Catabolism of vasoactive polypeptides by perfused rat liver

Abstract

Exsanguinated rat liver preparations perfused in situ with oxygenated saline solutions inactivated recirculating bradykinin (BK) at rates of 2.3 to 9.1 and isoleucyl5 angiotensin II (AII) at rates of 2.8 to 15.0 nmoles X min-1 X g-1 of liver, depending on the initial concentration of the peptides in the perfusion fluid (3.1 to 18.9 X 10(-6) M for BK and 8.5 to 17.0 X 10(-6) M for AII). On the other hand, at similar concentrations, recirculation of isoleucyl5 Angiotensin I (AI) for 8 min did not lead to decrease of its biological activity when assayed on the isolated rat uterus. Following a single passage through liver, picomole amounts of both BK and AII were inactivated by about 90% as revealed by assays on a superfused rat uterus. The potency ratio AI:AII, assayed on a superfused rat uterus was 1:22 and changed to 1:5 following a single passage of both peptides through liver. This finding and the separation of 4.9% of AII on carboxymethylcellulose columns following recirculation of AI through rat liver indicate a conversion of AI into AII. The dipeptides Phe-Arg, Ser-Pro and Gly-Phe were identified among the hydrolysis products of perfused BK. A peptidyldipeptide hydrolase (EC 3.4.15) may be responsible for both the BK inactivation and AI conversion. The inactivation of AII cannot be attributed to the same enzyme.

Hepatic conversion of angiotensin I and the portal hypertensive response to angiotensin II in normal and regenerating liver

“…As we could not observe any increase in the portal pressure, there were two possibilities: (i) the amount of angiotensin (1-7) produced is not enough to cause any effect or (ii) this peptide has no pressor effect in the intrahepatic circulation. To address this point, we administrated exogenous angiotensin (1)(2)(3)(4)(5)(6)(7) at concentrations that, in other vascular territories, are effective. 10 The lack of the hemodynamic effect of angiotensin (1-7) and the fact that its biological effects are not attributed to the binding to the AT1 and/or AT2 receptors reinforces the conclusion that the pressor effect induced by the injected AI is a consequence of its conversion to AII.…”

“…2,3 Recently we demonstrated that the PHR induced by AI is a consequence of its mandatory conversion into AII. 4 Although AII is the main active product of the RAS, there is evidence suggesting that AI or AII hydrolysis by peptidases other than the ACE generates biologically active peptides, mainly angiotensin (1)(2)(3)(4)(5)(6)(7).…”

Pharmacological Activities and Hydrolysis by Peptidases of [Phospho-Ser6]-Bradykinin (pS6-BK)

“…5B). Captopril has a small protecting effect in [pS 6 ]Bk clearance that probably occurs because the clearance of Bk in liver is done mainly by TOP [20,21] that is unable to hydrolyze [pS 6 ]Bk ( Table 2). The Bk portal hypertensive response is higher than that of [pS 6 ]Bk but its response lasts longer as can be evaluated by comparison of the areas under the curves as in Fig.…”

“…Monovascular rat liver perfusion was performed as previously described [19][20][21]. Briefly, the rat was anesthetized with urethane (1.3 g/kg, i.p), the abdominal and thoracic cavities were opened and the portal vein and vena cava were cannulated.…”

Angiotensin II or epinephrine hemodynamic and metabolic responses in the liver of L-NAME induced hypertension and spontaneous hypertensive rats

“…Besides converting angiotensin (Ang) I in AngII, it is the major kininase involved in bradykinin degradation in the liver[10]. In 1976, Borges et al[11] showed that both AngI and AngII infused into the portal vein of a rat induced hypertensive effect, and they also demonstrated for the first time the conversion of AngI into AngII by the rat liver. This hypertensive response induced by AngII is mediated by AT1 receptor because when losartan was co-infused with AngII into the liver portal vein it abolished the hypertension response[12].…”