Plasma Angiotensin-(1-8) Octapeptide Measurement to Assess Acute Angiotensin-Converting Enzyme Inhibition with Captopril Administered Parenterally to Normal Subjects

Nussberger, Jürg; Waeber, Gérard; Waeber, Bernard; Bidiville, J.; Brunner, Hans R.

doi:10.1097/00005344-198806000-00013

Cited by 23 publications

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“…In normal volunteers injected with captopril intravenously, we also observed no fall in blood pressure despite a dose-dependent fall in plasma Ang II to nondetectable levels. 12 CGP 38560A was well tolerated by all volunteers, and no side effects were noticed in the presence of peak plasma levels of CGP 38560A, which were more than three orders of magnitude higher than the in vitro inhibition constant (Ki) value reported earlier.…”

Section: Drug Levelsmentioning

confidence: 60%

“…Discussion Several renin inhibitors have been studied in animals, 11 but only two have been evaluated in humans. 12 Since active renin represents the ratelimiting step in the production of Ang II, the potent effector hormone of the renin-angiotensin system, renin inhibitors are designed to counteract this renin activity and hence to limit the generation of Ang II. Investigation of the effeet of renin inhibitors on the components of the human renin-angiotensin system must therefore be based on reliable monitoring of these variables, particularly on the measurement of Ang II concentrations, and technical aspects have to be considered when plasma renin activities are reported.…”

Section: Drug Levelsmentioning

confidence: 99%

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Hemodynamic and biochemical consequences of renin inhibition by infusion of CGP 38560A in normal volunteers.

et al. 1989

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Hemodynamic and biochemical effects of the new renin inhibitor CGP 38560A (molecular weight 826) were tested in 15 healthy volunteers after a single-blind, randomized, placebocontrolled protocol. At a 2-week interval, groups of five subjects received a 30-minute infusion of either 5% dextrose or CGP 38560A 50, 125, or 250 Mg/kg. Blood pressure, heart rate, plasma renin activity, active and total renin, angiotensin-(l-8)octapeptide (angiotensin II), and aldosterone were sequentially measured up to 3 hours from the onset of the infusion. There was no consistent change in blood pressure or heart rate. Plasma renin activity and angiotensin II decreased dose dependently, and peak suppression was observed at the end of the infusion of CGP 38560A and after the 250-/xg/kg dose. Plasma renin activity fell from 1.0±0.19 (mean±SEM) to less than 0.05 ng/ml/hr in all five subjects (/><0.001), and angiotensin II fell from 7.7±1.2 to 2.6±0.9 femtomole/ml (p<0.01). Active renin rose fourfold from 24±1.9 to 98±14 pg/ml (/><0.001) at the end of the infusion of the high dose. Plasma angiotensin II returned toward its initial values much faster than plasma renin activity and active renin. In conclusion, CGP 38560A was well tolerated. It induced a dose-dependent decrease in angiotensin II and plasma renin activity and a long-lasting and dose-dependent rise in active renin. The doses used did not reduce plasma angiotensin II maximally despite reduction of plasma renin activity to unmeasurable levels. Thus, the measurement of plasma renin activity cannot replace that of plasma angiotensin II to evaluate the efficacy of renin inhibitors. {Hypertension 1989; 13:948-953) T he success of angiotensin converting enzyme inhibitors in the therapy of hypertension and heart failure is mainly attributed to decreased production of angiotensin-(l-8)octapeptide (Ang II). The lack of specificity of converting enzyme, which also modifies the metabolism of at least bradykinin and substance P, might play a role in causing side effects such as cough or angioneurotic edema. Drugs that inhibit Ang II generation without modifying the metabolism of bradykinin and other peptides may lack untoward effects of converting enzyme inhibitors. This goal could be achieved by preventing the generation of angiotensin I (Ang I) instead of blocking its conversion to Ang II. Since renin generates Ang I from angioten- sinogen, it was logical to attempt inhibition of this first, specific, and rate-limiting reaction of the reninangiotensin system. The purpose of the present study was to evaluate the new renin inhibitor CGP 38560A. By comparison with the two renin inhibitors that have been administered to human beings, the renin inhibitory peptide 1 and the H-142, 2 CGP 38560 has a molecular weight (mol wt) of 826 instead of 1,319 and 1,210, respectively. CGP38560A seems more potent in vitro since its IC50 was calculated at 0.7 nM compared with 2 juM for the renin inhibitory peptide and 10 nM for the H-142. The effects of the CGP 38560A on blood pressure and the main biochem...

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Section: Drug Levelsmentioning

confidence: 60%

Section: Drug Levelsmentioning

confidence: 99%

Hemodynamic and biochemical consequences of renin inhibition by infusion of CGP 38560A in normal volunteers.

et al. 1989

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“…These results are at variance with the low unmeasurable levels which were observed in all healthy volunteers tested previously with 25 mg intravenous captopril. 23 It is therefore possible that plasma ANG II was less suppressed after the infusion of the renin inhibitor at the doses selected than after ACE inhibition. A definite conclusion is not possible since plasma ANG II was not measured during the initial captopril test, which was only used to screen renin-dependent hypertension, and moreover, the discriminatory power of plasma ANG II measurements at these low levels may still need to be improved.…”

Section: Discussionmentioning

confidence: 99%

Plasma Angiotensins, Renin, and Blood Pressure During Acute Renin Inhibition by CGP 38 560A in Hypertensive Patients

Jeunemaı̂tre

Ménard

Nussberger

et al. 1989

American Journal of Hypertension

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The new renin inhibitor CGP 38560A has been shown to block angiotensin (ANG) production in healthy volunteers. In order to determine its potential antihypertensive effect, the compound was administered in a 30-min infusion, in 12 hypertensive patients (mean blood pressure ( T he goal of research on renin inhibition is to achieve a more specific blockade of the reninangiotensin system (RAS) than is possible with angiotensin converting enzyme (ACE) inhibi tion. Indeed, renin is an enzyme which acts on a unique substrate, angiotensinogen, whereas converting en zyme splits several substrates, including bradykinin, which may enhance the efficacy of this therapeutic ap proach to hypertension and congestive heart failure, and may also cause some of its side-effects. 1 It is also expected that the clinical use of renin inhibitors will provide a better tool than ACE inhibitors for investigat ing the contribution of the RAS to the regulation of blood pressure and general hemodynamics. The angio tensin II (ANG II) antagonist, saralasin, and the ACE inhibitor, teprotide, were the first pharmacological tools used for this purpose. Depending on the prevailing plasma renin activity (PRA), their hypotensive effects were substantially different. 2 They both lowered blood pressure more when the prevailing PRA was high; over-

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“…No fall in blood pressure was observed in normal volunteers after intravenous administration of captopril in doses that completely suppressed plasma angiotensin II levels. 23 It should be kept in mind that use of blood pressure as an end point for testing the efficacy of a drug that interferes specifically with one hypertensive mechanism is only valid if it is established beyond any doubt that the blood pressure under the circumstances prevailing during the testing is really dependent on this pressor mechanism. For instance, there would probably be little disagreement that the renin-angiotensin system does not play a predominant role in all hypertensive patients, and there are clearly some patients in whom complete blockade of the system would not be expected to reduce blood pressure.…”

Section: Discussionmentioning

confidence: 99%

Hemodynamic and humoral effects of the new renin inhibitor enalkiren in normal humans.

et al. 1989

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The effect of the renin inhibitor enalkiren (Abbott-64662) was evaluated in eight normal volunteer subjects on a standardized sodium diet (100 mmol/day) by measurement of various components of the renin-angiotensin system and drug levels in plasma. On day 1, vehicle and doses of 0.001, 0.003, and 0.01 mg/kg i.v. were administered within 2 minutes at 90-minute intervals. On day 2, vehicle and doses of 0.01, 0.03, and 0.1 mg/kg i.v. were given. With the higher doses, blood pressure tended to decrease slightly with no change in heart rate. Plasma renin activity and plasma angiotensin-(l-8)octapeptide (angiotensin II) fell markedly in a dose-dependent manner. Inhibition of plasma renin activity was maximal 5 minutes after administration of the drug and persisted 90 minutes after the doses of 0.03 and 0.1 mg/kg. Not surprisingly, there was a close correlation between plasma renin activity and plasma angiotensin II levels (r=0.81, n=28, p<0.001). In contrast, active and total renin measured directly by monoclonal antibodies rose in dose-related fashion in response to renin inhibition. Pharmacokinetic parameters were calculated using the plasma drug concentrations obtained up to 6 hours after the 0.1 mg/kg dose. By means of a two-compartment model, plasma mean half-life of the drug was estimated at 1.60±0.43 hours. (Hypertension 1989;13:941-947) O ver the last decade, inhibition of the reninangiotensin system by converting enzyme inhibition has proved very effective for the treatment of hypertension and congestive heart failure.12 Converting enzyme inhibitors block the generation of angiotensin II, a potent pressor hormone. Because converting enzyme is identical to kininase II, it also contributes to the inactivation of the vasodilator hormone bradykinin.3 Accordingly, converting enzyme inhibition does not provide a totally specific means of blocking the reninangiotensin system. Furthermore, the disappearance of angiotensin II from the plasma triggers counterregulatory mechanisms that tend to limit the efficacy of angiotensin converting enzyme (ACE) inhibition. Thus, renin secretion is stimulated and, as a consequence, plasma angiotensin I is elevated. Even in the presence of pronounced ACE inhibition, some angtiotensin II may still be generated. More specific tools for blocking of the reninangiotensin system would be useful. Renin inhibitors have the theoretical advantage of specificity since renin has no known substrate other than angiotensinogen.5 So far, at least experimentally, renin has been blocked by means of various approaches: specific renin antibodies, 6 phospholipids, 78 peptides related to the renin prosegment, 9 pepstatin and its derivatives, 1011 and analogues of the renin substrate. The latter are derived from the minimal sequence of angiotensinogen reacting with renin.12 Actual inhibitors of this class contain a reduced bond between two amino acids at the cleavage site of renin. 13 The inhibitors seem to act by mimicking the transition state of the substrate formed during hydrolysis. Such compounds hav...

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Plasma Angiotensin-(1-8) Octapeptide Measurement to Assess Acute Angiotensin-Converting Enzyme Inhibition with Captopril Administered Parenterally to Normal Subjects

Cited by 23 publications

References 0 publications

Hemodynamic and biochemical consequences of renin inhibition by infusion of CGP 38560A in normal volunteers.

Hemodynamic and biochemical consequences of renin inhibition by infusion of CGP 38560A in normal volunteers.

Plasma Angiotensins, Renin, and Blood Pressure During Acute Renin Inhibition by CGP 38 560A in Hypertensive Patients

Hemodynamic and humoral effects of the new renin inhibitor enalkiren in normal humans.

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