Activation of Inactive Plasma Renin by Plasma and Tissue Kallikreins

1979 ◽  
Vol 57 (4) ◽  
pp. 351-357 ◽  
Author(s):  
F. H. M. Derkx ◽  
H. L. Tan-Tjiong ◽  
A. J. Man In 'T Veld ◽  
M. P. A. Schalekamp ◽  
M. A. D. H. Schalekamp
Keyword(s):  
Active Form ◽  
Plasma Renin ◽  
Exchange Chromatography ◽  
Acid Activation ◽  
Ph Profile ◽  
Simultaneous Generation ◽  
Inactive Renin ◽  
Fletcher Factor

1. Normal human plasma contains a pro-activator of inactive renin. The pro-activator is activated at physiological pH in plasma that has been pretreated with acid. This activation in vitro leads to the conversion of inactive renin into the active form with simultaneous generation of kallikrein activity. 2. The endogenous activator of inactive renin has the same pH profile and inhibitor spectrum as plasma kallikrein. 3. Inactive renin can also be activated by exposure of plasma to exogenous trypsin, and in normal plasma the quantities of inactive renin that are activated after acidification and with trypsin are identical. Prekallikrein (Fletcher factor)-deficient plasma, however, has much lower renin activity after acidification than with trypsin. Thus acid activation of inactive renin depends on plasma prekallikrein, whereas the action of trypsin is independent of prekallikrein. 4. Highly purified tissue (pancreatic) kallikrein, in a concentration of less than 2 × 10−8 mol/l, activates inactive renin that has been isolated from plasma by ion-exchange chromatography. In this respect it is at least 100 times more potent than trypsin. 5. It is therefore possible that plasma and/or tissue (renal) kallikreins are also involved in the activation of inactive renin in vivo.

Absence of Activation in Vitro of Renin in Rat Plasma

1982 ◽  
Vol 62 (4) ◽  
pp. 435-437 ◽  
Author(s):  
M. H. De Keijzer ◽  
A. P. Provoost ◽  
F. H. M. Derkx
Keyword(s):  
Human Plasma ◽  
Active Form ◽  
Plasma Renin ◽  
Rat Plasma ◽  
Plasma Renin Concentration ◽  
Inactive Form ◽  
Inactive Renin

1. Rat plasma was subjected at 4°C to various treatments known to convert inactive renin into its active form in human plasma. 2. No statistical differences in plasma renin concentration were found when the levels after the various treatments were compared with that of untreated rat plasma. 3. It is concluded that, in contrast to human plasma, no inactive form of renin is present in rat plasma.

BIOLOGICAL SIGNIFICANCE OF ACTIVE AND INACTIVE RENIN IN MAN

1980 ◽  
Vol 85 (1) ◽  
pp. 137-143 ◽  
Author(s):  
P. LIJNEN ◽  
A. AMERY ◽  
R. FAGARD ◽  
L. VERSCHUEREN
Keyword(s):  
Plasma Concentrations ◽  
Biological Significance ◽  
Plasma Renin ◽  
Angiotensin I ◽  
Vitro Assay ◽  
Arterial Blood ◽  
Inactive Renin ◽  
Change In Mean

SUMMARY The biological significance of active and inactive renin was investigated by comparison of an in-vitro assay of active, total and inactive plasma renin concentration (PRC), plasma renin activity (PRA) and plasma concentrations of angiotensin I and II with an in-vivo change in mean arterial blood pressure (MAP) produced by antagonism of angiotensin with treatment with saralasin and by blockade of angiotensin-converting enzyme by treatment with captopril. A significant relationship between the changes in MAP during treatment with saralasin and captopril with the pretreatment levels of PRA, active and total PRC and angiotensin II were found; while the pre-existing level of inactive renin was not a predictor for the hypotensive effect of saralasin and captopril. During treatment with saralasin and captopril significant increases in PRA, plasma angiotensin I concentration and total and active PRC were found and no change in inactive PRC was observed.

Generation of Inactive Renin in Vitro and in Vivo: Reversible Inactivation of the Active Plasma Enzyme in Rats

1982 ◽  
Vol 63 (s8) ◽  
pp. 171s-174s ◽  
Author(s):  
Jack D. Barrett ◽  
Peter Eggena ◽  
Mohinder P. Sambhi
Keyword(s):  
Active Form ◽  
Renin Angiotensin System ◽  
Active Plasma ◽  
Reversible Inactivation ◽  
Active Renin ◽  
Plasma Enzyme ◽  
Inactive Renin ◽  
Rate Of Decline

1. Active and total (trypsin treatment) plasma renins were measured in normal Wistar rats and in rats in which the renin-angiotensin system was stimulated by ether anaesthesia. 2. After incubation of normal plasma in vitro in the absence of angiotensinase inhibitors, active renin declined. This decline was shown to be due to the conversion of active renin into an inactive form, which could be re-activated by trypsin. 3. In plasma from renin-stimulated rats, the rate of decline of active renin in vitro was accelerated; however, the relative amount of inactive renin generated was decreased. 4. Ligation of the kidneys of the ether-anaesthetized animal resulted in a build-up in vivo of inactive renin concomitant with the decline of active renin. 5. These data demonstrate the conversion of active into inactive renin in vitro and indicate that inactive renin can also be generated in vivo from the active form of the enzyme. 6. Multiple forms of inactive renin may exist; some may be true ‘prorenins’ (renin zymogens) produced in the kidney, and others may result from post-biosynthetic modifications of the active plasma enzyme.

Chickpea (Cicer arietinum L.) Lectin Exhibit Inhibition of ACE-I, α-amylase and α-glucosidase Activity

2019 ◽  
Vol 26 (7) ◽  
pp. 494-501 ◽  
Author(s):  
Sameer Suresh Bhagyawant ◽  
Dakshita Tanaji Narvekar ◽  
Neha Gupta ◽  
Amita Bhadkaria ◽  
Ajay Kumar Gautam ◽  
...  
Keyword(s):  
Biological Effects ◽  
Exchange Chromatography ◽  
Health Concern ◽  
Carbohydrate Binding ◽  
Dependent Manner ◽  
Concentration Dependent Manner ◽  
Ic50 Values ◽  
Chickpea Lectin

Background: Diabetes and hypertension are the major health concern and alleged to be of epidemic proportions. This has made it a numero uno subject at various levels of investigation. Glucosidase inhibitor provides the reasonable option in treatment of Diabetes Mellitus (DM) as it specifically targets post prandial hyperglycemia. The Angiotensin Converting Enzyme (ACE) plays an important role in hypertension. Therefore, inhibition of ACE in treatment of elevated blood pressure attracts special interest of the scientific community. Chickpea is a food legume and seeds contain carbohydrate binding protein- a lectin. Some of the biological properties of this lectin hitherto been elucidated. Methods: Purified by ion exchange chromatography, chickpea lectin was tested for its in vitro antioxidant, ACE-I inhibitory and anti-diabetic characteristic. Results: Lectin shows a characteristic improvement over the synthetic drugs like acarbose (oral anti-diabetic drug) and captopril (standard antihypertensive drug) when, their IC50 values are compared. Lectin significantly inhibited α-glucosidase and α-amylase in a concentration dependent manner with IC50 values of 85.41 ± 1.21 ҝg/ml and 65.05 ± 1.2 µg/ml compared to acarbose having IC50 70.20 ± 0.47 value of µg/ml and 50.52 ± 1.01 µg/ml respectively. β-Carotene bleaching assay showed antioxidant activity of lectin (72.3%) to be as active as Butylated Hydroxylanisole (BHA). In addition, lectin demonstrated inhibition against ACE-I with IC50 value of 57.43 ± 1.20 µg/ml compared to captopril. Conclusion: Lectin demonstrated its antioxidant character, ACE-I inhibition and significantly inhibitory for α-glucosidase and α-amylase seems to qualify as an anti-hyperglycemic therapeutic molecule. The biological effects of chickpea lectin display potential for reducing the parameters of medically debilitating conditions. These characteristics however needs to be established under in vivo systems too viz. animals through to humans.

EXTRAHEPATIC AND EXTRARENAL RENIN INACTIVATION IN THE DOG

1974 ◽  
Vol 60 (2) ◽  
pp. 217-222
Author(s):  
R. FAGARD ◽  
E. FOSSION ◽  
M. CAMPFORTS ◽  
A. AMERY
Keyword(s):  
Blood Vessels ◽  
Pulmonary Circulation ◽  
Plasma Renin ◽  
Glass Container ◽  
Plasma Renin Concentration ◽  
Vascular Beds ◽  
Extrarenal Renin

SUMMARY It was demonstrated previously that renin disappears quickly from the circulation after nephrectomy in the hepatectomized dog. In the present study the plasma renin concentration (PRC) was measured in the efferent and afferent blood vessels of several vascular beds (pulmonary circulation, splanchnic region, spleen, both inferior limbs and pelvis, head) in the anhepatic and in the anhepatic and anephric dog in order to investigate extrarenal and extrahepatic renin inactivation. However, no significant arteriovenous differences in PRC could be traced. The blood of these dogs kept in vitro at 37 °C in a glass container showed no decline in PRC within 3 h of removal. Therefore no specific extrahepatic and extrarenal renin-inactivating mechanism was found which could explain the rapid disappearance of renin from the blood in vivo in the anhepatic and anephric dog.

scholarly journals Cathepsin L inhibition suppresses drug resistance in vitro and in vivo: a putative mechanism

2009 ◽  
Vol 296 (1) ◽  
pp. C65-C74 ◽  
Author(s):  
Xin Zheng ◽  
Fei Chu ◽  
Pauline M. Chou ◽  
Christine Gallati ◽  
Usawadee Dier ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Cancer Cell ◽  
Trichostatin A ◽  
Cathepsin L ◽  
Active Form ◽  
Cancer Resistance ◽  
Protease Inhibition ◽  
Resistance To Chemotherapy

Cathepsin L is a lysosomal enzyme thought to play a key role in malignant transformation. Recent work from our laboratory has demonstrated that this enzyme may also regulate cancer cell resistance to chemotherapy. The present study was undertaken to define the relevance of targeting cathepsin L in the suppression of drug resistance in vitro and in vivo and also to understand the mechanism(s) of its action. In vitro experiments indicated that cancer cell adaptation to increased amounts of doxorubicin over time was prevented in the presence of a cathepsin L inhibitor, suggesting that inhibition of this enzyme not only reverses but also prevents the development of drug resistance. The combination of the cathepsin L inhibitor with doxorubicin also strongly suppressed the proliferation of drug-resistant tumors in nude mice. An investigation of the underlying mechanism(s) led to the finding that the active form of this enzyme shuttles between the cytoplasm and nucleus. As a result, its inhibition stabilizes and enhances the availability of cytoplasmic and nuclear protein drug targets including estrogen receptor-α, Bcr-Abl, topoisomerase-IIα, histone deacetylase 1, and the androgen receptor. In support of this, the cellular response to doxorubicin, tamoxifen, imatinib, trichostatin A, and flutamide increased in the presence of the cathepsin L inhibitor. Together, these findings provided evidence for the potential role of cathepsin L as a target to suppress cancer resistance to chemotherapy and uncovered a novel mechanism by which protease inhibition-mediated drug target stabilization may enhance cellular visibility and, thus, susceptibility to anticancer agents.

Renal effects induced by prolonged mPGES1 inhibition

2014 ◽  
Vol 306 (1) ◽  
pp. F68-F74 ◽  
Author(s):  
Francisco Salazar ◽  
Michael L. Vazquez ◽  
Jaime L. Masferrer ◽  
Gabriel Mbalaviele ◽  
Maria T. Llinas ◽  
...  
Keyword(s):  
Renal Function ◽  
Plasma Renin ◽  
In Vivo Studies ◽  
Renal Effects ◽  
Excretory Function ◽  
Membrane Bound ◽  
Inflammatory Drugs ◽  
Chronically Instrumented Dogs

The importance of membrane-bound PGE synthase 1 (mPGES1) in the regulation of renal function has been examined in mPGES1-deficient mice or by evaluating changes in its expression. However, it is unknown whether prolonged mPGES1 inhibition induces significant changes of renal function when Na+ intake is normal or low. This study examined the renal effects elicited by a selective mPGES1 inhibitor (PF-458) during 7 days in conscious chronically instrumented dogs with normal Na+ intake (NSI) or low Na+ intake (LSI). Results obtained in both in vitro and in vivo studies have strongly suggested that PF-458 is a selective mPGES1 inhibitor. The administration of 2.4 mg·kg−1·day−1 PF-458 to dogs with LSI did not induce significant changes in renal blood flow (RBF) and glomerular filtration rate (GFR). A larger dose of PF-458 (9.6 mg·kg−1·day−1) reduced RBF ( P < 0.05) but not GFR in dogs with LSI and did not induce changes of renal hemodynamic in dogs with NSI. Both doses of PF-458 elicited a decrease ( P < 0.05) in PGE2 and an increase ( P < 0.05) in 6-keto-PGF1α. The administration of PF-458 did not induce significant changes in renal excretory function, plasma renin activity, and plasma aldosterone and thromboxane B2 concentrations in dogs with LSI or NSI. The results obtained suggest that mPGES1 is involved in the regulation of RBF when Na+ intake is low and that the renal effects elicited by mPGES1 inhibition are modulated by a compensatory increment in PGI2. These results may have some therapeutical implications since it has been shown that prolonged mPGES1 inhibition has lower renal effects than those elicited by nonsteroidal anti-inflammatory drugs or selective cyclooxygenase-2 inhibitors.

Effect of angiotensin II and sodium depletion on angiotensinogen production

1980 ◽  
Vol 238 (2) ◽  
pp. E145-E149 ◽  
Author(s):  
H. C. Herrmann ◽  
B. J. Morris ◽  
I. A. Reid
Keyword(s):  
Angiotensin Ii ◽  
Actinomycin D ◽  
Ethinyl Estradiol ◽  
Intraperitoneal Administration ◽  
Plasma Renin ◽  
Sodium Depletion ◽  
Liver Slices ◽  
Plasma Angiotensin

An in vitro preparation of liver slices was used to study the effect of angiotensin II and sodium depletion on the synthesis of angiotensinogen in rats. Two other treatments known to increase plasma angiotensinogen concentration in vivo, viz., intraperitoneal administration of dexamethasone or ethinyl estradiol, resulted in an increase in the rate of release of angiotensinogen by liver slices; this increase was inhibited by adding actinomycin D or vincristine to the incubation medium. Intravenous infusion of angiotensin II (33 ng/min for 3 days) also produced a marked increase in the release of angiotensinogen concentration and a decrease in plasma renin activity. In contrast, no change in the rate of release of angiotensinogen was observed in rats depleted of sodium for 7--14 days, even though these animals exhibited a marked increase in plasma angiotensin II concentration. Plasma angiotensinogen concentration decreased by 30%, presumably as a consequence of the accompanying increase in renin secretion. These results provide further evidence that the synthesis of angiotensinogen may be increased by angiotensin II, but indicate that the circulating level of angiotensin II in sodium-deficient animals is not sufficiently high to produce this response.

In vitro secretion of atrial natriuretic factor: receptor-mediated release of prohormone

1988 ◽  
Vol 254 (5) ◽  
pp. R809-R814 ◽  
Author(s):  
A. T. Veress ◽  
S. Milojevic ◽  
C. Yip ◽  
T. G. Flynn ◽  
H. Sonnenberg
Keyword(s):  
Atrial Natriuretic Factor ◽  
Active Form ◽  
High Concentration ◽  
Natriuretic Factor ◽  
Rat Hearts ◽  
Agonist Concentration ◽  
Atrial Natriuretic Factor Receptor ◽  
Atrial Natriuretic

Secretion of atrial natriuretic factor (ANF) in vivo is thought to be mediated by atrial distension. We have shown previously that nonstretched atria can release natriuretic activity in vitro when stimulated by certain agonists. In the present study atrial appendages from freshly excised rat hearts were incubated at 37 degrees C for up to 1 h in the presence of either vasopressin (5 X 10(-9) mol/l) or angiotensin II (2.5 X 10(-7) mol/l). Aliquots of postincubation media were injected intravenously into anesthetized bioassay rats to determine natriuretic activity. Control media, in which atria had been incubated without agonist, did not cause natriuresis. Significant increases in sodium excretion were seen after injection of media in which atria had been incubated in the presence of either agonist. Injection of medium with the same agonist concentration did not result in comparable natriuresis. Radioimmunoassay (RIA) indicated a high concentration of immunoactive ANF in the natriuretic media. However, radioreceptor assay (RRA) of the same media gave apparent ANF concentrations that were lower by about three orders of magnitude. Because the antibody used in the RIA cross reacts with ANF prohormone, whereas the RRA is sensitive only to the active form, we concluded that agonist-induced, stretch-independent release of ANF is in the form of prohormone, which can be converted to the active hormone in the circulation of the bioassay animal. The conclusion of prohormone release was confirmed by liquid chromatography. The data thus suggest that receptor-mediated as well as stretch-induced ANF secretion may be important in regulating the activity of the ANF system.

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