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Effects of a specific and long-acting renin inhibitor in the marmoset
Abstract:
Inhibition of renin was induced in conscious marmosets with CGP 29 287, Z-Arg-Arg-Pro-Phe-His-Sta-Ile-His-Lys (Boc)-OMe, a renin inhibitor with a prolonged duration of action. In vitro, CGP 29 287 is a potent inhibitor of primate plasma renin (inhibitory concentration, 50%: human = 1 X 10(-9) M; marmoset = 5 X 10(-9) M) and less potent against dog (2 X 10(-7) M) or rat (3 X 10(-5) M) plasma renin. CGP 29 287 is a weak inhibitor of other aspartic proteases such as porcine pepsin or bovine cathepsin D (inhibitory concentration, 50% = 4 X 10(-5) M). In furosemide-treated marmosets, CGP 29 287 lowered blood pressure and inhibited plasma renin activity during intravenous infusion and after intravenous bolus injection. The duration of action after intravenous injection was dose dependent and ranged from 1 hour after 0.1 mg/kg to more than 3 hours after 10 mg/kg. High doses of CGP 29 287 (100 mg/kg) were active after oral administration. In all experiments a close relation between inhibition of plasma renin activity and reduction of blood pressure was found. A maximum hypotensive response to CGP 29 287 was associated with complete inhibition of plasma renin activity, and the recovery of blood pressure was accompanied by recovery of plasma renin activity. The hypotensive effects of CGP 29 287 were smaller in untreated than in furosemide-treated marmosets. CGP 29 287 had no influence on blood pressure in marmosets after bilateral nephrectomy or after pretreatment with a converting enzyme inhibitor.(ABSTRACT TRUNCATED AT 250 WORDS)
Insights
CGP 29 287, a novel renin inhibitor, effectively lowers blood pressure in marmosets by inhibiting plasma renin activity. Its prolonged action and oral efficacy demonstrate potential for treating hypertension.
Area of Science:
- Pharmacology
- Cardiovascular Research
Background:
- The renin-angiotensin-aldosterone system plays a crucial role in blood pressure regulation.
- Renin inhibition is a therapeutic target for managing hypertension.
Purpose of the Study:
- To evaluate the efficacy and pharmacokinetic profile of CGP 29 287, a novel renin inhibitor.
- To investigate the relationship between renin inhibition and blood pressure reduction.
Main Methods:
- In vitro assessment of CGP 29 287's inhibitory potency against primate and other animal plasma renin.
- In vivo studies in conscious marmosets to assess blood pressure and plasma renin activity following CGP 29 287 administration (intravenous and oral).
- Comparison of effects in furosemide-treated versus untreated marmosets, and after bilateral nephrectomy or converting enzyme inhibitor pretreatment.
Main Results:
- CGP 29 287 demonstrated potent inhibition of primate plasma renin in vitro.
- In marmosets, CGP 29 287 dose-dependently lowered blood pressure and inhibited plasma renin activity.
- A strong correlation was observed between plasma renin activity inhibition and blood pressure reduction, with effects seen after oral administration at high doses.
Conclusions:
- CGP 29 287 is a potent and effective renin inhibitor with a prolonged duration of action.
- The study confirms the critical role of renin in blood pressure regulation and highlights CGP 29 287's potential as an antihypertensive agent.