Giapreza: A Look at the Pharmacology of Ang2

Angiotensin-II (Ang2) is now an FDA approved vasopressor. With this new addition to the available options, experts are combing over the available literature to determine whether to incorporate it into their daily practices. The ATHOS-3 trial has demonstrated that Ang2 is, at minimum, effective and safe when added to norepinephrine or other similarly dosed vasopressors.¹ Although this trial should be critically appraised and has been done so by EMCrit, REBEL EM and others, let's take a step back and examine the pharmacology of Ang2. By doing so, hopefully we can add some perspective to how it is exerting its effects and maybe even predict some therapeutic misadventures that are likely to occur, once exposed to thousands of patients in real-world settings.

Ang2 is a critical element in the renin-angiotensin-aldosterone system (RAAS). RAAS is analogous to the coagulation cascade, in that, the one we all learned in school tremendously over simplified. Similarly, stating Ang2 is a vasopressor via agonist actions on the AT1 receptor is an oversimplification. Acknowledging that this is a complex pathway, to understand the effects of Ang2 let’s look at some elements of the RAAS in more depth from our core pharmacology textbooks.^2,3

Ang2 Basics^2,3

Angiotensinogen is converted to angiotensin-I (Ang1) by renin. From our understanding of the pharmacotherapy for hypertension, we are familiar with the conversion of Ang1 by angiotensin converting enzyme (ACE) to Ang2. Ang2, then goes on to exert its effects on angiotensin 1 (AT1) and AT2 receptors.

The AT1 agonist effects lead to increased peripheral resistance via the coupling of Gq to activate the PLCβ—IP3–Ca2+ pathway. The AT2 agonist effects lead to decreased resistance through numerous mechanisms, including NO synthesis, bradykinin production, and inhibition of Ca2+ channel antagonism

The net effect is AT1 agonist effects, under normal physiological scenarios.

Lesser-Known RAAS Elements (Ang3, Ang4, Ang(1-7), and ACE2)^2,3

Ang1 is a decapeptide consisting of the following peptide sequence: Asp-Arg-Val-Tyr-Ile-His-Pro-Phe-His-Leu. Thus, Ang1 can be referred to as Ang(1-10), and depending on the location of enzymatic cleavage, downstream Ang metabolites follow a logical nomenclature (ie, Ang(1-7), Ang(2-8), Ang(3-8), etc.). This is relevant, because there are other metabolites from Ang1 other than Ang2 that have physiologic effects and follow this nomenclature.

Ang2 can be converted by aminopeptidase (AP) to Ang3 and again by AP to Ang4, which have effects on AT2 and AT4 receptors, respectively.

Ang3 has about the same effects of aldosterone equal to Ang2 but is 25% as potent (vs Ang2) on blood pressure (BP) elevation and 10% as potent (vs Ang2) on adrenal medulla stimulation. Ang4 has minimal hemodynamic effects but has some fascinating effects on memory and cognition

ACE2, different from ACE, and expressed in the endothelium of heart, kidneys, and testes, produces Ang(1-7) either directly from Ang1 to Ang(1-7) or by metabolizing Ang2 to Ang(1-7). The actions of Ang(1-7) on Mas receptors oppose those of Ang2 similar to AT2 activation. However, in most physiological scenarios, the ratio of ACE-Ang2/ACE2-Ang(1—7) favors the effects of Ang2.^2-4

Ang(1-7) is gaining attention in terms of therapeutic benefit itself. There is growing research in humans based on animal models supporting its numerous potential benefits, including, but not limited to anti-arrhythmic effects, antithrombosis, protection of endothelial function, improvement in NO release, and increased cardiac output.⁴

There are several other newly identified components of RAAS, including alamandine, AngA, Ang(1-9), Ang(1-5), MrgD receptors.

The complex effects of these peptides are outlines in the Table.^2-4Table: Complex Effects of Peptides

Peptide

Formation pathway

Effects

Ang2

ACE on Ang1

Chymase on Ang1

Cathepsin G

Tonin

Chymostatin-sensitive AngII-generating enzyme

Heart chymase

AT1 agonist effects

• Coupling of Gq to activate the PLCβ—IP3–Ca2+ pathway

AT2 agonist effects

• Activation of phosphoprotein phosphatases
• K+ channels
• NO synthesis, cyclic GMP
• Bradykinin production
• Inhibition of Ca2+ channel functions

Other effects

• CNS Increased secretion of vasopressin and ACTH
• Cell growth Stimulation of Jak2, ERK1/2, and NFκB
• ROS generation through activity on membrane-bound NADH/NADPH oxidase
• Stimulation of endothelin 1 and superoxide anion

Ang3

[aka Ang(2—8)]

AP on Ang2

ACE on Ang(2—10)

• Induces aldosterone synthesis and release equal to Ang2
• 25% as potent (vs Ang2) on BP elevation
• 10% as potent (vs Ang2) adrenal medulla stimulation

Ang(1-7)

Endopeptidases on Ang1

Prolylcarboxypeptidase on Ang2

Opposes Ang2, depending on the ACE-Ang2/ACE2-Ang(1—7) activity ratio

Binds primarily to Mas receptors (AT2 to a lesser extent)

• Vasodilation, includes NO production, potentiates bradykinin vasodilation.
• Anti-angiogenic, anti-proliferative, and anti-thrombotic effects

Ang4

[aka Ang(3-8)]

AP-M on Ang3

Acts on AT4 receptors

• Subtype of AT4 receptors are insulin-regulated aminopeptidase (IRAPs).
• Ang4 inhibits IRAPs and enables accumulation of various neuropeptides linked to memory potentiation, renal vasodilation, natriuresis, neuronal differentiation, hypertrophy, inflammation, and extracellular matrix remodeling.
• AT4 co-localizes with the glucose transporter GLUT4.

Net Effects of Ang2

Once formed, the effects of Ang2 can be described in 3 main phases: fast pressor response; slow pressor response; and vascular/cardiac remodeling and hypertrophy.

Fast Pressor Response^2,3

Naturally, the fast pressor response is the desirable effect of the newly approved Giapreza, the brand name for Ang2. Breaking down the fast pressor response further, there are 3 mechanisms by which Ang2 exerts the fast pressor response:

• As previously stated, stimulation of the Gq—PLC–IP3–Ca2+ pathway --> rapid increase in peripheral resistance Ang2 can also increase the BP set point for baroreceptor reflex through actions in the central nervous system, thus causing either no change in HR or a slight decrease
• Inhibition of norepinephrine reuptake (increased release from nerve terminals) and by enhancing the vascular response to norepinephrine
• Depolarization of adrenal chromaffin cells, leading to release of catecholamines

Sast Pressor Response/Vascular and Cardiac Remodeling^2,3

The slow pressor response, with an onset after days of continuous therapy with Ang2, is a result of sodium reabsorption in the proximal tubule and further sodium retention through the actions of aldosterone. Ultimately, this sodium retention leads to increased plasma volumes. However, Ang2 can have complex effects on renal function. Depending on renal hemodynamics, Ang2 can either cause GFR to be increased or decreased.

Decreases in GFR can occur as a result of Ang2, through increased resistance renal vascular smooth muscle, by enhancing renal sympathetic tone, and by facilitating intrarenal adrenergic transmission. Increased GFR can occur during renal artery hypotension (ie, shock), the effects of Ang2 are on the efferent arteriole, thus an increase in GFR. On the flip side, giving this patient an ACEi/ARB would potentiate acute renal failure.

To a lesser extent, Ang2 stimulates the synthesis of endothelin-1 and superoxide anion. By these mechanisms over time and from our understanding of the neurohormonal theory of heart failure, Ang2 stimulates remodeling of the cardiovascular system. This inflammatory chemokine and cytokine response to Ang2 involved in vascular and cardiac remodeling also results in the increased release of plasminogen activator inhibitor 1 and augmenting the expression of adhesion proteins in vascular cells, which may be of concern in the critically ill.^2,3

Ang2 is certainly not a straightforward drug that we are adding to the already complex pharmacotherapy in shock. While the pharmacology of Ang2 is supportive of the theory of addressing multiple pathways of improving vascular resistance and perfusion, there are numerous unanswered questions.⁵

Some risks of complications or blunting of benefits of Ang2 could be observed with concomitant neutral endopeptidase inhibitors (aka NEP, neprilysin) such as sacubitril, or DPP4 inhibitors by limiting the production of Ang(1-7).

Some other critiques of Ang2 I have heard anecdotally include the incidence of thrombosis in ATHOS-3. As outlined above, though this is certainly possibly explained through some of the unwanted effects of Ang2, the available evidence is certainly not sufficiently powered to appropriately describe this risk. A lack of mortality/morbidity benefit is another common critique. I think this is another scenario where would we expect a vasopressor to improve mortality in a large, diverse population? Probably not. However, in specific patient cases, there may be a morbidity benefit that may be small but clinically important.

Although it is easy to critique Ang2 and its evidence, we must not forget that no available vasopressor has gone through any regulatory approval for use, yet we use them daily. Furthermore, sympathomimetics and vasopressin have similar, complex effects on numerous other physiologic pathways that led to their associated deleterious effects. I think Ang2 will have a role in the management of shock. However, I do not expect it to replace any available regimen and would not be surprised if there are serious adverse events that arise in clinical practice.

References

1. Khanna A, English SW, Wang XS. Angiotensin II for the treatment of vasodilatory shock. N Engl J Med. 2017;377(5):419-430. doi: 10.1056/NEJMoa1704154.

2. Reid IA. Vasoactive peptides. In: Katzung BG, Trevor AJ, eds. Basic & Clinical Pharmacology. 14th ed. New York, NY: McGraw-Hill; 2017.

3. Hilal-Dandan R. Renin and angiotensin. In: Brunton LL, Knollman BC, Hilal-Dandan R, eds. Goodman & Gilman's: The Pharmacological Basis of Therapeutics. 13th ed. New York, NY: McGraw-Hill; 2017.

4. Chawla LS, Busse LW, Brasha-Mitchell E, Alotaibi Z. The use of angiotensin II in distributive shock. Crit Care. 2016;20(1):137. doi: 10.1186/s13054-016-1306-5.

5. Busse LW, McCurdy MT, Ali O, Hall A, Chen H, Ostermann M. Crit Care. 2017;21(1)324. doi: 10.1186/s13054-017-1896-6.