Effects of Renin Inhibition in the Conscious Primate Macaca fascicularis

• Published in: Hypertension (Dallas, Tex. 1979) Tex. 1979), 1989-11, Vol.14 (5), p.480-487
• Main Authors: Hui, Kwan Y, Knight, Delvin R, Nussberger, Jiirg, Hartley, L Howard, Vatner, Stephen F, Haber, Edgar
• Format: Article
• Language: English
• Subjects: Angiotensin I - pharmacology; Angiotensin II - blood; Angiotensin II - pharmacology; Animals; Blood Pressure - drug effects; Captopril - pharmacology; Diet, Sodium-Restricted; Dose-Response Relationship, Drug; Furosemide - pharmacology; Heart Rate - drug effects; Macaca mulatta; Oligopeptides - adverse effects; Oligopeptides - pharmacology; Osmolar Concentration; Renin - antagonists & inhibitors; Renin - blood; Renin - pharmacology; Space life sciences; Structure-Activity Relationship
• ISSN: 0194-911X; 1524-4563
• DOI: 10.1161/01.HYP.14.5.480

Pro-His-Pro-Phe-His-Statine-Ile-Phe-NH2 (R-Pep-27), a potent renin inhibitory peptide, was infused into the conscious, sodium-depleted Macaca fascicularis at doses of 0, 0.1,1, 4, 16, and 32 jug/kg/min for 10 minutes. At all doses greater than 0.1 /μg/kg/min, there was a parallel decrease in mean arterial pressure (MAP), plasma renin activity, and plasma angiotensin II (Ang II) concentration. On the other hand, assays with monoclonal antibodies specific for total renin and active renin demonstrated that the peptideʼs inhibition of circulating active renin stimulated the release of both. The maximal effective R-Pep-27 dose was approximately 16 Aig/kg/min, which reduced MAP by an average of 15.8±1.4 mm Hg (n=14) and plasma renin activity and plasma Ang II concentration to 3% (n=9) and 15% (n=5), respectively, of the pretreatment values. At 0.1 /tμ/kg/min, there was no significant decrease in MAP; however, measurement of plasma renin activity showed an average decrease in activity of 42% (n=3). No significant change in the heart rate was observed at all the doses studied. For comparison, intravenous captopril (400 /i.g/kg bolus) was administered after the MAP of the monkeys had recovered from the peptide experiments, and it reduced MAP by 25.1 ±2.4 mm Hg (n=10) without significantly changing plasma renin activity. As anticipated, injection of angiotensin I (80–160 ng/kg bolus) into sodium-depleted monkeys during peptide infusion caused a transient rise in MAP of 14.8±5.4 mm Hg (n=4) above the mean pretreatment value. Similar injection under the influence of captopril had no pressor effect. Injection of purified human renin (0.01–0.02 Goldblatt units/kg/min i.v.) into sodium-replete monkeys raised the MAP by an average of 36.5 mm Hg (n=2). Simultaneous intravenous infusion of R-Pep-27 at 100 jLtg/kg/min for 8–12 minutes caused the elevated MAP to return to normal. This study reveals the effects of blockade of circulating renin in a conscious primate model and suggests that R-Pep-27 will find use as a clinical tool in investigations of the role of renin in essential hypertension.