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Effects of renin inhibition in the conscious primate Macaca fascicularis
K Y Hui1, D R Knight, J Nussberger
1Massachusetts General Hospital, Boston 02114.
Abstract:
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 micrograms/kg/min for 10 minutes. At all doses greater than 0.1 microgram/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 peptide's inhibition of circulating active renin stimulated the release of both. The maximal effective R-Pep-27 dose was approximately 16 micrograms/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 microgram/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 micrograms/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.(ABSTRACT TRUNCATED AT 250 WORDS)
Insights
The renin inhibitory peptide R-Pep-27 effectively lowered blood pressure and plasma renin activity in sodium-depleted monkeys. However, it also stimulated renin release, indicating a complex feedback mechanism.
Area of Science:
- Pharmacology
- Cardiovascular Physiology
- Renin-Angiotensin System
Background:
- The renin-angiotensin system (RAS) plays a crucial role in regulating blood pressure.
- Renin inhibitors are a potential therapeutic target for hypertension.
- Understanding the in vivo effects of novel renin inhibitors is essential.
Purpose of the Study:
- To evaluate the efficacy and effects of the novel renin inhibitory peptide R-Pep-27 in conscious, sodium-depleted non-human primates.
- To assess the impact of R-Pep-27 on mean arterial pressure (MAP), plasma renin activity (PRA), and angiotensin II (Ang II) levels.
- To investigate the compensatory responses of the renin system to R-Pep-27 administration.
Main Methods:
- Infusion of R-Pep-27 at various doses (0-32 µg/kg/min) into conscious, sodium-depleted Macaca fascicularis.
- Measurement of mean arterial pressure (MAP), plasma renin activity (PRA), and plasma angiotensin II (Ang II) concentration.
- Assays using monoclonal antibodies to differentiate total and active renin.
- Comparison with captopril and angiotensin I administration.
Main Results:
- R-Pep-27 significantly reduced MAP, PRA, and Ang II at doses >0.1 µg/kg/min, with maximal effect at ~16 µg/kg/min.
- MAP decreased by 15.8 mmHg and PRA/Ang II to 3%/15% of baseline at the maximal dose.
- While inhibiting active renin, R-Pep-27 stimulated the release of both total and active renin.
- Captopril caused a larger MAP reduction without altering PRA; angiotensin I transiently increased MAP.
Conclusions:
- R-Pep-27 is a potent renin inhibitor with significant blood pressure-lowering effects in vivo.
- The peptide's action triggers a compensatory increase in renin release, suggesting a feedback loop.
- Further research is needed to understand the long-term implications of this stimulated renin release.