Angiotensins and Related Peptides Products

Definition
Angiotensin, a protein, causes blood vessels to constrict, and drives blood pressure up. It is part of the renin-angiotensin system, which is a major target for drugs that lower blood pressure.

Discovery
Angiotensin was independently isolated by two groups and named "hypertensin" in Argentina and "angiotonin" in the United States and was later shown to be an octapeptide ^{1, 2, 3}.

Types
The original angiotensin⁴ (Angiotensin-1) gives rise to Angiotensin-2 by removal of a C-terminal dipeptide. This reaction is mediated by angiotensin converting enzyme in plasma, liver and nerve tissues. Further removal of the aminoterminal amino acid from angiotensin-2 by an aspartate amino peptidase yields Angiotensin-3 (called also angiotensin (2-8); abbr. Ang (2-8). Removal of the terminal arginine from Angiotensin-3 yields angiotensin-4 (called also Angiotensin-2(3-8); abbr. Ang-2(3-8)). Angiotensin-(1-7) (abbr. Ang (1-7)) is a peptide formed endogenously from either Ang-1 or Ang-2.

Structural Characteristics
The amino acid sequence of horse hypertensin II has been determined by the use of chymotrypsin, the fluorodinitrobenzene method, and stepwise phenylisothiocyanate degradation. The amino acids of hypertensin II are arranged in the following order¹: asp-arg-val-tyr-iso-hist-pro-phe.

Related Peptides
Potentiation of the hypotensive effect of bradykinin by angiotensin-(1-7)-related peptides: In a study, the bradykinin potentiating activity and ACE inhibitory activity of several Ang-(1-7)-related peptides was evaluated: Ang-(2-7), Ang-(3-7), Ang-(4-7), Ang-(1-6), Ang-(1-5) and the selective antagonist of Ang-(1-7): D-[Ala⁷]Ang-(1-7) (A-779). In vivo experiments were performed in freely moving Wistar rats. ACE activity was evaluated by a fluorometric assay in rat plasma using Hip-His-Leu as a substrate. Intravenous injections of Ang-(1-7) (2.2 nmol) transformed the effect of a single dose of bradykinin (1 nmol) into the effect produced by a double dose. A similar bradykinin potentiating activity was demonstrated for Ang-(2-7) and Ang-(3-7). On the other hand, Ang-(1-5), Ang-(1-6), Ang-(4-7) and A-779 did not change the hypotensive effect of bradykinin in doses ranging from 8 up to 25 nmols. The hypotensive effect of bradykinin was increased by intravenous infusion (0.3 ng/min) of Ang-(1-7) > Ang-(2-7) > Ang-(3-7). Conversely, Ang-(1–5), Ang-(1–6), Ang-(4–7) or A-779 did not change the hypotensive effect of bradykinin. ACE inhibition with Ang-(1–7) related peptides occurred in the order: Ang-(2–7) = Ang-(3–7) > Ang-(1–7) [>>] Ang-(1–5) > Ang-(4–7) = Ang-(1–6) = A-779. A-779 in concentrations up to 10^-5 M did not change the ACE inhibitory activity of Ang-(1–7). These results suggest that Ang-(1–7), Ang-(2–7) and Ang-(3–7) can modulate bradykinin actions in vivo⁵.

Mode of Action
The renin-angiotensin system is a central component of the physiological and pathological responses of cardiovascular system. Its primary effector hormone, angiotensin II (Ang II), not only mediates immediate physiological effects of vasoconstriction and blood pressure regulation, but is also implicated in inflammation, endothelial dysfunction, atherosclerosis, hypertension, and congestive heart failure. The myriad effects of Ang II depend on time (acute vs. chronic) and on the cells/tissues upon which it acts. In addition to inducing G protein- and non-G protein-related signaling pathways, Ang II, via AT(1) receptors, carries out its functions via MAP kinases (ERK 1/2, JNK, p38MAPK), receptor tyrosine kinases [PDGF, EGFR, insulin receptor], and nonreceptor tyrosine kinases [Src, JAK/STAT, focal adhesion kinase (FAK)]. AT(1)R-mediated NAD(P)H oxidase activation leads to generation of reactive oxygen species, widely implicated in vascular inflammation and fibrosis. Ang II also promotes the association of scaffolding proteins, such as paxillin, talin, and p130Cas, leading to focal adhesion and extracellular matrix formation. These signaling cascades lead to contraction, smooth muscle cell growth, hypertrophy, and cell migration, events that contribute to normal vascular function, and to disease progression⁶

Functions
Angiotensin receptors are present in many tissue types, including adrenal cortex, renal glomeruli, heart, hypothalamus, liver, pancreas, pituitary, platelets, renal tubules, uterus and vascular smooth muscle. Two high-affinity receptor subtypes have been identified by radioligand binding with antagonists: losartan (DuP 753/MK954) identifies AT1 receptors; PD123177 and CGP42112A are markers for AT2 receptors. Angiotensin II may be produced locally in tissues outside the humoral system. For example, it is found in the brain, kidney and heart. Within the brain, the heptapeptide angiotensin(1-7) mimics some effects of angiotensin II, but may be formed directly from angiotensin I. Evidence for non-ACE-mediated angiotensin II production has been reported in the heart. Intravascular angiotensin II receptors are implicated in the central release of vasopressin and other hypophyseal hormones, in increasing sympathetic outflow, in the thirst response and, possibly, in cognitive function; in the inotropic and chronotropic effects of angiotensin II on the heart as well as in growth/hypertrophy; in the control of aldosterone release and in the balance between cortisol and aldosterone secretion; and in modulating sodium, chloride and bicarbonate transport within the kidney ⁷.

References

1. Skeggs LT, Lentz KE, Kahn, Jr, Shumway NP, Woods KR (1956). The amino acid sequence of hypertensin II. J Exp Med., 104:193-197.
2. Bumpus FM, Schwartz H and Page IH (1957) Synthesis and pharmacology of the octapeptide angiotonin. Science., 125:886-887.
3. Elliott DF,Peart WS (1956). Amino acid sequence in a hypertensin. Nature, 177:527-528.
4. Ion Haulica, Walther Bild and Dragomir N Serban (2005). Review: Angiotensin Peptides and their Pleiotropic Actions. Renin Angiotensin Aldosterone Syst., 6: 121.
5. Paula RD, Lima CV, Britto RR, Campagnole-Santos MJ, Khosla MC, Santos RA (1999). Potentiation of the hypotensive effect of bradykinin by angiotensin-(1-7)-related peptides. Peptides., 20(4):493-500.
6. Mehta PK, Griendling KK  (2007). Angiotensin II cell signaling: physiological and pathological effects in the cardiovascular system. Am J Physiol Cell Physiol., 292(1):82-97.
7. Lees KR, MacFadyen RJ, Doig JK, Reid JL (1993). Role of angiotensin in the extravascular system. J Hum Hypertens., 7(2):7-12.