Converting Enzyme Determines Plasma Clearance of Angiotensin-(1–7)

Abstract

Abstract-We determined the mechanism accounting for the removal and metabolism of angiotensin-(1-7) [Ang-(1-7)] in 21 anesthetized spontaneously hypertensive (SHR), 18 age-matched normotensive Sprague-Dawley (SD), and 36 mRen-2 transgenic (TG ϩ ) rats. Animals of all 3 strains were provided with tap water or tap water containing losartan, lisinopril, or a combination of lisinopril and losartan for 2 weeks. On the day of the experiment, Ang-(1-7) was infused for a period of 15 minutes at a rate of 278 nmol ⅐ kg Ϫ1 ⅐ min Ϫ1. After this time, samples of arterial blood were collected rapidly at regular intervals for the assay of plasma Ang-(1-7) levels by radioimmunoassay. Infusion of Ang-(1-7) had a minimal effect on vehicle-treated SD rats but elicited a biphasic pressor/depressor response in vehicle-treated SHR and TG ϩ rats. In lisinopril-treated rats, Ang-(1-7) infusion increased blood pressure, whereas losartan treatment abolished the pressor component of the response without altering the secondary fall in arterial pressure. Combined treatment with lisinopril and losartan abolished the cardiovascular response to Ang-(1-7) in all 3 strains. In vehicle-treated SD, SHR and TG ϩ the half-life (t 1/2 ) of Ang-(1-7) averaged 10Ϯ1, 10Ϯ1, and 9Ϯ1 seconds, respectively. Lisinopril alone or in combination with losartan produced a statistically significant rise in the half-life of Ang-(1-7) in all 3 strains of rats. Plasma clearance of Ang-(1-7) was significantly greater in the untreated SD rats compared with either the SHR or TG ϩ rat. Lisinopril treatment was associated with reduced clearance of Ang-(1-7) in all 3 strains. Concurrent experiments in pulmonary membranes from SD and SHR showed a statistically significant inhibition of 125 I-Ang-(1-7) metabolism in the presence of lisinopril. These studies showed for the first time that the very short half-life of Ang-(1-7) in the circulation is primarily accounted for peptide metabolism by ACE. These findings suggest a novel role of ACE in the regulation of the production and metabolism of the two primary active hormones of the renin angiotensin system. (Hypertension. 1998;32:496-502.)

Angiotensin‐(1‐7): Pharmacology and New Perspectives in Cardiovascular Treatments

“…Thus, inhibiting this pathway would effectively prolong the t 1 2 of the peptide. Moreover, the plasma clearance of Ang-(1-7) was 6.5 ± 0.9 L min −1 kg −1 in normotensive SD rats, whereas the plasma clearance in SHR and Tg (+) rats was significantly decreased by 39% and 60%, respectively (SHR, 4.0 ± 0.2 L min −1 kg −1 ; Tg (+) , 2.6 ± 0.1 L min −1 kg −1 ) (Yamada et al 1998), suggesting that the plasma Ang-(1-7) is cleared from the body much slower in the two hypertensive strains (Fig. 3).…”

“…In a vital study by Yamada et al (1998), the baseline circulating t 1 2 of vehicle-treated Sprague-Dawley rats (SDs), SHRs, and hypertensive [mRen2]27 transgenic rats [Tg (+) ] was about 10 seconds, although baseline values of the peptide were much higher in the SHRs and Tg (+) compared to the normotensive SDs (377 ± 88 pmol/L, 367 ± 122 pmol/L, and 137 ± 18 pmol/L, respectively). The t 1 2 values were increased 4-to 6-fold with ACE inhibitor (lisinopril) treatment, whereas the ARB and losartan, had no significant effect.…”

“…* * P < 0.001. Adapted from Yamada et al 1998. is responsible, at least in part, for the metabolism of Ang-(1-7) to the inactive metabolite, Ang-(1-5) Deddish et al 1998;Allred et al 2000). Thus, inhibiting this pathway would effectively prolong the t 1 2 of the peptide.…”

Effect of Angiotensin (1-7) on Heart Function in an Experimental Rat Model of Obesity

“…Thus, the findings of Ferreira et al seemed to be due to local production of cardiac Ang(1-7), whereas our results were rather caused by systemic alterations. Santos et al (2004) measured Ang(1-7) in the same model as we used, demonstrating elevated Ang(1-7) plasma concentration, but unaltered tissue levels, which may be a result of the short half-life of Ang(1-7), which is about 10 s (Yamada et al, 1998).…”

ANG II, ANG-(1-7), ALDO and AVP biphasic effects on Na+/H+ transport: the role of cellular calcium

“…The half-life of ANG-(1-7) is several seconds, and ACE inhibitors, which inhibit the metabolism of ANG-(1-7) into ANG-(1-5), increase the half-life of ANG-(1-7) [167].…”