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

Abstract

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...

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

“…A long-lasting suppression of PRA mea sured by a conventional method was present for 150 min after the end of this renin inhibitor infusion, despite a normalization of plasma ANG II. 6 In another investigation, the same doses of this renin inhibitor were infused in normal volunteers after a mild sodium deple tion induced by furosemide 40 mg. 7 Plasma ANG II was measured by the same method as in the previous exper iment, 14 but PRA was investigated by the ANG I trap ping assay. 7 The inhibition of PRA-TA was much shorter than the inhibition of PRA observed in the vol unteers not subjected to sodium restriction.…”

“…6 In another investigation, the same doses of this renin inhibitor were infused in normal volunteers after a mild sodium deple tion induced by furosemide 40 mg. 7 Plasma ANG II was measured by the same method as in the previous exper iment, 14 but PRA was investigated by the ANG I trap ping assay. 7 The inhibition of PRA-TA was much shorter than the inhibition of PRA observed in the vol unteers not subjected to sodium restriction. However, it was still present 90 min after the end of the renin-inhibitor infusion, whereas ANG II levels returned to their initial values at 30 min.…”

“…CGP 38 560A is a potent, lowmolecular-weight, human renin inhibitor, 5 which has been shown to decrease blood pressure of marmosets, and to be well tolerated by normal volunteers maintained on a normal sodium diet 6 or after mild sodium depletion. 7 …”

Angiotensin II generation in vivo: does it involve enzymes other than renin and angiotensin-converting enzyme?

“…[6][7][8] Further evidence is provided by the marked suppression of plasma Ang I and Ang II levels by renin inhibitors. [9][10] Although serine proteases may contribute to Ang peptide formation at tissue sites of inflammation, 1 the available evidence indicates that nonrenin pathways of Ang formation are clearly unable to compensate for renin deficiency or inhibition.…”

Renal and endocrine responses to a renin inhibitor, enalkiren, in normal humans.

“…The Ang II assay in the present study measures irAng II, and the antiserum also has crossreactivity to angiotensin fragments. High-performance liquid chromatography separation improves the specificity of the angiotensin assay 18 and should be used in future studies in which renin and ACE inhibition are compared.…”