatment suggest local synthesis and support the postulate of an independent renin-angiotensin system in the central nervous system.

Angiotensinogen↗
PubMed1984

Interaction of prostaglandin E2 and beta-adrenergic catecholamines in the regulation of uterine smooth muscle motility and adenylate cyclase in the rat.

Prostaglandin E2 (PGE2) increased the force of the spontaneous contractions of the rat myometrium and decreased the sensitivity of the uterus to the relaxing effects of the specific beta-adrenergic catecholamine agonist isoprenaline. Prostaglandin E2, at concentrations above 10 mumol/l, increased cyclic AMP production by intact muscle strips. The muscle strips were far more sensitive, however, to the inhibitory effect PGE2 had on isoprenaline-dependent cyclic AMP production (threshold less than 0.001 nmol/l). Both PGE2 and isoprenaline stimulated adenylate cyclase activity of a myometrial subcellular (particulate) fraction in a guanyl nucleotide-requiring manner. When present in saturating concentrations (100 mumol/l), the stimulatory effects were not additive, suggesting that the receptors for the two agonists competed for the same catalytic subunit of adenylate cyclase or for the same guanyl nucleotide-requiring factor which couples receptors and enzyme. If muscle strips were incubated with PGE2 before the preparation of the adenylate cyclase-containing particulate fraction, the enzyme became less responsive to stimulation by guanyl nucleotide and by isoprenaline and PGE2 in the presence of guanyl nucleotide. The PGE2 receptor may therefore interact with the beta-adrenoreceptor to inhibit isoprenaline-dependent cyclic AMP production by intact muscle cells by desensitizing adenylate cyclase, possibly at the level of the guanyl nucleotide-dependent coupling step.

Adenylyl Cyclases↗
PubMed1984

Renal effects of nitrendipine monotherapy in essential hypertension.

Ten male patients with essential hypertension were studied on a constant diet (100 mEq of sodium daily) while on placebo, immediately following a 20-mg oral dose of nitrendipine, and during 1 week of nitrendipine therapy (10 mg twice daily). After 2 weeks of outpatient follow-up on 20-40 mg nitrendipine daily, the patients were readmitted and restudied with the same protocol. Glomerular filtration rate, effective renal blood flow, blood volume, and cardiac output were determined isotopically. Free water clearance and osmolar clearance following a water load were also measured. Twenty-four-hour urinary creatinine and electrolyte excretion were measured during the hospitalization periods. Blood pressure decreased significantly during the acute and chronic periods when compared to placebo. During the first 7 days of nitrendipine treatment, urinary sodium excretion increased significantly from control, and a mean deficit of 148 +/- 7 mEq (p less than 0.001) was calculated. There was a mean weight loss of 1.0 +/- 0.1 kg (p less than 0.05) after a week of treatment. Glomerular filtration rate, renal blood flow, blood volume, cardiac output, plasma renin activity, plasma catecholamines, and urinary aldosterone remained unchanged from control in both the acute and chronic periods. Compared to the placebo period, free water clearance (1.8 +/- 0.6 versus 2.9 +/- 0.5 ml/min; p less than 0.05) and osmolar clearance (1.9 +/- 0.3 versus 2.9 +/- 0.5 ml/min; p less than 0.05) increased significantly in the chronic period. The natriuresis and diuresis associated with nitrendipine therapy without any changes in renal function may represent a direct renal tubular effect of the drug.

Adult↗
PubMed1983

An increase in high-molecular weight renin substrate associated with estrogenic hypertension.

We have previously reported that estrogens have the potential to induce new forms of renin substrate in addition to elevating the major circulating form of this protein. One of these estrogen-induced forms had a molecular weight in excess of 150,000. In this study we have compared the plasma concentration of the high-molecular-weight renin substrate in normotensive women receiving estrogen therapy and women with estrogenic hypertension. A statistically significant elevation of this protein was associated with estrogenic hypertension and normotensive pregnant women at term. This form of renin substrate differed from the major form with respect to electrophoretic mobility, isoelectric point, and immunologic cross-reactivity. In addition, kinetic analysis indicated that this high-molecular-weight substrate has a significantly higher affinity for the enzyme renin than the major circulating form (Km = 1800 +/- 290 versus 3520 +/- 260 ng angiotensin I equivalents/ml). These results suggest that in addition to renin substrate concentration, substrate composition may play an important role in blood pressure regulation.

Adult↗
PubMed1983

Hormonal and hemodynamic effects of short- and long-term clonidine therapy in patients with mild-to-moderate hypertension.

Two studies of the responses to clonidine as the sole antihypertensive drug in the treatment of mild-to-moderate hypertension are reported. In the first, 11 patients with mild hypertension were treated with 0.1 mg clonidine twice daily for eight weeks. Those patients with "low renin" hypertension (n = 7) were noted to show an increase in plasma renin activity; the patients with "normal renin" hypertension (n = 4) tended to show a decrease. Both groups had a similar decrease in blood pressure. The changes in renin activity correlated significantly (p less than 0.01) with the small changes in endogenous creatinine clearance (r = 0.84). In the second study, 16 patients with mild-to-moderate essential hypertension were treated for three months with 0.2 mg clonidine three times daily. Blood pressure decreased from 167 +/- 4/105 +/- 2 to 140 +/- 3/90 +/- 2 mm Hg (p less than 0.01). Blood pressure changes correlated with decreases in plasma catecholamines (r = 0.61, p less than 0.001) and heart rate (r = 0.78, p less than 0.001). No significant changes in cardiac output, blood volume, renal blood flow, or glomerular filtration rate were noted. Clonidine is an effective and safe therapy when used as the sole medication in treating mild-to-moderate hypertension.

Adult↗
PubMed1983

The renin-angiotensin system in association with hyperreninaemic hypoaldosteronism in neoplasia induced hypercalcaemia.

The renin-angiotensin system was examined in Fischer rats at 7, 11 and 14 days after Leydig cell tumour transplantation, and in age matched controls. Mean arterial blood pressure (MAP), active plasma renin and serum calcium were higher (P less than 0.01) in the tumour transplant rats than in the controls at 11 days after transplantation. There was a positive correlation of both active renin and MAP with serum calcium at this time. Although inactive renin levels were elevated in the tumour transplanted rats, the ratio of inactive to active renin was decreased in comparison to controls. Plasma norepinephrine, active renin and plasma angiotensin II were higher in tumour rats at 14 days. Nevertheless, basal levels of aldosterone and MAP as well as aldosterone responses to graded infusion of angiotensin II, ACTH and KCl were decreased in the tumour rats at 14 days. Moderate hypercalcaemia (day 7 and 11), induced by Leydig cell transplantation in the Fischer rat, is associated, therefore with elevated blood pressure which appears to be related, in part, to activation of the renin-angiotensin system. However, severe hypercalcaemia (day 14) was associated with hypotensive hyperreninaemic hypoaldosteronism state.

Adrenocorticotropic Hormone↗
PubMed1982

Clonidine, a centrally acting sympathetic inhibitor, as monotherapy for mild to moderate hypertension.

Sixteen patients with uncomplicated essential hypertension were treated with 0.2 mg of clonidine three times daily as the sole antihypertensive drug. Blood pressure decreased from 167 +/- 4/105 +/- 2 to 139 +/- 3/89 +/- 2 mm Hg (mean +/- standard error of the mean) after 1 week (p less than 0.001) and remained at 140 +/- 3/90 +/- 2 mm Hg after 3 months of therapy. There were no significant changes in cardiac output, blood volume, renal blood flow or glomerular filtration rate during clonidine therapy. Clonidine significantly decreased plasma catecholamines and there was a linear correlation between the change in blood pressure and decreases in plasma catecholamine concentration (r = 0.61, p less than 0.001). There was also a significant correlation between the decreases in heart rate and blood pressure (r = 0.78, p less than 0.001). It is concluded that clonidine can be used effectively and safely as the sole agent in the treatment of mild to moderate hypertension.

Adult↗
PubMed1982

Hormonal changes associated with hypertension in neoplasia-induced hypercalcemia.

Neoplasia-induced hypercalcemia in the Fischer rat results in hypertension 1 wk after Leydig cell tumor transplantation. Systolic blood pressure, plasma catecholamine, prolactin, plasma renin activity (PRA), and aldosterone responses to immobilization stress were evaluated in Fischer rats 10 days after tumor transplantation and in age-matched nontransplanted controls. Basal systolic blood pressure, norepinephrine, and PRA levels at 10 days after tumor transplantation were higher in association with elevated calcium levels in tumor-transplanted rats than in controls. Systolic pressure, norepinephrine, and epinephrine responses to immobilization stress were greater in the hypercalcemia 10-day transplanted rats. Although basal levels of prolactin and aldosterone were similar in the two groups. These observations suggest that elevated levels of the vasoactive hormones norepinephrine and angiotensin may play a pivotal role in development of hypertension in association with neoplasia-induced hypercalcemia. Further, neoplasia-induced hypercalcemia in the Fischer rat is associated with a relative hyperreninemic hypoaldosteronism state.

Aldosterone↗
PubMed1982

Effects of stimulation of renin release on trypsin-activable renin in rat plasma.

Little information is available concerning inactive renin in rat plasma. A renin assay method has now been developed for measurement of active and inactive renin in approximately 0.1 ml rat plasma. Trypsin treatment of plasma (5.0 mg trypsin/ml plasma for 5 min at 0 degrees C) to maximally increase the rate of angiotensin I generation did not alter the Km or pH optimum of the renin reaction. Utilizing trypsin, 79 +/- 6% of the total renin (active + inactive) in normal rat plasma is in the inactive form. In vivo stimulation of renin by restraint stress induces a reciprocal change in active and inactive plasma plasma renin, and exposure of animals to ether elevates active and total renin, whereas inactive renin shows a small but nonstatistical decline. Although a parallel disappearance of active and inactive renin is observed after bilateral nephrectomy of the pentobarbital-anesthetized animal, complete occlusion of the renal arteries and veins after ether-induced renin stimulation results in a significant increase of inactive renin. This suggests that possibility of formation of inactive renin from the active enzyme in high renin states. These studies indicate that the balance of active and trypsin-activable renins in rat plasma may be dependent or not only the method but also the degree of in vivo renin stimulation.

Angiotensin I↗
PubMed1982

In vitro generation of inactive renin in hypertensive human plasma.

When plasma from normal and hypertensive human subjects is incubated at pH 7.4 in the absence of angiotensinase inhibitors, a significant decline of active plasma renin occurs. The fall of active renin was more pronounced in the plasma from normotensive controls and was accompanied by a fall of total renin without change of inactive renin. In hypertensive subjects total renin levels (trypsin treatment) did not change. The fall of active renin in plasma from hypertensive subjects was due therefore to its in vitro conversion to an inactive form of renin which could be reactivated by trypsin. If reversible inactivation of active plasma renin occurs in vivo, inactivated active renin may contribute to a portion of the plasma pool of inactive renin. This form of inactive renin which may be activable in vivo would not therefore represent a renin precursor or "prorenin" of renal origin.

Cold Temperature↗
PubMed1982

Trypsin activable renin in rat plasma. Effects of acute and chronic perturbation of the renin system.

Plasma levels of active and inactive renin were measured in the rat following manipulation of renin release. In the anesthetized rat intravenous captopril or sodium nitroprusside resulted in elevation of active renin only. Neither active nor inactive renin were altered following ether anesthesia of 2 hour bilaterally nephrectomized animals. Elevated levels of active and total renin were observed in anesthetized Wistar rats that had received oral captopril for a 6 week period. Renin substrate was decreased suggesting that blood angiotensin II exerts a tonic influence on renin substrate. In sodium deplete SHR, sacrificed by decapitation, chronic captopril resulted in a significant increase of both the active and inactive form of the enzyme concomitant with blood pressure reduction. The present data further confirm the independent control of active and inactive renin in the rat.

Animals↗