A novel mechanism of mechanical stress-induced angiotensin II type 1–receptor activation without the involvement of angiotensin II

The angiotensin II (AngII) type 1 (AT(1)) receptor is a seven transmembrane-spanning G-protein-coupled receptor, and the activation of AT(1) receptor plays an important role in the development of load-induced cardiac hypertrophy. Locally generated AngII was believed to trigger cardiac hypertrophy by an autocrine or paracrine mechanism. However, we found that mechanical stress can activate AT(1) receptor independently of AngII. Without the involvement of AngII, mechanical stress not only activates extracellular signal-regulated kinases in vitro, but also induces cardiac hypertrophy in vivo. All of these events are inhibited by candesartan as an inverse agonist for AT(1) receptor. It is conceptually novel that AT(1) receptor directly mediates mechanical stress-induced cellular responses, and inverse-agonist activity emerges as an important pharmacological parameter for AT(1)-receptor blockers that determines their efficacy in preventing organ damage in cardiovascular diseases.     

Do all angiotensin II type 1 receptor blockers have the same beneficial effects?

Angiotensin II type 1 (AT(1)) receptor blockers (ARBs) are highly selective for the AT(1) receptor, which is a member of the G protein-coupled receptor superfamily (GPCRs), and block the diverse effects (hypertension, hypertrophy, heart failure, proteinuria etc.) of angiotensin II. Many ARBs are in clinical use and have been shown to be safe and effective. Over the past several years, reports have discussed the different degrees of the beneficial effects of ARBs. As ARBs do not all have the same effects, the benefits conferred by ARBs may not be class effects. These different effects may be due to differences in the molecular characteristics of ARBs. The results reported by Le et al. in this issue highlight the different characteristics of two ARBs, olmesartan and telmisartan, and suggest that the higher degree of insurmountability, slower dissociation, and higher affinity of olmesartan compared to telmisartan for AT(1) receptors may help it to form a tight binding complex with this receptor. A better understanding of the different molecular mechanisms for each ARB could be useful for the treatment of patients.     

Effects of angiotensin II and its metabolites in the rat coronary vascular bed: is angiotensin III the preferred ligand of the angiotensin AT2 receptor?

Aminopeptidases metabolize angiotensin II to angiotensin-(2-8) (=angiotensin III) and angiotensin-(3-8) (=angiotensin IV), and carboxypeptidases generate angiotensin-(1-7) from angiotensin I and II. Angiotensin-converting enzyme (ACE) inhibitors and/or angiotensin II type 1 (AT1) receptor blockers affect the concentrations of these metabolites, and they may thus contribute to the beneficial effects of these drugs, possibly through stimulation of non-classical angiotensin AT receptors. Here, we investigated the effects of angiotensin II, angiotensin III, angiotensin IV and angiotensin-(1-7) in the rat coronary vascular bed, with or without angiotensin AT1 - or angiotensin II type 2 (AT2) receptor blockade. Results were compared to those in rat iliac arteries and abdominal aortas. Angiotensin II, angiotensin III and angiotensin IV constricted coronary arteries via angiotensin AT1 receptor stimulation, angiotensin III and angiotensin IV being approximately 20- and approximately 8000-fold less potent than angiotensin II. The angiotensin AT2 receptor antagonist PD123319 greatly enhanced the constrictor effects of angiotensin III, starting at angiotensin III concentrations in the low nanomolar range. PD123319 enhanced the angiotensin II-induced constriction at submicromolar angiotensin II concentrations only. Angiotensin-(1-7) exerted no effects in the coronary circulation, although, at micromolar concentrations, it blocked angiotensin AT1 receptor-induced constriction. Angiotensin AT2 receptor-mediated relaxation did not occur in iliac arteries and abdominal aortas, and the constrictor effects of the angiotensin metabolites in these vessels were identical to those in the coronary vascular bed. In conclusion, angiotensin AT2 receptor activation in the rat coronary vascular bed results in vasodilation, and angiotensin III rather than angiotensin II is the preferred endogenous agonist of these receptors. Angiotensin II, angiotensin III, angiotensin IV and angiotensin-(1-7) do not exert effects through non-classical angiotensin AT receptors in the rat coronary vascular bed, iliac artery or aorta.     

Does the angiotensin II receptor antagonist losartan improve cognitive function?

Newer classes of antihypertensive agents, such as angiotensin II receptor antagonists, may offer benefits to patients in addition to their ability to lower blood pressure. It is accepted that chronic hypertension contributes to the development of cerebrovascular and cardiovascular disease, and several studies have demonstrated a link between hypertension and reduced cognitive function, especially in patients not receiving antihypertensive medication. In an initial clinical trial, the angiotensin II receptor antagonist losartan was shown to improve cognitive function in patients with hypertension, including in those who were elderly (up to 73 years of age). This effect cannot be explained by a reduction in blood pressure alone and is likely to involve interactions with the diverse biological actions of the renin-angiotensin system. Improving or maintaining cognitive function in patients with hypertension may translate into economic benefits beyond those expected due to blood pressure control, and would result in considerable quality-of-life benefits for the aging population.     

Imaging the high-affinity state of the dopamine D2 receptor in vivo: Fact or fiction?

Positron Emission Tomography (PET) has been used for more than three decades to image and quantify dopamine D2 receptors (D2R) in vivo with antagonist radioligands but in the recent years agonist radioligands have also been employed. In vitro competition studies have demonstrated that agonists bind to both a high and a low-affinity state of the D2Rs, of which the high affinity state reflects receptors that are coupled to G-proteins and the low-affinity state reflects receptors uncoupled from G-proteins. In contrast, antagonists bind with uniform affinity to the total pool of receptors. Results of these studies led to the proposal that D2Rs exist in high and low-affinity states for agonists in vivo and sparked the development and use of agonist radioligands for PET imaging with the primary purpose of measuring the proportion of receptors in the high-affinity (activating) state. Although several lines of research support the presence of high and low-affinity states of D2Rs and their detection by in vivo imaging paradigms, a growing body of controversial data has now called this into question. These include both in vivo and ex vivo studies of anesthesia effects, rodent models with increased proportions of high-affinity state D2Rs as well as the molecular evidence for stable receptor-G-protein complexes. In this commentary we review these data and discuss the evidence for the in vivo existence of D2Rs configured in high and low-affinity states and whether or not the high-affinity state of the D2R can, in fact, be imaged in vivo with agonist radioligands.     

Targeting the renin–angiotensin system for the reduction of cardiovascular outcomes in hypertension: angiotensin-converting enzyme inhibitors and angiotensin receptor blockers

Agents that counteract the negative impact of the renin–angiotensin–-aldosterone system (RAAS) are effective antihypertensives and reduce the risk of developing Type 2 diabetes. Contrary to common perception, angiotensin-converting enzyme inhibitors do not share the apparent benefit of angiotensin II receptor blockers (ARBs) in reducing risk of cardiovascular-disease outcomes, particularly stroke, in randomised clinical trials. RAAS agents, especially ARBs, are well tolerated. Use of ARBs alone or in combination with other classes of antihypertensive agents to lower blood pressure and/or medications to control other conditions (e.g., insulin sensitivity) reduces risk of cardiovascular disease outcomes and Type 2 diabetes with excellent tolerability. Selected issues related to use of RAAS agents as antihypertensive therapies (e.g., Type 2 diabetes, global risk management, multiple drug therapy and coronary heart disease) are addressed.     

Effect of converting enzyme inhibition and angiotensin receptor blockade on the vasoconstriction mediated by α1 and α2 stimulation in pithed normotensive rats

Summary The effect of functional impairment of the renin-angiotensin system on the vasoconstriction mediated by postsynaptic ₁ and ₂-adrenoceptors in pithed normotensive rats was studied. Selective ₁-adrenoceptor stimulation was induced by intravenously administered cirazoline, whereas B-HT 920 was used as a selective agonists at ₂-adrenoceptors. The angiotensin converting enzyme was inhibited by intravenous treatment of the pithed rats with captopril, teprotide or enalapril. Blockade of angiotensin receptors was produced by intravenously applied [Sar¹ Ala⁸]angiotensin II (saralasin). Pretreatment with angiotensin converting enzyme inhibitors or with saralasin in doses which produced a maximal reduction in basal diastolic blood pressure, only slightly attenuated the hypertensive response to cirazoline. In contrast, these drugs provoked a most significant reduction of the ₂-adrenoceptor mediated vasoconstriction. Restoration of the basal diastolic blood pressure by intravenous infusion with angiotensin II or with vasopressin completely reversed the inhibitory effect of captopril on the vasopressor response to B-HT 920. One hour after bilateral nephrectomy, captopril still reduced the ₂-adrenoceptor mediated vasoconstriction. However, 18–24 h after bilateral nephrectomy, captopril had no additional inhibitory effect on the vasopressor response to selective ₂-adrenoceptor stimulation. It is concluded that in pithed normotensive rats the pressor response to ₂-adrenoceptor stimulation is significantly potentiated by endogenous angiotensin II, even at low circulating levels of the octapeptide. The modulatory action of angiotensin II on the -adrenoceptor mediated vasoconstriction probably represents an effect on the basal arteriolar muscular tone rather than a specific interaction.     

Telmisartan prevents the progression of renal injury in daunorubicin rats with the alteration of angiotensin II and endothelin-1 receptor expression associated with its PPAR-γ agonist actions

Angiotensin II (Ang II) receptor blocker (ARB) suppresses the progression of kidney disease. However, there is limited information regarding the nephroprotective effect of ARB in daunorubicin (DNR)-induced nephrotoxicity in rats. We examined the alteration of the renal Ang II and endothelin-1 (ET-1) receptor expression and the action of telmisartan, an ARB, on DNR-induced nephrotoxicity. Sprague-Dawley rats were treated with a cumulative dose of 9 mg/kg DNR (i.v.). Telmisartan was administered orally every day for 6 weeks. DNR rats showed nephrotoxicity as evidenced by worsening renal function, which was evaluated by measuring protein in urine, levels of urea and creatinine in serum, lipid profiles, malondialdehyde level, and the glutathione peroxidase activity in kidney tissue. These changes were reversed by treatment with telmisartan, which resulted in significant improvement in renal function. Furthermore, telmisartan increased nephrin protein expression, and down-regulated renal expression of Ang II and its receptor Ang II type I. Renal protein expressions of ET-1 and its receptor ET-receptor type A were increased in DNR rats, and treatment with telmisartan attenuated these increased expressions. Telmisartan mediated a further increase in the expression of peroxisome proliferator-activated receptor-γ (PPAR-γ). In addition, the expressions of cyclooxygenase-2 and cellular adhesion molecules were increased in DNR rats, which were attenuated by telmisartan. In conclusion, telmisartan has a protective effect on DNR-induced nephrotoxicity through Ang II and ET-1, with the alteration of their receptor expressions, which is associated with its anti-inflammatory and anti-oxidant effects at least in part through PPAR-γ agonistic actions.     

Conundrum of angiotensin II and TGF-β interactions in aortic aneurysms

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Highlights► The renin angiotensin system plays a critical role on aortic aneurysmal formation and development. ► Angiotensin II and TGF-β have potential interactions in the development of aortic aneurysms. ► The definitive roles of TGF-β in the development of aortic aneurysms need to be clarified.     

Azilsartan medoxomil in the treatment of hypertension: the definitive angiotensin receptor blocker?

Introduction: Azilsartan medoxomil is the newest angiotensin receptor blocker marketed for the treatment of arterial hypertension. The aim of this article was to review the available evidence about this drug alone or combined with other antihypertensive agents in the treatment of hypertensive population.

Areas covered: For this purpose, a search on MEDLINE and EMBASE databases was performed. The MEDLINE and EMBASE search included both medical subject headings (MeSHs) and keywords including azilsartan or azilsartan medoxomil or angiotensin receptor blockers or renin angiotensin system or chlorthalidone and hypertension. References of the retrieved articles were also screened for additional studies. There were no language restrictions.

Expert opinion: Azilsartan medoxomil has a potent and persistent ability to inhibit binding of angiotensin II to AT1 receptors, which may play a role in its superior blood pressure (BP) -lowering efficacy compared with other drugs, including ramipril, candesartan, valsartan or olmesartan, without an increase of side effects. Chlortalidone is a diuretic which significantly differs from other classic thiazides and has largely demonstrated clinical benefits in outcome trials. The fixed-dose combination of azilsartan and chlorthalidone has been shown to be more effective than other potent combinations of angiotensin receptor blockers plus hydrochlorothiazide, with a good tolerability profile.     

Can the renin-angiotensin system protect against stroke? A focus on angiotensin II receptor blockers

From a patient's perspective, stroke is the most devastating form of cardiovascular disease, representing the number one cause of permanent disability in the United States. Treatment of hypertension significantly reduces the risk of stroke; however, it is unclear whether all antihypertensive agents are equivalent in this regard. Angiotensin-converting enzyme (ACE) inhibitors have been shown to reduce the risk of cardiovascular events, including stroke. Although attenuation of the renin-angiotensin system (RAS) is often credited with the blood pressure-independent effects of this class of agents, this hypothesis has not been confirmed with regard to the end point of stroke. In fact, drugs that activate the RAS, such as diuretics and dihydropyridine calcium channel blockers, are as effective or superior to ACE inhibitors for stroke prevention. Angiotensin II receptor blockers (ARBs) selectively block the angiotensin II subtype I receptor, which results in a reflexive increase in levels of angiotensin II and unopposed activation of angiotensin II subtype 2 receptors. Clinical trials comparing ARBs with active controls have reported significant reductions in stroke in ARB-treated patients. Data on ARBs and other drugs that activate the RAS (diuretics and dihydropyridine calcium channel blockers) support a potential role for the RAS in protecting against stroke. Ongoing trials with ARBs are evaluating stroke as a primary end point, and results should help to further elucidate the role of ARBs in this disease. Until then, it is prudent to treat hypertension with an agent or combination of agents that are likely to result in a rapid and sustained reduction in blood pressure, taking into consideration patient characteristics, comorbidities, tolerability, and cost.     

Effect of angiotensin Ⅱ type 1 receptor on delayed rectifier potassium current in catecholaminergic CATH.a cells

AIM: To study the modulatory effects of angiotensin Ⅱ (Ang Ⅱ) on the delayed rectifier potassium (Kv) current (IKv) and its underlying intracellular mechanism in the catecholaminergic system of rats. METHODS: AT1 and AT2 receptors of the differentiated and undifferentiated CATH.a cells were determined by radioligands binding assay. The IKv was recorded with the whole cell patch-clamp configuration in voltage clamp mode on CATH.a cells. RESULTS: The Ang Ⅱ receptor proteins including AT1 and AT2 receptors were expressed in CATH.a cells, and the number of the former was significantly more than the latter (P<0.01). The IKv of CATH.a cells was reduced by superfusion with the Ang Ⅱ (100 nmol/L) (P<0.05) in the presence of the AT2 receptor antagonist PD123319, but was not affected by only superfusion with PD123319. The effect of Ang Ⅱ on IKv in CATH.a cells was completely inhibited by addition of AT1 receptor antagonist losartan. Superfusion with Ang Ⅱ (100 nmol/L) plus U73122, an inhibitor of     

Angiotensin II type 2 receptor agonists--where should they be applied?

It is now widely accepted that the renin-angiotensin system (RAS) not only contributes to pathological mechanisms involved, e.g. in hypertension or hypertensive and diabetic end-organ damage, but also harbors a "protective arm" represented mainly by two receptors, the AT2 (angiotensin type 2) receptor and the Mas receptor, both mediating tissue-protective and pro-regenerative actions. Several compounds are currently in preclinical and clinical development, which aim at targeting the "protective RAS" by agonism on the AT2 or the Mas receptor. In a recent issue of Expert Opinion on Investigational Drugs Koen Verdonk and co-authors review the physiology and patho-physiology of the AT2 receptor and discuss potential future clinical indications and putative adverse effects of AT2 receptor agonists. This article comments the review by Verdonk et al., suggests some additional possible indications, and particularly re-reviews whether there is preclinical in vivo evidence for adverse effects of AT2 receptor agonists.     

Obesity and gastrointestinal hormones-dual effect of angiotensin II receptor blockade and a partial agonist of PPAR-γ

Obesity is strongly associated with type 2 diabetes, hypertension, and hyperlipidemia, which is one of the leading causes of mortality and morbidity worldwide. It is now clear that gut hormones play a role in the regulation of body weight and represent therapeutic targets for the future treatment of obesity. Recent evidence demonstrated that dysregulation of adipocytokine functions seen in abdominal obesity may be involved in the pathogenesis of the metabolic syndrome. Angiotensinogen, the precursor of angiotensin (Ang) II, is produced primarily in the liver, but also in adipose tissue, where it is up-regulated during the development of obesity and involved in blood pressure regulation and adipose tissue growth. Importantly, blockade of the RAS attenuates weight gain and adiposity by enhanced energy expenditure. The favorable metabolic effects of telmisartan have been related to its Ang II receptor blockade and action as a partial agonist of peroxisome proliferators activated receptor (PPAR)-γ. PPARγ plays an important role in regulating carbohydrate and lipid metabolism, and ligands for PPARγ can improve insulin sensitivity and reduce triglyceride levels. We designed a comparative study of telmisartan and losartan in ApoE-deficient mice. Treatment with telmisartan or losartan significantly reduced the development of lipid-rich plaque. However, treatment with telmisartan significantly improved endothelial dysfunction and inhibited lipid accumulation in the liver. These favorable characteristics of telmisartan might be due to its action as a partial agonist of PPAR-γ, beyond its blood pressure-lowering effect, through Ang II blockade, which may be called "metabosartan".     

Troglitazone induces cytotoxicity in part by promoting the degradation of peroxisome proliferator-activated receptor �� co-activator-1�� protein

BACKGROUND AND PURPOSE

Troglitazone (Tro), rosiglitazone (Rosi) and pioglitazone (Pio) are anti-diabetic thiazolidinediones that function as ligands for peroxisome proliferator-activated receptor γ (PPARγ); however, Tro has been withdrawn from the market due to liver toxicity issues. Mitochondrial dysfunction induced by Tro has been suggested to be an important mechanism behind its cytotoxicity. Constitutively active nuclear hormone receptors, oestrogen-related receptor α and γ are thought to regulate mitochondrial mass and oxidative phosphorylation together with their co-activators PPARγ co-activator-1α and -1β (PGC-1α and PGC-1β). Hence, in this study, we investigated whether Tro affects the expression and activity levels of these regulators.

EXPERIMENTAL APPROACH

Cellular viability was measured by an ATP-based assay. Mitochondrial mass and reactive oxygen species (ROS) were quantified by two different fluorogenic probes. Apoptosis was measured by an Annexin-V-based kit. Gene expression at the levels of mRNA and protein was measured by quantitative RT-PCR and Western analysis. Over-expression of PGC-1α was mediated by an adenovirus.

KEY RESULTS

Tro, but not Rosi or Pio, selectively stimulated PGC-1α protein degradation. As a result, Tro reduced mitochondrial mass, and superoxide dismutases 1 and 2 expressions, but induced ROS to initiate apoptosis. Using a ubiquitin–proteasome inhibitor MG132, it was established that blocking PGC-1α degradation partially suppressed the reduction of mitochondrial mass. Importantly, over-expressing PGC-1α partially restored the Tro-suppressed mitochondrial mass and attenuated the cytotoxic effects of Tro.

CONCLUSIONS AND IMPLICATIONS

Collectively, these results suggest that PGC-1α degradation is an important mechanism behind the cytotoxic effects of Tro in the liver.     

Discovery of a series of imidazo[4,5-b]pyridines with dual activity at angiotensin II type 1 receptor and peroxisome proliferator-activated receptor-γ

Mining of an in-house collection of angiotensin II type 1 receptor antagonists to identify compounds with activity at the peroxisome proliferator-activated receptor-γ (PPARγ) revealed a new series of imidazo[4,5-b]pyridines 2 possessing activity at these two receptors. Early availability of the crystal structure of the lead compound 2a bound to the ligand binding domain of human PPARγ confirmed the mode of interaction of this scaffold to the nuclear receptor and assisted in the optimization of PPARγ activity. Among the new compounds, (S)-3-(5-(2-(1H-tetrazol-5-yl)phenyl)-2,3-dihydro-1H-inden-1-yl)-2-ethyl-5-isobutyl-7-methyl-3H-imidazo[4,5-b]pyridine (2l) was identified as a potent angiotensin II type I receptor blocker (IC(50) = 1.6 nM) with partial PPARγ agonism (EC(50) = 212 nM, 31% max) and oral bioavailability in rat. The dual pharmacology of 2l was demonstrated in animal models of hypertension (SHR) and insulin resistance (ZDF rat). In the SHR, 2l was highly efficacious in lowering blood pressure, while robust lowering of glucose and triglycerides was observed in the male ZDF rat.