Alternative pathways for angiotensin II generation in the cardiovascular system

The classical renin-angiotensin system (RAS) consists of enzymes and peptides that regulate blood pressure and electrolyte and fluid homeostasis. Angiotensin II (Ang II) is one of the most important and extensively studied components of the RAS. The beneficial effects of angiotensin converting enzyme (ACE) inhibitors in the treatment of hypertension and heart failure, among other diseases, are well known. However, it has been reported that patients chronically treated with effective doses of these inhibitors do not show suppression of Ang II formation, suggesting the involvement of pathways alternative to ACE in the generation of Ang II. Moreover, the finding that the concentration of Ang II is preserved in the kidney, heart and lungs of mice with an ACE deletion indicates the important role of alternative pathways under basal conditions to maintain the levels of Ang II. Our group has characterized the serine protease elastase-2 as an alternative pathway for Ang II generation from Ang I in rats. A role for elastase-2 in the cardiovascular system was suggested by studies performed in heart and conductance and resistance vessels of normotensive and spontaneously hypertensive rats. This mini-review will highlight the pharmacological aspects of the RAS, emphasizing the role of elastase-2, an alternative pathway for Ang II generation.

Cardiovascular actions of angiotensin-(1-7)

Angiotensin-(1-7) (Ang-(1-7)) is now considered to be a biologically active member of the renin-angiotensin system. The functions of Ang-(1-7) are often opposite to those attributed to the main effector component of the renin-angiotensin system, Ang II. Chronic administration of angiotensin-converting enzyme inhibitors (ACEI) increases 10- to 25-fold the plasma levels of this peptide, suggesting that part of the beneficial effects of ACEI could be mediated by Ang-(1-7). Ang-(1-7) can be formed from Ang II or directly from Ang I. Other enzymatic pathways for Ang-(1-7) generation have been recently described involving the novel ACE homologue ACE2. This enzyme can form Ang-(1-7) from Ang II or less efficiently by the hydrolysis of Ang I to Ang-(1-9) with subsequent Ang-(1-7) formation. The biological relevance of Ang-(1-7) has been recently reinforced by the identification of its receptor, the G-protein-coupled receptor Mas. Heart and blood vessels are important targets for the formation and actions of Ang-(1-7). In this review we will discuss recent findings concerning the biological role of Ang-(1-7) in the heart and blood vessels, taking into account aspects related to its formation and effects on these tissues. In addition, we will discuss the potential of Ang-(1-7) and its receptor as a target for the development of new cardiovascular drugs.

Niveles de angiotensina (1-7) en ratas con distinto genotipo de enzima convertidora de angiotensina I y efecto de la hipertensión renovascular / Levels of angiotensin (1-7) in rats with different ace genotypes and effect of renovascular hypertension

La mayor actividad de la enzima convertidora de angiotensina I (ECA) determina mayores niveles de angiotensina (Ang) II y menores de Ang-(1-7). Hemos observado mayores niveles de Ang II en ratas normotensas con mayor actividad de ECA y simultáneamente mayor hipertensión renovascular. Planteamos que en esta situación los niveles de Ang (1-7) podrían modificarse por la HTA y además ser inversamente proporcionales a la actividad de ECA y a los niveles de Ang II. Métodos: se determinó angiotensina II y (1-7) plasmáticas en ratas normotensas e hipertensas renovasculares (modelo Goldblatt 2 riñones, 1 clip) en cepas F2 homocigotas Brown Norway (BN, con ECA elevada) o Lewis (con ECA baja). Resultados: Promedio (ES). Los niveles de hipertensión arterial e HVI fueron similares en ambas cepas en los grupos Goldblatt. Los niveles plasmáticos de Ang II fueron 509 (37) U/ml en ratas BN normotensas y 173 (25) U/mL en ratas Lewis normotensas (p <0,05). Los niveles plasmáticos de Ang (1-7) fueron 4 veces mayores en ratas Lewis normotensas que las normotensas BN (p <0,05) y se elevaron significativamente con la hipertensión (p <0,05). Conclusión: Estos resultados podrían explicar la diferencia en la magnitud de la HTA observada previamente entre ambos genotipos de ECA y la mayor tendencia a presentar hipertensión arterial en hombres que presentan el alelo D del polimorfismo ECA I/D.

Discrepancy between plasma angiotensin converting enzyme activity and in vivo extent of angiotensin I conversion in hypertensive rats

The relationship of plasma angiotensin converting enzyme (ACE) activity to changes in theextent of angiotensin I (ANG I) conversion in vivo in rats with short-term and chronic (8 weeks) hypertension was examined. Plasma ACE activity was measured by a fluorimetric assay and the extent of ANG I conversion was calculated from the equipressor doses of ANG I and ANGII in conscious rats. The extent of ANG I conversion was higher in chronic on-kidney, one clip hypertensive rats than in the normotensive age-matched control rats (64.1 ñ 3.6% vs 34.8 ñ 5.2%), while no difference was found in the ACE activity measured in plasma from both groups. In rats with acute hypertension, produced upon unclamping the renal pedicle occluded for 5hours,the extent of ANG i conversion was increased when compared to the period prior to renal pedicle occlusion (from 38.8ñ4.1% to 68.6ñ8.5%),and plasma ACE activity remained unchanged. These results indicate that circulating ACE cannot be used as an index of ANG I conversionin vivo and support the proposal that tissue ACE is responsible for the augmented ANG I conversion observed in vivo in both acute renal hypertension and chronic one-kidney, one clip hypertension