Key result
Oral administration of RB150, an aminopeptidase A inhibitor prodrug, dose-dependently reduced blood pressure in spontaneously hypertensive rats with an ED50 of /kg.
Why the study?
Does oral administration of RB150 reduce blood pressure in spontaneously hypertensive rats?
Does oral administration of RB150 reduce blood pressure in spontaneously hypertensive rats?
Oral RB150, an aminopeptidase A inhibitor, effectively reduces blood pressure in hypertensive rats and potentiates the effects of systemic RAS blockers, suggesting a novel central antihypertensive strategy.
Answers are grounded in this paper and cite their sources.
Hypothesis-generating for central aminopeptidase A inhibition in hypertension; leaves open translation to human therapy.
Brain renin-angiotensin system hyperactivity has been implicated in the development and maintenance of hypertension. We reported previously in the brain that aminopeptidase A and aminopeptidase N are involved in the metabolism of angiotensin II and angiotensin III, respectively. By using in vivo specific and selective aminopeptidase A and aminopeptidase N inhibitors, we showed that angiotensin III is one of the main effector peptides of the brain renin-angiotensin system, exerting a tonic stimulatory control more than blood pressure in hypertensive rats. Aminopeptidase A, the enzyme generating brain angiotensin III, thus represents a potential target for the treatment of hypertension. We demonstrated here the antihypertensive effects of RB150, a prodrug of the specific and selective aminopeptidase A inhibitor, EC33, in spontaneously hypertensive rats, a model of human essential hypertension. Oral administration of RB150 in conscious spontaneously hypertensive rats inhibited brain aminopeptidase A activity, demonstrating the central bioavailability of RB150 and its ability to generate EC33 into the brain. Oral RB150 treatment dose-dependently reduced blood pressure in spontaneously hypertensive rats with an ED(50) of 30 mg/kg, lasting for several hours. This decrease in blood pressure is partly attributed to a decrease in sympathetic tone, reducing vascular resistance. This treatment did not modify systemic renin-angiotensin system activity. Concomitant oral administration of RB150 with a systemic renin-angiotensin system blocker, enalapril, potentiated the RB150-induced blood pressure decrease achieved in <2 hours. Thus, RB150 may be the prototype of a new class of centrally active antihypertensive agents that might be used in combination with classic systemic renin-angiotensin system blockers to improve blood pressure control.
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Marc et al. (2012) studied Hypertension. RB150 (aminopeptidase A inhibitor prodrug) was evaluated on Blood pressure. Oral administration of RB150, an aminopeptidase A inhibitor prodrug, dose-dependently reduced blood pressure in spontaneously hypertensive rats with an ED50 of /kg.
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