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Journal ArticleDOI

In-Vivo and In-Vitro Conversion of Angiotensin I to Angiotensin II in Dog Blood

01 May 1970-Circulation Research (Lippincott Williams & Wilkins)-Vol. 26, Iss: 5, pp 591-599
TL;DR: Observations indicate that the major site of conversion of angiotensin I to ang Elliotensin II is in the pulmonary capillary bed, and the kidnev may participate as a secondary site, as indicated by the different metabolites.
Abstract: The conversion of angiotensin I to angiotensin II was studied in vivo in the intact anesthetized dog and in vitro in whole blood and plasma treated with various anticoagulants by fractionation of radioactively labeled peptides and by radioimmunoassay. After injection of angiotensin I into the pulmonary artery at 10,000 times the physiologic level, approximately 50% of the injected material was recovered in the aorta. Fifty three percent of the material recovered had been converted to angiotensin II, as measured both by peptide release and by radioimmunoassay. Following injection of 1000 to 10,000 times physiologic levels of angiotensin I into the renal artery, 7 to 10% of the immunoreactive material in the venous effluent after a single circulation time was angiotensin II. There was no evidence of conversion in the liver or hindlimb. Conversion in vitro was far slower than in vivo, the half-life in fresh blood being 3 minutes, with longer times observed in anticoagulated plasmas. The major metabolite of in-vivo conversion was leucine, of in-vitro conversion, histidyl leucine. These observations indicate that the major site of conversion of angiotensin I to angiotensin II is in the pulmonary capillary bed. The kidnev may participate as a secondary site. Conversion in plasma probably plays no important physiologic role. The mechanism of organ and plasma conversion may differ, as indicated by the different metabolites.
Citations
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Journal ArticleDOI
12 Mar 1976-Science
TL;DR: Fluorescein-labeled antibody to rabbit pulmonary angiotensin-converting enzyme localized in the vascular endothelium of rabbit lung, liver, adrenal cortex, pancreas, kidney, and spleen demonstrated immunoreactivity.
Abstract: Fluorescein-labeled antibody to rabbit pulmonary angiotensin-converting enzyme localized in the vascular endothelium of rabbit lung, liver, adrenal cortex, pancreas, kidney, and spleen. Epithelial cells of the renal proximal tubules were the only parenchymal cells among the organs studied that demonstrated immunoreactivity.

622 citations

Journal ArticleDOI
TL;DR: Although ACE was first considered to be a carboxypeptidase-type enzyme, its actions go beyond cleaving dipep-tides from the free C-terminal end of peptide substrates, some of the basic properties of this enzyme remain unexplained.
Abstract: Many of the properties of angiotensin I converting enzyme or kininase II (ACE) have been discussed in extenso in the literature. The mode of action of ACE inhibitors has been studied in experimental animals and used clinically in millions of patients. The relatively few side effects have also been amply scrutinized. Nevertheless, some of the basic properties of this enzyme remain unexplained. For instance, although ACE was first considered to be a carboxypeptidase-type enzyme (peptidyl dipeptidase or dipeptidyl carboxypeptidase) (1,2) its actions go beyond cleaving dipep-tides from the free C-terminal end of peptide substrates. ACE inactivates substance P in spite of its blocked C-terminus, primarily by releasing the C-terminal tripeptide Gly-Leu-Met-NH2 (3). The blocked C-terminal tripep-tide, Arg-Pro-Gly-NH2, is also released from the luteinizing hormone releasing hormone (LHRH) (A). ACE, surprisingly, also cleaves the protected the N-terminal tripeptide

548 citations


Cites background or result from "In-Vivo and In-Vitro Conversion of ..."

  • ...Other investigators (23, 29) found about the same percent conversion in the dog in vivo....

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  • ...Other workers confirmed the importance of the lung in the conversion of angiotensin I, but they found greater converting activity in the renal (20-23), peripheral (24, 25), and splanchnic (26) circulation than was suspected from the initial research....

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Journal ArticleDOI
TL;DR: High specific activities of converting enzyme were found in lung and in segments of the digestive tract, but the highest activities were in testis and epididymis, associated with tubular fluids, but not in sperm cells.

413 citations

Journal ArticleDOI
TL;DR: The role of the kidney in blood-pressure regulation was established by TIGERSTEDT and Bergman at the close of the 19th century as discussed by the authors, who produced hypertension in dogs by injecting a cr...
Abstract: TIGERSTEDT and Bergman established a role for the kidney in blood-pressure regulation at the close of the 19th century. In a classic experiment, they produced hypertension in dogs by injecting a cr...

278 citations

References
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Journal ArticleDOI
TL;DR: Renin activity increased with Na restriction, was significantly higher on upright activity during both normal and restricted Na intake, and was most markedly elevated following the diuretic.
Abstract: A radioimmunoassay for angiotensin I and its application to the determination of renin activity is described. The assay employs antibodies raised to copolymers of angiotensin I and succinylated poly-l-lysine. Angiotensin labeled with 125I and purified by high voltage paper electrophoresis is employed as a tracer. Incubation is carried out in plasma in the presence of 3 metal binding reagents which serve to inhibit effectively proteolytic attack on angiotensin I. Immunoassay of generated angiotensin I is carried out directly on plasma diluted 1:20. Fifteen normal volunteers were studied on a metabolic ward at 2 levels of Na intake, during recumbency and upright posture, and following the administration of furosemide. Renin activity increased with Na restriction, was significantly higher on upright activity during both normal and restricted Na intake, and was most markedly elevated following the diuretic. Renin values obtained by immunoassay of angiotensin I correspond closely to those observed by ...

2,348 citations


"In-Vivo and In-Vitro Conversion of ..." refers methods in this paper

  • ...The conversion of angiotensin I to angiotensin II in whole blood and in the intact dog was examined by radioimmunoassay techniques (8, 9)....

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  • ...This combination has been shown (8) to be effective in inhibiting angiotensin I conversion and angiotensinase activity in plasma....

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Journal ArticleDOI
TL;DR: It has been shown by use of isolated, perfused rat kidneys that hypertensin II is a potent vasoconstrictor substance while hypertensIn I is not, and it would appear that in intact animals the pressor activity of hypertens in I results from its rapid conversion to hypertENSin II.
Abstract: It has been shown by use of isolated, perfused rat kidneys that hypertensin II is a potent vasoconstrictor substance while hypertensin I is not. Hence it would appear that in intact animals the pressor activity of hypertensin I results from its rapid conversion to hypertensin II. An enzyme which effects this conversion has been procured from horse plasma in a semipurified form by means of ammonium sulfate fractionation and isoelectric precipitation. A method is described for estimating the activity of the enzyme. An example of the use of the preparation in converting purified hypertensin I to hypertensin II has been described.

945 citations


"In-Vivo and In-Vitro Conversion of ..." refers background in this paper

  • ...(12) on converting enzyme isolated from horse plasma....

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  • ...Plasma (12) and extracts of several organs of the rat, including kidney, ileum, liver, heart, and brain, as well as the* lung (13), have converting enzyme activity, the physiologic significance of which is questionable....

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Journal ArticleDOI
25 Nov 1967-Nature
TL;DR: Results obtained with the blood bathed organ technique indicate that angiotensin I is converted rapidly to angiotENSin II in the pulmonary circulation and not by an enzyme in the blood.
Abstract: Results obtained with the blood bathed organ technique indicate that angiotensin I is converted rapidly to angiotensin II in the pulmonary circulation and not by an enzyme in the blood.

571 citations


"In-Vivo and In-Vitro Conversion of ..." refers background or methods or result in this paper

  • ...Our results derived from radioactive peptide measurements were comparable to those of Ng and Vane (3) with heparinized whole blood for short incubation times (8 vs....

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  • ...Thus, the lung is considered the principal site of formation of circulating angiotensin II (3)....

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  • ...An increase in biologic activity of angiotensin I has been observed after a single passage through the pulmonary circulation (3-7)....

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  • ...Our finding of extensive conversion in the intact pulmonary circulation confirms the observations of others (3-7) using bioassay techniques....

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  • ...Angiotensin I conversion proceeds at a much slower rate in extracorporeal blood than in the intact animal (3)....

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Journal ArticleDOI
13 Apr 1968-Nature
TL;DR: The results of the blood-bathed organ technique do not support hypotheses which suggest a completely intra-renal role for the renin–angiotensin system.
Abstract: The blood-bathed organ technique has been used to demonstrate that angiotensin I is converted to angiotensin II in the lungs, but not in other vascular beds. The results do not support hypotheses which suggest a completely intra-renal role for the renin–angiotensin system.

295 citations


"In-Vivo and In-Vitro Conversion of ..." refers background or methods or result in this paper

  • ...Angiotensin II inactivation has been demonstrated in intact (4, 10, 15) and isolated perfused (16) kidneys....

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  • ...Our finding of extensive conversion in the intact pulmonary circulation confirms the observations of others (3-7) using bioassay techniques....

    [...]

  • ...An increase in biologic activity of angiotensin I has been observed after a single passage through the pulmonary circulation (3-7)....

    [...]

  • ...Angiotensin I conversion has not been demonstrated in femoral, carotid, renal, or total peripheral vascular beds of the intact animal or the isolated perfused kidney by the blood-bathed organ technique (4, 10)....

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Journal ArticleDOI
30 Nov 1968-Nature
TL;DR: This communication describes some of the enzymes in extracts of dog lung that metabolize angiotensins I and II and particularly those catalysing the conversion ofAngiotensin I to angiotENSin II (“converting enzyme”) and the enzyme(s) responsible for the inactivation of ang Elliotensin II and angiotsin I are referred to as “destroying enzyme’.
Abstract: RECENT work1 has established the crucial part played by the pulmonary circulation in the pharmacodynamics of the renin-angiotensin system in the dog. It is the only vascular bed that does not inactivate all or part of the angiotensin II passing through it, and it is the only vascular bed that converts circulating angiotensin I to angiotensin II (refs. 1 and 2). The differences between the metabolism of these peptides by the lungs and by other vascular beds might be a result of differences in the enzymes present in the tissues. This communication describes some of the enzymes in extracts of dog lung that metabolize angiotensins I and II and particularly those catalysing the conversion of angiotensin I to angiotensin II (“converting enzyme”). The enzyme(s) responsible for the inactivation of angiotensin II and angiotensin I are referred to as “destroying enzyme”.

236 citations


"In-Vivo and In-Vitro Conversion of ..." refers background in this paper

  • ...In addition, angiotensin Iconverting activity has been demonstrated in cell-free extracts of lung tissue (11)....

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