angiotensin-i and enalkiren

The human renin infused rat model (HRIRM) was used as an in vivo small-animal model for evaluating the efficacy of a collection of inhibitors of human renin. The intravenous infusion of recombinant human renin (2.4 microg x kg(-1) x min(-1)) in the ganglion-blocked, nephrectomized rat produced a mean blood pressor response of 47+/-3 mm Hg (1 mm Hg = 133.3 Pa), which was reduced by captopril, enalkiren, and losartan in a dose-dependent manner following oral administration, with ED50 values of 0.3+/-0.1, 2.5+/-0.9, and 5.2+/-1.6 mg/kg, respectively. A series of peptidomimetic P2-P3 butanediamide renin inhibitors inhibited purified recombinant human renin in vitro in a concentration-dependent manner, with IC50 values ranging from 0.4 to 20 nM at pH 6.0, with a higher range of IC50 values (0.8-80 nM) observed at pH 7.4. Following i.v. administration of renin inhibitors, the pressor response to infused human renin in the HRIRM was inhibited in a dose-dependent manner, with ED50 values ranging from 4 to 600 microg/kg. The in vivo inhibition of human renin following i.v. administration in the rat correlated significantly better with the in vitro inhibition of human renin at pH 7.4 (r = 0.8) compared with pH 6.0 (r = 0.5). Oral administration of renin inhibitors also resulted in a dose-dependent inhibition of the pressor response to infused human renin, with ED50 values ranging from 0.4 to 6.0 mg/kg and the identification of six renin inhibitors with an oral potency of <1 mg/kg. The ED50 of renin inhibitors for inhibition of angiotensin I formation in vivo was highly correlated (r = 0.9) with the ED50 for inhibition of the pressor response. These results demonstrate the high potency, dose dependence, and availability following oral administration of the butanediamide series of renin inhibitors.

Topics: Administration, Oral; Angiotensin I; Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Blood Pressure; Captopril; Dipeptides; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Ganglionic Blockers; Humans; In Vitro Techniques; Losartan; Male; Rats; Rats, Sprague-Dawley; Recombinant Proteins; Renin; Time Factors

Over a period of several years, methods of measuring circulating angiotensin II have been progressively improved and it has now become possible to measure circulating angiotensin II with a high degree of accuracy. The main ingredients in this new methodology are bonded-phase silica for quantitative angiotensin extraction from biological fluids and antibodies with a high affinity to angiotensin II to provide for the sensitivity of the radio-immunoassay, high performance liquid chromatography to guarantee the specificity for the angiotensin-(1-8)octapeptide, and a renin inhibitor in the blood sampling tube to prevent any in vitro angiotensin II generation. With this new methodology it can be demonstrated that after the first administration of a full dose of an angiotensin converting enzyme (ACE) inhibitor, plasma angiotensin II virtually disappears from the circulation, whereas with chronic administration which induces a marked increase in renin secretion and thereby in angiotensin I levels, angiotensin II clearly remains present in plasma at peak inhibition, though at a much lower level than before ACE inhibition. Plasma angiotensin II levels were decreased equally and dose-dependently by the administration of two renin inhibitors, CGP 38560A and A64662. However, in man these compounds have so far only been tested with single administration. In conclusion, the measurement of plasma angiotensin II equally reflects the degree of ACE and renin inhibition, and is therefore the only logical approach to evaluation of the efficacy and potency of ACE inhibitors and renin antagonists.

Topics: Angiotensin I; Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Dipeptides; Humans; Oligopeptides; Renin