Angiotensin II Research & Studies

Angiotensin II receptor blockers are a class of medications that selectively inhibit the binding of angiotensin II to the angiotensin type 1 receptor. This inhibition produces vasodilation, decreases aldosterone secretion, and lowers blood pressure. Angiotensin II receptor blockers are commonly prescribed for hypertension, congestive heart failure, and chronic kidney disease, including diabetic nephropathy. Their therapeutic role overlaps with that of angiotensin-converting enzyme inhibitors, but angiotensin II receptor blockers offer a valuable alternative for patients who experience adverse effects, such as cough or angioedema, with angiotensin-converting enzyme inhibitors. Although generally well-tolerated, angiotensin II receptor blockers may lead to hyperkalemia, hypotension, dizziness, or renal impairment. These medications are contraindicated during pregnancy and require caution in patients with bilateral renal artery stenosis. When combined with potassium-sparing diuretics or supplements, the risk of hyperkalemia increases. Their favorable safety and efficacy profiles make angiotensin II receptor blockers an important component of cardiovascular and renal disease management.

The objective of this study was to describe the implementation and outcomes of a protocol outlining angiotensin-II utilization for vasoplegia following cardiac surgery.

Dengue is a disease caused by a flavivirus that is transmitted principally by the bite of an Aedes aegypti mosquito and represents a major public-health problem. Many studies have been carried out to identify soluble factors that are involved in the pathogenesis of this infection. Cytokines, soluble factors, and oxidative stress have been reported to be involved in the development of severe disease. Angiotensin II (Ang II) is a hormone with the ability to induce the production of cytokines and soluble factors related to the inflammatory processes and coagulation disorders observed in dengue. However, a direct involvement of Ang II in this disease has not been demonstrated. This review primarily summarizes the pathophysiology of dengue, the role of Ang II in various diseases, and reports that are highly suggestive of the involvement of this hormone in dengue.

Angiotensin-II (Ang-II), a major target for treatment of cardiovascular disease, promotes cardiovascular dysfunction by directly modulating structure and function of vascular cells. Inflammasome components are expressed in the vasculature and are activated by specific stimuli. However, whether Ang-II activates the inflammasome in vascular cells or inflammasome activation contributes to Ang-II-induced vascular damage is still not fully elucidated. We tested the hypothesis that Ang-II induces endothelial dysfunction, vascular remodeling, and high blood pressure via inflammasome activation. C57BL6/J wild type (WT) and Caspase-1 knockout (Casp1-/-) mice were infused with vehicle or Ang-II for two weeks (490 ng/Kg/day) to determine whether the inflammasome contributes to vascular damage induced by Ang-II. Rat Aortic Vascular Smooth Muscle cells (RASMC) were used to determine if the interaction between Ang-II and inflammasomes causes migration and proliferation of vascular smooth muscle cells. Ex vivo studies revealed that Ang-II infusion induced vascular oxidative stress, endothelial dysfunction and vascular remodeling in WT mice. Casp1-/- mice were protected against Ang-II-induced vascular injury. In vitro experiments, Ang-II activated the NLRP3 inflammasome in RASMC, i.e. Ang-II increased Caspase-1 (Casp1) activity and cleavage of pro-interleukin (IL)-1β. MCC950 (NLRP3 receptor antagonist) prevented Ang-II-induced vascular migration and proliferation, but failed to reduce reactive oxygen species production. In conclusion, Ang-II leads to inflammasome activation in the vasculature contributing to endothelial dysfunction and vascular remodeling. Taken together, we place inflammasomes as a possible therapeutic target in conditions associated with increased Ang-II levels.

Septic shock is a life threatening condition and a medical emergency. It is associated with organ dysfunction and hypotension despite optimal volume resuscitation. Refractory septic shock carries a very high rate of mortality and is associated with ischemic and arrhythmogenic complications from high dose vasopressors. Angiotensin II (AT-II) is a product of the renin-angiotensin-aldosterone system. It is a vasopressor agent that has been recently approved by FDA to be used in conjunction with other vasopressors (catecholamines) in refractory shock and to reduce catecholamine requirements. We have reviewed the physiology and current literature on AT-II in refractory septic/vasodilatory shock. Larger trials with longer duration of follow-up are warranted to address the questions which are unanswered by the ATHOS-3 trial, especially pertaining to its effects on lungs, brain, microcirculation, inflammation, and venous thromboembolism risk.

Vasodilatory shock that does not respond to high-dose vasopressors is associated with high mortality. We investigated the effectiveness of angiotensin II for the treatment of patients with this condition.

Refractory septic shock is defined as persistently low mean arterial blood pressure despite volume resuscitation and titrated vasopressors/inotropes in patients with a proven or suspected infection and concomitant organ dysfunction. Its management typically requires high doses of catecholamines, which can induce significant adverse effects such as ischemia and arrhythmias. Angiotensin II (Ang II), a key product of the renin-angiotensin-aldosterone system, is a vasopressor agent that could be used in conjunction with other vasopressors to stabilize critically ill patients during refractory septic shock, and reduce catecholamine requirements. However, very few clinical data are available to support Ang II administration in this setting. Here, we review the current literature on this topic to better understand the role of Ang II administration during refractory septic shock, differentiating experimental from clinical studies. We also consider the potential role of exogenous Ang II administration in specific organ dysfunction and possible pitfalls with Ang II in sepsis. Various issues remain unresolved and future studies should investigate important topics such as: the optimal dose and timing of Ang II administration, a comparison between Ang II and the other vasopressors (epinephrine; vasopressin), and Ang II effects on microcirculation.

The angiotensin II receptor antagonists, also known as angiotensin receptor blockers (ARBs), are a family of agents that bind to and inhibit the angiotensin II type 1 receptor (AT1) and thus inhibit the renin-angiotensin system and its cascade of effects in causing arteriolar contraction and sodium retention. While angiotensin converting enzyme (ACE) inhibitors block the cleavage of angiotensin I to angiotensin II, the active peptide that causes a pressor response, the ARBs inhibit its peripheral action. The ARBs reduce blood pressure in animal models as well as in humans. Since their introduction in 1995, these agents have been used widely in the therapy of hypertension and to reduce the complications of hypertensive cardiovascular disease and diabetic nephropathy. The ARBs in clinical use in the United States include eight agents of similar chemical structure and activity, but somewhat different pharmacokinetics: losartan (Cozaar: 1995), valsartan (Diovan: 1996), irbesartan (Avapro: 1997), eprosartan (Teveten: 1997), candesartan (Atacand: 1998), telmisartan (Micardis: 1998), olmesartan (Benicar: 2002) and azilsartan (Edarbi: 2011). All of these agents have been associated with a minimal rate of serum enzyme elevations during chronic therapy (0.2% to 2%) which are usually mild-to-moderate in severity, self limited, and rarely require dose modification or discontinuation. As a class, the ARBs have been associated with rare instances of acute liver injury that is usually self limited in duration, but varies in clinical expression, being usually hepatocellular but occasional cholestatic in nature. The most common presentation of liver injury due to these agents is a cholestatic hepatitis arising within 1 to 8 weeks of starting and resolving as rapidly with stopping. Rare instances of prolonged jaundice have been described but not acute liver failure or autoimmune chronic hepatitis. Several Individual case reports of clinically apparent liver injury have been published in the literature for losartan, valsartan, irbesartan olmesartan and candesartan, but not specifically for azilsartan, eprosartan, and telmisartan, probably because these three have been in use for a shorter period of time and in fewer subjects. Most ARBs and particularly olmesartan have been linked to rare instances of severe sprue-like enteropathy. The enteropathy typically presents with severe diarrhea and weight loss with variable degrees of fatigue, nausea and abdominal discomfort arising 6 months to many years after starting the ARB. Small intestinal histological findings resemble those of celiac disease with flattening of the duodenal villuous pattern and villous atrophy. However, anti-transglutaminase and endomysial antibodies (the serologic markers of celiac disease) are negative and there is little or no response to a gluten-free diet. Withdrawal of the ARB, however, results in prompt improvement in the diarrhea and gradual resolution of duodenal villous flattening. Some cases of this drug induced enteropathy have had accompanying serum aminotransferase elevations and fatty liver by imaging or liver biopsy, which, along with the diarrhea, resolve rapidly with stopping the medication.

Hypertension is associated with an increased risk of thrombosis that appears to involve an interaction between the renin-angiotensin system and hemostasis. In this study we determined whether angiotensin II-mediated thrombosis occurs in arterioles and/or venules and assessed the involvement of type 1 (AT₁), type 2 (AT₂), and type 4 (AT₄) angiotensin II receptors, as well as receptors for endothelin 1 and bradykinin 1 and 2 in angiotensin II-enhanced microvascular thrombosis. Thrombus development in mouse cremaster microvessels was quantified after light/dye injury using the time of onset of the thrombus and time to blood flow cessation. Wild-type and AT₁ receptor-deficient mice were implanted with an angiotensin II-loaded ALZET pump for 2 weeks. Angiotensin II administration in both wild-type and ATAT₁ receptor-deficient mice significantly accelerated thrombosis in arterioles. Genetic deficiency and pharmacological antagonism of AT₁ receptors did not alter the thrombosis response to angiotensin II. Isolated murine platelets aggregated in response to low (picomolar) but not high (nanomolar) concentrations of angiotensin II. The platelet aggregation response to angiotensin II depended on AT₁ receptors. Antagonism of AT₂ receptors in vivo significantly prolonged the onset of angiotensin II-enhanced thrombosis, whereas an AT₄ receptor antagonist prolonged the time to flow cessation. Selective antagonism of either endothelin 1 or bradykinin 1 receptors largely prevented both the onset and flow cessation responses to chronic angiotensin II infusion. Our findings indicate that angiotensin II induced hypertension is accompanied by enhanced thrombosis in arterioles, and this response is mediated by a mechanism that involves AT₂, AT₄, bradykinin 1, and endothelin 1 receptor-mediated signaling.

The renin--angiotensin system (RAS) is a system of enzymes and hormones that regulate blood pressure and electrolyte and fluid homeostasis in mammals. Angiotensin II (Ang-II) is one of the most important and well-known components of RAS. It is formed from the protein precursor angiotensinogen by the sequential actions of proteolytic enzymes. The classic pathway of Ang-II generation includes a reaction catalyzed by angiotensin-converting enzyme (ACE). However, there are alternative pathways for the generation of Ang-II. In this paper, possible routes of formation of Ang-II in the human body are reviewed. Various Ang-II-generating enzymes (tonin, cathepsin G, chymase, etc.) and their properties are considered. The classification of these enzymes is also considered.

Acute blockade of the renin-angiotensin system with the parenterally active angiotensin II antagonist saralasin has been shown to effectively lower blood pressure in a large fraction of patients with essential hypertension and to improve hemodynamics in some patients with congestive heart failure. It is now possible to antagonize chronically angiotensin II at its receptor using the non-peptide angiotensin II inhibitor losartan (DuP 753, MK 954). When administered by mouth, this compound induces a dose-dependent inhibition of the pressor response to exogenous angiotensin II. This effect is closely related to circulating levels of the active metabolite E3174. Preliminary studies performed in hypertensive patients suggest that losartan has a blood pressure lowering action equivalent to that of an ACE inhibitor. Whether this compound will compare favorably with ACE inhibitors requires however further investigation.