Search PubMed⌕ Search

Biomedical subjects

J E Sealey

Publications and source records attributed to J E Sealey.

At least 91 records · Page 5Linked to original sources
PubMed1987

The cat: an animal model for studies of inactive renin.

Inactive renin, prorenin, is found in high concentrations in human plasma. We report herein the characteristics of trypsin-activated inactive renin from cat kidney and plasma. Cat and human plasma inactive renin were activated by similar concentrations of trypsin. As in humans, there was more inactive than active renin in cat plasma; also, inactive renin was low but detectable after nephrectomy. Trypsin-activated renal inactive renin, purified on Cibacron blue agarose and pepstatin-amino-hexyl-Sepharose chromatography, was inhibited by pepstatin and by a renin inhibitor similarly to cat and human active renins. The pH optimum of cat renin was biphasic: the higher peak of active renin was at pH 5.7, whereas that of activated inactive renin was at pH 7.5. As in humans, active and inactive plasma renin increased during sodium depletion and inactive renin increased during beta-adrenergic blockade, while active renin decreased. These results demonstrate that cat inactive renin is similar to human prorenin. Therefore, the cat may be a useful model for the study of prorenin.

Adrenergic beta-Antagonists↗
PubMed1987

Sequential changes in plasma luteinizing hormone and plasma prorenin during the menstrual cycle.

Prorenin, the enzymatically inactive biosynthetic precursor of renin, is secreted by the kidneys. However, the ovaries appear to be the source of the cyclical increase in plasma prorenin that occurs in the middle of the menstrual cycle. In this study we examined the temporal relationship between changes in plasma prorenin and LH in normal women to determine whether ovarian prorenin secretion might be stimulated by LH. Blood was collected from nine normal women daily for 7 days in the midcycle period and from six of them every 8 h on 6 of these days. Time zero was taken as the highest plasma LH value. The initial rise in LH (-24 h) preceded the initial rise in prorenin (-8 h) and the LH peak preceded the prorenin peak by 8-16 h. These sequential increases in plasma LH and prorenin occurred in the presence of high plasma estradiol levels. While LH fell in parallel with estradiol, the prorenin peak was more sustained and plasma prorenin remained above baseline at 40 and 48 h, at a time when both estradiol and LH had reached a new basal level. These results suggest that gonadotropins stimulate ovarian prorenin release. The timing of the changes in plasma prorenin and its presence in high concentrations in ovarian follicular fluid suggest that prorenin may be involved in the process of ovulation. The results also suggest that changes in plasma prorenin may determine the activity of an ovarian renin system that functions independently of circulating active renin.

Adult↗
PubMed1987

Ovarian prorenin.

We review here recent evidence that the ovaries synthesize and secrete prorenin and we explore the possible reasons why prorenin, and not active renin, is formed almost exclusively in this extra-renal site. Very high concentrations of prorenin are present in the human ovary in the fluid inside mature follicles. This ovarian prorenin appears to be secreted into the circulation since plasma prorenin increases in normal women for two to three days at mid-menstrual cycle, at the time of ovulation. No change in plasma active renin occurs at this time. Plasma prorenin increases much more at mid-cycle in women whose ovaries have been hyperstimulated with gonadotropins. Their mid-cycle increment in plasma prorenin (after hCG) is directly related to the number of ovarian follicles. Plasma prorenin also increases markedly (10-fold) in pregnant women within two weeks after conception, in parallel with the rise in endogenous hCG. The ovaries are the apparent source of the increase in plasma prorenin during pregnancy since no such increase occurred in a woman with ovarian failure who conceived after receiving a donor egg. These results suggest that the ovaries synthesize and secrete prorenin in response to stimulation by gonadotropic hormones. Future studies will investigate the potential role of ovarian prorenin in human reproductive function. We postulate the existence of a prorenin receptor which activates prorenin and, in consequence, activates a local renin-angiotensin system. The functioning of this system may be regulated by changes in prorenin and its receptor.

Animals↗
PubMed1986

Prorenin in high concentrations in human ovarian follicular fluid.

Although the kidney is a major source of prorenin, the precursor of renin, there are extrarenal sources for plasma prorenin that have not been identified. The selective increase in plasma prorenin at the time of ovulation suggested that one of these sources might be the ovary. Prorenin was therefore measured in fluid aspirated from 18 ovarian follicles and in plasma collected from three women who were undergoing in vitro fertilization. The follicular fluid contained high concentrations of prorenin that were approximately 12 times higher than plasma prorenin. The prorenin from follicular fluid was immunochemically identical to kidney and plasma prorenin. Thus, the ovary is a likely source for the ovulatory peak of plasma prorenin.

Angiotensinogen↗
PubMed1986

Prorenin as a reproductive hormone. New form of the renin system.

Prorenin, the biosynthetic precursor of renin, is synthesized by the kidneys. Herein is reviewed recent evidence that the ovaries also secrete prorenin. It was found that prorenin is present in mature human ovarian follicular fluid in extremely high concentrations and that plasma prorenin levels increase transiently in blood during the menstrual cycle at the time of ovulation. No change in plasma active renin levels occurs at this time. Plasma prorenin level also increases 10-fold in pregnant women very soon after conception. The ovaries are apparently the source of this rise, since plasma prorenin levels did not increase in a pregnant woman with ovarian failure who received a donor egg. All of these changes in plasma prorenin levels appear to be caused by gonadotropic hormones. These results suggest a role for ovarian prorenin in human reproductive function. They may have relevance to studies of female infertility, birth control, and toxemia of pregnancy. They also suggest that a renin system exists that is regulated by changes in prorenin.

Animals↗
PubMed1986

The captopril test for identifying renovascular disease in hypertensive patients.

To develop a screening test for identifying renovascular hypertension, the blood pressure and plasma renin activity responses to an oral test dose of captopril were studied in 246 quietly seated hypertensive patients. The following criteria were developed that exploit the hyperresponsiveness of renin secretion in renovascular hypertensive patients: a 60-minute post-captopril plasma renin activity of 12 ng/ml per hour or more and an absolute plasma renin activity increase of 10 ng/ml per hour or more, along with a 150 percent increase in plasma renin activity (or a 400 percent increase if the baseline plasma renin activity was below 3 ng/ml per hour). Retrospectively, the test identified, among 200 hypertensive patients without evidence of renal dysfunction, all 56 patients with proved renovascular disease. In this group, false-positive results occurred only in two of 112 patients with essential hypertension and in six with secondary hypertension. Nine untreated patients had blood pressure levels of less than 160/100 mm Hg. The test was neither as sensitive nor specific in the 46 patients with renal insufficiency. This study demonstrates that the renin response to oral captopril is a useful screening test for identifying patients with unilateral or bilateral renovascular disease. Since the test also characterizes the renin dependency of the hypertension, it may have other diagnostic and therapeutic uses.

Blood Pressure↗
PubMed1986

Sodium and water balance in chronic congestive heart failure.

As the characteristics of sodium and water balance in heart failure remain undefined, we evaluated the hemodynamic, metabolic, and hormonal effects of balanced sodium intake in 10 patients with chronic congestive heart failure. We discontinued diuretics to avoid their confounding influence, and all patients received 1 wk of 10 meq and 100 meq balanced sodium intake and controlled free water. Comparing sodium intake of 10 with 100 meq, the following observations were made. There was weight gain (2.0 kg) and increased sodium excretion (11 +/- 3 to 63 +/- 15 meq/24 h), unaccompanied by increase of blood volume. Both renin-angiotensin system and sympathetic nervous system activity were greater during the 10 meq diet, and suppressed with the 100 meq sodium diet. For both diets, plasma renin and urinary aldosterone excretion were correlated with urinary sodium excretion (r = -0.768, r = -0.726, respectively; P less than 0.005). Systemic hemodynamics were minimally changed with increased sodium intake. However, reversal of vasoconstriction by captopril during the 10 meq diet, and its ineffectiveness during the 100 meq diet, indicated a renin-dependent mechanism in the former, and a renin-independent mechanism in the latter diet. There were two subgroups of response to the 100 meq diet: one group (n = 5) achieved neutral balance, while the second (n = 5) avidly retained sodium and water. Renin-angiotensin system activity was significantly higher in the latter group, and the mechanism for differences in sodium excretion for the subgroups could not be identified by blood volume or hemodynamic parameters. Orthostatic hypotension during tilt was greater during the 10 meq sodium diet, and in all cases, related to ineffective hemodynamic and hormonal compensatory responses.

Adult↗
PubMed1986

Increased plasma renin and aldosterone in patients treated with cisplatin-based chemotherapy for metastatic germ-cell tumors.

Twenty-four normotensive males in complete remission (CR) for 9+ to 54+ months after cisplatin-based chemotherapy for metastatic germ-cell tumors were evaluated for evidence of alterations in the renin-aldosterone axis and renal function. Abnormally high ambulatory plasma renin activity was seen in 14 of 19 patients with 24-hour urine sodium excretion greater than 50 mEq. This was correlated with elevated ambulatory plasma aldosterone (P = .009) and 24-hour urinary aldosterone excretion (P = .01). The mean serum magnesium value (1.34 +/- .05 mEq/L) was subnormal. Therapy resulted in an increase in serum creatinine during treatment (P less than .0001), an increase in BUN (P less than .01), and decrease in serum phosphorus (P less than .001). The relationship between the alterations in the renin-aldosterone axis and abnormal renal tubular function remains to be determined. In view of reports of cardiovascular toxicity after treatment for germ-cell tumors, and evidence individually linking both magnesium deficiency and increased plasma renin activity (PRA) to cardiovascular consequences, these abnormalities in renin and magnesium metabolism suggest that patients treated with cisplatin-based chemotherapy should be carefully observed for the development of delayed cardiovascular toxicities.

Adult↗
PubMed1986

Effects of altered dietary calcium intake in experimental hypertension: role of intracellular free magnesium.

Blood pressure, ionic and hormonal effects of high (1.8%) versus low (0.2%) dietary calcium intakes were explored in uninephrectomized DOC-NaCl rats, in two-kidney, one clip (2K, 1C) Goldblatt hypertensive rats and their respective controls. High-calcium diets lowered blood pressure (P less than 0.05) in DOC-NaCl and in control uninephrectomized rats drinking 1% NaCl. However, calcium loading in renin-dependent 2K, 1C rats elevated blood pressure (P less than 0.05) but had no effect in sham-operated controls. Plasma renin activity rose in all animals, while serum ionized calcium rose significantly only in dietary salt-loaded animals. Intracellular free magnesium levels were consistently, inversely linked to blood pressure (r = -0.92, P less than 0.001). This linkage was independent of plasma renin activity, serum ionized calcium values and dietary calcium content. These results demonstrate that the same alteration in dietary mineral content can produce opposite blood pressure effects in different pathophysiological subtypes of hypertensive disease. We conclude that intracellular free magnesium levels directly participate in the final common pathway of events regulating blood pressure and vasoconstrictor tone.

Animals↗
PubMed1986

Renin relationship to sex, race and age in a normotensive population.

The relationship of renin activity to sex, race (black or white) and age (less than 50 or greater than or equal to 50 years of age) was examined in 236 normal subjects measure yearly for up to 9 years. There were 58 white women (34 less than 50 years, 24 greater than or equal 50 years), 66 white men (30 less than 50 years, 36 greater than or equal to 50 years), 57 black women (34 less than 50 years, 23 greater than or equal to 50 years) and 55 black men (34 less than 50 years, 21 greater than or equal to 50 years). The results showed men had higher mean renin activities than women, whites had higher activities than blacks and those of under 50 years had higher activities than those of over 50 years. However, the sex and race differences primarily occurred as a consequence of a lack of decline in renin activity with age among white men. The relationship with age as a continuous variable was weak (r = -0.21) and no relationship with age was found in 22 subjects with a least 7 years of data. No significant differences in urinary sodium excretion were observed between the groups. These results suggest that renin activity tends to be lower in older subjects and that differences in renin activity related to sex and race, while statistically significant, may not be physiologically important.

Age Factors↗
PubMed1986

Acid-activatable inactive renin in cat plasma and kidney.

Inactive renin has been identified in cat plasma and kidney extracts. It is identical to human plasma prorenin in all respects tested except that the pH optimum of activated cat inactive renin is slightly different from that of active renin. To further investigate whether cat inactive renin is indeed prorenin we examined whether it could be reversibly acid-activated, an unusual characteristic of human prorenin. We found that dialysis of partially purified, cat renal inactive renin to pH 3.3 caused reversible acid activation. In plasma, when acidification was followed by a second dialysis to pH 7.4 at 4 degrees C, irreversible activation took place, just like human prorenin. Unlike human angiotensinogen, cat angiotensinogen was apparently not affected by acid dialysis. These results suggest that cat inactive renin is most likely prorenin.

Animals↗
PubMed1986

Plasma prorenin during early pregnancy: ovarian secretion under gonadotropin control?

To explore the time-course and the source of the changes in plasma prorenin that occur in early pregnancy we studied a normal subject (subject 1), an in vitro fertilization (IVF) patient (subject 2) and an ovarian failure patient who received a donor egg (subject 3). Day 0 was the luteinizing hormone (LH) peak (subject 1), the day of human chorionic gonadotropin (hCG) administration (subject 2) or 3 days before embryo transfer (subject 3). In subjects 1 and 2 prorenin increased transiently (three- and ninefold respectively) on days 0-4, then returned towards baseline and began to increase again around day 12 to a maximum (six- and 26-fold baseline) around day 20. Active renin was consistently less than 10% of total renin. In the ovarian-failure patient only small fluctuations occurred in total renin yet her hCG was 137 mlU/ml on day 15, proving that she was pregnant. These results suggest that the prorenin rise that occurs at mid-menstrual cycle and following conception may be due to ovarian prorenin secretion in response to stimulation by gonadotropic hormones.

Adult↗
PubMed1986

Correlation between plasma renin activity and birth weight in hypertensive pregnancy.

Plasma renin activity (PRA) was measured in the late third trimester in 26 hypertensive pregnant women and correlated with their infants' birth weights. Seven pre-eclamptics, six chronic hypertensives and 13 chronic hypertensives with superimposed pre-eclampsia were studied. Plasma renin activity was lower in 13 mothers with small for gestational age (SGA) infants (5.2 +/- 0.89 ng/ml per h, compared with 13 mothers with appropriate for gestational age (AGA) infants (16.65 +/- 2.37 ng/ml per h, P less than 0.001. The mean PRA was also lower in mothers with babies weighing less that 2500 g, regardless of gestational age, compared with 11 mothers with babies weighing more than 2500 g, (7.58 +/- 1.61 versus 15.86 +/- 2.73 ng/ml per h, P less than 0.050. Mean PRA was not significantly different in the different hypertensive groups, although women with chronic hypertension appeared to have lower PRA than pre-eclamptics. Our data suggest that in gestational hypertension, low PRA is associated with low infant birth weight, and that late third trimester PRA may therefore identify those at risk for poor fetal outcome.

Adult↗
PubMed1985

Immunological evidence that inactive renin is prorenin.

Antibody raised to a synthetic dodecapeptide, corresponding to the C-terminal portion of the human renin pro-segment, was tested for its ability to recognize highly purified human inactive or active (mature) renins; immune complexes were detected by precipitation with protein A-Sepharose. Serial antibody dilutions caused identical binding of renal or plasma inactive renins but failed to bind active renin. In contrast, antibody to active renin recognized both active and inactive forms. Reversible acid activation of inactive renin enhanced its binding to the anti-prorenin antibody, whereas irreversible trypsin activation significantly reduced binding. Binding was abolished following prolonged exposure to trypsin or if inactive renin was acidified prior to trypsin treatment. These results indicate that inactive renin shares immunochemical determinants with prorenin; they suggest that acidification alters the conformation of the pro-segment and that trypsin can convert the molecule both to fully mature renin and to intermediate form(s).

Animals↗
PubMed1985

Plasma prorenin in first-trimester pregnancy: relationship to changes in human chorionic gonadotropin.

Prorenin and human chorionic gonadotropin are both synthesized in chorionic cells. The relationship of changes in maternal plasma prorenin to changes in human chorionic gonadotropin were therefore evaluated during the first trimester. In samples submitted to the routine chemistry laboratory for detection of pregnancy a positive relationship was observed between prorenin and beta human chorionic gonadotropin during the 5 weeks following conception. Subsequently human chorionic gonadotropin continued to rise but prorenin had reached a plateau. Serial studies in one subject demonstrated that prorenin had increased to 65% of maximum by the thirteenth day following conception whereas human chorionic gonadotropin had risen to only 0.2% of maximum. By 3 to 5 days post partum, beta human chorionic gonadotropin had fallen by 98% but prorenin had fallen by only 50%. The early rise in prorenin following conception and the relatively slow fall post partum suggest that pregnancy-related changes in maternal plasma prorenin are of maternal, not fetal, origin.

Chorionic Gonadotropin↗
PubMed1985

Immediate converting-enzyme inhibition with intravenous enalapril in chronic congestive heart failure.

To test the hypothesis that intravenous enalapril is a useful pharmacologic probe of the renin angiotensin system, intravenous enalapril was administered to 9 patients with severe congestive heart failure (CHF). This produced abrupt and complete blockade of converting enzyme, with peak effect occurring at 30 minutes, as reflected by increases of plasma renin activity (from 16.8 +/- 6 to 86.6 +/- 23 ng/ml/hour) and decreases of plasma aldosterone levels (from 46 +/- 14 to 25 +/- 6 ng%) (both p less than 0.05). With reduction of angiotensin II--mediated vasoconstriction, systemic vascular resistance decreased markedly (from 1,974 +/- 233 to 1,400 +/- 136 dyne s cm-5) and cardiac index was improved (from 1.88 +/- 0.9 to 2.20 +/- 0.21 liters/min/m2) (both p less than 0.05). The time course of angiotensin II levels suggested that the lack of a cumulative effect from additive doses of intravenous enalapril was a reflection of complete inhibition of converting enzyme. One patient did not respond to enalapril; despite comparable hemodynamic severity of CHF, the renin-angiotensin system was not activated in this patient. Thus, intravenous enalapril is capable of rapid and complete inhibition of converting enzyme for the accurate assessment of angiotensin II--mediated vasoconstriction in patients with severe CHF.

Adult↗