Abstract P152: Aminopeptidase A in the Brain Exerts Cardiovascular Action via Degradation of Kallidin to Bradykinin

Abstract

Objective: Aminopeptidase A (APA) degrades of various sympathomodulatory peptides such as angiotensin (Ang) II, cholecystkinin-8, neurokinin B and kallidin. APA activity is increased in the brain of hypertensive rats. A centrally acting APA inhibitor prodrug is currently under investigation in clinical trial for treatment of hypertension. In previous reports, a role of APA in the brain on cardiovascular regulation was researched focus on only renin-angiotensin system. We previously reported that intracerebroventricular(icv) administration of APA increased blood pressure and that this pressor response was partially blocked by angiotensin receptor blocker. In this study, we evaluated a role of APA on cardiovascular regulation focusing on peptides other than Ang II. Method: Eleven weeks old Wistar Kyoto rats were used. We icv administrated 800 ng/8 μL of APA after pretreatment of following drugs, i) 8μL of artificial cerebrospinal fluid (aCSF) as a control, ii) 80 nmol/8 μL of amastatin which is a non-specific aminopeptidase inhibitor, iii) 1 nmol/8 μL of HOE-140 which is a bradykinin receptor blocker to evaluate the involvement of degradation of kallidin to bradykinin by APA. Result: i) Icv administration of APA after pretreatment of aCSF increased blood pressure rapidly. Blood pressure reached a peak within 1 minute. The elevated blood pressure decreased gradually and reached baseline blood pressure in 10 minutes. A peak pressor response is 25.5±1.4 mmHg (n=5). ii) Icv pretreatment of amastatin or HOE-140 did not change the blood pressure. A peak pressor response induced by APA is 13.1±4.1 mmHg (n=6, p<0.05 vs aCSF). iii) Icv pretreatment of HOE-140 did not change the blood pressure. A peak pressor response induced by APA is 21.2±1.8 mmHg (n=4, p<0.05 vs aCSF). Conclusion: 1) Icv administration of APA increased blood pressure by APA enzymatic activity. 2) Cardiovascular regulation of APA in the brain is due to not only degradation of Ang II to Ang III but also degradation of kallidin to bradykinin. Clinical implication: We think inhibition of APA in the brain may be a unique therapeutic target which affects several cardiovascular peptides in the brain.