Spectrum of use for the angiotensin-receptor blocking drugs

The renin-angiotensin system (RAS) plays an important role in regulating blood pressure, and maintaining fluid and electrolyte balance. Angiotensin II is the principal mediator of the RAS and has been implicated in the development of hypertension as well as other forms of cardiovascular and renal disease. Angiotensin II-receptor antagonists are a new class of drugs that inhibit the RAS by selectively blocking the AT₁ receptor. These compounds therefore provide more specific and thorough blockade of the RAS by inhibiting the deleterious actions of angiotensin II at the receptor level, irrespective of how this peptide is formed. The increased specificity of action of angiotensin II-receptor antagonists may also circumvent unwanted side-effects normally associated with angiotensin-converting enzyme (ACE) inhibitors (eg, cough and angioedema) as these agents do not interfere with the metabolism of other peptides (eg, bradykinin, substance P, etc.). There is still some concern with angiotensin II-receptor antagonists and the long-term effects of hyper-stimulation of the unopposed AT₂ receptor that is caused by elevated levels of angiotensin II. However, it appears that stimulation of the AT₂ receptor may actually contribute to the beneficial effects of angiotensin II-receptor antagonists by counteracting the effects mediated by the AT₁ receptor. Angiotensin II-receptor antagonists display great therapeutic promise in the field of cardiovascular medicine and are currently being exploited as new antihypertensive agents. These drugs have demonstrated safety, efficacy, and tolerability; however, morbidity and mortality data are still lacking. Nonetheless, it is likely that angiotensin II-receptor antagonists will become part of the medical arsenal against cardiovascular and renal disease, thus consideration should be given to their future use as first-line antihypertensive agents.     

Angiotensin II type 2 receptor-interacting protein prevents vascular senescence

Angiotensin II type 2 (AT₂) receptor-interacting protein (ATIP), which interacts with the C-terminal tail of the AT₂ receptor, regulates the functions of the AT₂ receptor. We have reported that AT₂ receptor stimulation attenuated vascular senescence. Therefore, we examined the possible negative role of ATIP in regulating vascular senescence. We generated ATIP-transgenic (Tg) mice, and cultured vascular smooth muscle cells (VSMCs). Persistent angiotensin II stimulation induced increases in SA-β-gal–positive cells and the level of a DNA damage marker, 8-OHdG in VSMC, whereas these effects of angiotensin II were attenuated in VSMC prepared from ATIP-Tg mice. Angiotensin II treatment also upregulated the expression of methyl methanesulfonate-sensitive 2 (MMS2), a DNA repair factor, and Src homology 2 domain-containing protein-tyrosine phosphatase 1 (SHP-1) activity, whereas these effects of angiotensin II were further enhanced in ATIP-Tg VSMC. In vivo, x-ray irradiation to mice caused increases in SA-β-gal–positive area and 8-OHdG level in the thoracic aorta; however, these effects were reduced in ATIP-Tg mice, with a significant increase in MMS2 expression. These results suggest that ATIP could inhibit VSMC senescence, involving MMS2 expression and SHP-1 activity. ATIP might be a new therapeutic molecule to treat vascular aging and age-related vascular diseases.     

Effect of angiotensin II type 2 receptor on stroke,cognitive impairment and neurodegenerative diseases

Here, we briefly review the role of the renin–angiotensin system (RAS) in cognitive impairment and neurodegenerative disease, mainly discussing our experimental studies on the angiotensin II type 2 (AT₂) receptor. Ischemic brain damage is enhanced in mice with overexpression of angiotensin II, with reduced cerebral blood flow in the penumbra and an increase in oxidative stress in the ischemic area. Angiotensin II binds two types of receptors, type 1 (AT₁) and type 2 (AT₂). Our previous experiments showed that AT₁ receptor signaling has a harmful effect, and AT₂ receptor signaling has a protective effect on the brain after stroke. AT₂ receptor signaling in bone marrow stromal cells or hematopoietic cells was shown to prevent ischemic brain damage after middle cerebral artery occlusion. In contrast, AT₂ receptor signaling also affects cognitive function. We showed that direct stimulation of the AT₂ receptor by a newly generated direct AT₂ receptor agonist, Compound 21 (C21), enhanced cognitive function in wild‐type (C57BL6) mice and an Alzheimer's disease mouse model with intracerebroventricular injection of amyloid β (1–40). Finally, we carried out clinical research by investigating the levels of RAS components in patients with neurodegenerative diseases. We observed a reduction of angiotensin II and angiotensin converting enzyme (ACE) 2 levels, and an increase in ACE level in cerebrospinal fluid from patients with multiple sclerosis. These results suggest that RAS is also involved in neurodegenerative disease. Therefore, regulation of RAS might be a new therapeutic target to protect neurons from neural diseases. Geriatr Gerontol Int 2012; ••: ••–•• .     

A critical role of cardiac fibroblast-derived exosomes in activating renin angiotensin system in cardiomyocytes

Chronic activation of the myocardial renin angiotensin system (RAS) elevates the local level of angiotensin II (Ang II) thereby inducing pathological cardiac hypertrophy, which contributes to heart failure. However, the precise underlying mechanisms have not been fully delineated. Herein we report a novel paracrine mechanism between cardiac fibroblasts (CF)s and cardiomyocytes whereby Ang II induces pathological cardiac hypertrophy. In cultured CFs, Ang II treatment enhanced exosome release via the activation of Ang II receptor types 1 (AT₁R) and 2 (AT₂R), whereas lipopolysaccharide, insulin, endothelin (ET)-1, transforming growth factor beta (TGFβ)1 or hydrogen peroxide did not. The CF-derived exosomes upregulated the expression of renin, angiotensinogen, AT₁R, and AT₂R, downregulated angiotensin-converting enzyme 2, and enhanced Ang II production in cultured cardiomyocytes. In addition, the CF exosome-induced cardiomyocyte hypertrophy was blocked by both AT₁R and AT₂R antagonists. Exosome inhibitors, GW4869 and dimethyl amiloride (DMA), inhibited CF-induced cardiomyocyte hypertrophy with little effect on Ang II-induced cardiomyocyte hypertrophy. Mechanistically, CF exosomes upregulated RAS in cardiomyocytes via the activation of mitogen-activated protein kinases (MAPKs) and Akt. Finally, Ang II-induced exosome release from cardiac fibroblasts and pathological cardiac hypertrophy were dramatically inhibited by GW4869 and DMA in mice. These findings demonstrate that Ang II stimulates CFs to release exosomes, which in turn increase Ang II production and its receptor expression in cardiomyocytes, thereby intensifying Ang II-induced pathological cardiac hypertrophy. Accordingly, specific targeting of Ang II-induced exosome release from CFs may serve as a novel therapeutic approach to treat cardiac pathological hypertrophy and heart failure.     

Novel actions of angiotensin II via its renal type-2 (AT2) receptor

The vast majority of the biologic effects of angiotensin II have been considered to be mediated by the subtype-1 (AT₁) receptor. The AT₂ receptor is expressed to a low degree in most adult cells and tissues, and its function has not been understood. Recent studies, however, have identified novel actions of angiotensin II mediated by the AT₂ receptor in the kidney. These AT₂ receptor actions have importance in the control of blood pressure and hypertension. The AT₂ receptor mediates a renal vasodilator cascade, including generation of bradykinin, nitric oxide, and cyclic GMP. This action of angiotensin II occurs when the renin-angiotensin system is activated, as in sodium depletion. The AT₂ receptor also appears to mediate prostaglandin (PG) F_α formation, probably by stimulating conversion of PGE2 to PGF_α. The AT₂ receptor plays a counter-regulatory vasodilator role opposing the vasoconstrictor actions of angiotensin II. The AT₁ and AT₂ receptors engage in inter-receptor “cross-talk.” In the absence of the AT₂ receptor, sustained angiotensin II pressor and antinatriuretic hypersensitivity occurs, mediated by a deficiency of bradykinin, nitric oxide, and cyclic GMP. The AT₂ receptor may play an important role in stimulating pressure natriuresis, but definitive studies are required to resolve this issue. The AT₂ receptor mediates several renal actions of angiotensin II, appears to be important in the physiologic regulation of blood pressure, and may be involved in the pathophysiology of hypertension.     

Assessing the Prognostic Implications of Myocardial Perfusion Studies: Identification of Patients at Risk vs Patients who May Benefit from Intervention?

Angiotensin II (AII), an octapeptide member of the renin-angiotensin system (RAS), is formed by the enzyme angiotensin converting enzyme (ACE) and exerts adverse cellular effects through an interaction with its type 1 receptor (AT₁R). Both ACE inhibitors and angiotensin receptor blockers (ARB) mitigate the vasoconstrictive, proliferative, proinflammatory, proapoptotic, and profibrotic effects of AII and are widely used as effective anti-remodeling agents in clinical practice. Prediction of individual response to these agents, however, remains problematic and is influenced by many factors including race, gender, and genotype. In addition, systemic and tissue RAS activity do not correlate closely. This report summarizes the results of on-going attempts to noninvasively determine tissue ACE activity and AT₁R expression using novel nuclear tracers. It is hoped that the availability of such imaging techniques improve treatment of heart failure through more selective pharmacologic intervention and better dose titration of available drugs.     

Angiotensin-receptor blockers: revival of the systemic prevention of restenosis?

Restenosis following percutaneous coronary transluminal angioplasty and stenting remains a significant problem, occurring in 15–50% of patients within 6–9 months of the intervention. Several pharmacological approaches to reduce restenosis have been evaluated but to date none have been approved for this indication. Angiotensin II has been implicated in the development of restenosis through several physiologic mechanisms, and thus control of the renin-angiotensin system may be a potential target for its prevention. Although human trials have shown that angiotensin-converting enzyme inhibitors do not reduce the risk of restenosis, early data suggest that the selective AT₁ angiotensin receptor blocker valsartan may be effective in preventing in-stent restenosis in patients with complex lesions.     

ARB and Cardioprotection

A growing body of evidence has suggested that the use of angiotensin II (Ang II) type 1 (AT₁) receptor blockers (ARBs) leads to a significant decrease in mortality and morbidity in patients with congestive heart failure. The AT₁ receptor is a seven-transmembrane G protein-coupled receptor, and is involved in regulating the physiological and pathological process of the cardiovascular system. Systemically and locally generated Ang II has agonistic action on AT₁ receptor. However, recent in vitro studies have demonstrated that AT₁ receptor is structurally flexible and instable, and has significant and varying levels of spontaneous activity in an Ang II-independent manner. Furthermore, mechanical stress activates AT₁ receptor by inducing conformational switch without the involvement of Ang II. Experimental studies have demonstrated that Ang II-independent activation of AT₁ receptor is profoundly relevant to the pathogenesis of cardiac remodeling in vivo, and that these agonist-independent activities of AT₁ receptor can be inhibited by inverse agonists, but not by neutral antagonists. Therefore, inverse agonist activity emerges as an important pharmacological parameter that contributes to cardioprotective effects of ARBs through inhibiting both Ang II-dependent and -independent activation of AT₁ receptor.     

Optimal strategies for preventing progression of renal disease: Should angiotensin converting enzyme inhibitors and angiotensin receptor blockers be used together?

Interruption of the renin-angiotensin system (RAS) with angiotensin converting enzyme (ACE) inhibitors or angiotensin AT₁ receptor blockers has been shown to delay progression in a variety of renal diseases, suggesting that the RAS, and its major effector molecule, angiotensin II, are important players in renal pathophysiology. Both antagonists combine inhibition of deleterious effects of angiotensin II with activation of potentially beneficial pathways mediated by nitric oxide and prostaglandins. Some concerns have been raised about the completeness of the RAS blockade achieved by these agents. ACE-independent pathways can generate angiotensin II, whereas increases in angiotensin II levels may compete with the AT₁ receptor blocker at the receptor site. It has been suggested that an ACE inhibitor/AT₁ receptor blocker combination offers a better therapeutic effect than treatment with either agent alone. In this review, we focus on mechanisms of actions of ACE inhibitors and AT₁ receptor blockers, implicate them in the rationale for the use of an ACE inhibitor/AT₁ receptor blocker combination, and discuss evidence evaluating the renal effects of the combination as compared to the effects of a single agent. There is a surprising lack of information about the nephroprotective potential of the combination, allowing no consistent conclusions about the superiority of the combination over the single agent. Several experimental and clinical reports suggest that in some conditions, the combination may be beneficial. Rather than providing unequivocal evidence for the use of combination treatment in the renal disease, these studies should be considered as stimuli for more detailed exploration of this issue.     

Apoptosis after reperfused myocardial infarction: Role of angiotensin II

Angiotensin II (Ang II) plays a significant role in apoptosis after myocardial infarction (MI) and reperfused MI. Cumulative evidence suggests that Ang II is a major contributor to cardiomyocyte (CM) apoptosis and left ventricular (LV) dysfunction after acute reperfused MI and that apoptosis mediates a major portion of early LV dysfunction. Importantly, blockade of the Ang II type 1 receptor (AT₁R) limits CM apoptosis and LV dysfunction after acute reperfused MI. Ang II type 2 receptor activation during AT₁R blockade contributes to these beneficial effects. The role of Ang II and apoptosis in chronic LV remodelling, healing and post-MI heart failure is more complex and involves effects on the CMs, fibroblasts and vascular cells. The long-term effects of agents targeting apoptosis after reperfused MI, including AT₁R blockade, on apoptosis in different cell types, windows of enhanced apoptosis and the appropriate timing of therapy need to be considered.     

The Role of Type 1 Angiotensin Receptors on T Lymphocytes in Cardiovascular and Renal Diseases

The renin–angiotensin system plays a critical role in the pathogenesis of several cardiovascular diseases, largely through activation of type I angiotensin (AT₁) receptors by angiotensin II. Treatment with AT₁ receptor blockers (ARBs) is a proven successful intervention for hypertension and progressive heart and kidney disease. However, the divergent actions of AT₁ receptors on individual cell lineages in hypertension may present novel opportunities to optimize the therapeutic benefits of ARBs. For example, T lymphocytes make important contributions to the induction and progression of various cardiovascular diseases, but new experiments indicate that activation of AT₁ receptors on T cells paradoxically limits inflammation and target organ damage in hypertension. Future studies should illustrate how these discrepant functions of AT₁ receptors in target organs versus mononuclear cells can be exploited for the benefit of patients with recalcitrant hypertension and other cardiovascular diseases.     

The significance of brain aminopeptidases in the regulation of the actions of angiotensin peptides in the brain

From the outset, the concept of a brain renin-angiotensin system (RAS) has been controversial and this controversy continues to this day. In addition to the unresolved questions as to the means by which, and location(s) where brain Ang II is synthesized, and the uncertainties regarding the functionality of the different subtypes of Ang II receptors in the brain, a new controversy has arisen with respect to the identity of the angiotensin peptide(s) that activate brain AT₁ receptors. While it has been known for some time that Ang III can activate Ang II receptors with equivalent or near-equivalent efficacy to Ang II, it has been proposed that in the brain, only Ang III is active. This proposal, which we have named “The Angiotensin III Hypothesis” states that Ang II must be converted to Ang III in order to activate brain AT₁ receptors. This review examines several aspects of the controversies regarding the brain RAS with a special focus on brain aminopeptidases, studies that either support or refute The Angiotensin III Hypothesis, and the implications of The Angiotensin III Hypothesis for the activity of the brain RAS. It also addresses the need for further research that can test The Angiotensin III Hypothesis and definitively identify the angiotensin peptide(s) that activate brain AT₁ receptor-mediated effects.     

Renal Angiotensin II Receptors,Hyperinsulinemia, and Obesity

Angiotensin II, via activation of AT₁ receptors in the kidney regulates sodium/fluid homeostasis and blood pressure. An exaggerated action of angiotensin II mediated via activation of AT₁ receptors has been implicated in the increased renal sodium retention and the resetting of the pressure natriuresis in obesity related hypertension. Treatment of obese Zucker rats with AT₁ receptor blockers reduces blood pressure to a greater extent and produces greater natriuresis. Also, there is an increased membranal AT₁ receptor numbers and angiotensin II produces greater activation of sodium transporters in the isolated tubules from obese Zucker rats. Interestingly, AT₂ receptors, which are believed to be beneficial to the renal and cardiovascular function in terms of their action on kidney and blood vessels, are greatly increased in proximal tubular membranes of obese Zucker rats. Whole animal and in vitro studies indicate that higher plasma insulin level, generally associated with obesity, is responsible for the up‐regulation of both AT₁ and AT₂ receptors in the kidney. Determining the consequence of selective blocking of AT₁ receptors and/or activation of the AT₂ receptors on renal and cardiovascular function, and the effect of lowering insulin on these receptors present an important area of further investigation in obesity.     

Efeitos cardiovasculares do receptor tipo 2 da angiotensina

The angiotensin type 2 receptor, AT₂R, has been described as having opposite effects to the angiotensin type 1 receptor, AT₁R. Although the quantities of the AT₂R found in the adult are low, its expression rises in pathological situations. The AT₂R has three major signaling pathways: activation of serine/threonine phosphatases (promoting apoptosis and antioxidant effects), activation of the bradykinin/NO/cGMP pathway (promoting vasodilation), and activation of phospholipase A2 (associated with regulation of potassium currents). The AT₂R appears to have effects in vascular remodeling, atherosclerosis prevention and blood pressure lowering (when associated with an AT₁R inhibitor). After myocardial infarction, the AT₂R appears to decrease infarct size, cardiac hypertrophy and fibrosis, and to improve cardiac function. However, its role in the heart is controversial. In the kidney, the AT₂R promotes natriuresis. Until now, treatment directed at the renin‐angiotensin‐aldosterone system has been based on angiotensin‐converting enzyme inhibitors or angiotensin type 1 receptor blockers. The study of the AT₂R has been revolutionized by the discovery of a direct agonist, C21, which promises to become part of the treatment of cardiovascular disease.     

Evidence for a local angiotensin-generating system and dose-dependent inhibition of glucose-stimulated insulin release by angiotensin II in isolated pancreatic islets

Aims/hypothesis A local angiotensin-generating system has been found in the exocrine pancreas. This study aimed, primarily, to investigate the existence of a local angiotensin-generating system in the pancreatic islets and, secondly, to elucidate its role in regulating insulin secretion.Methods Real-time RT-PCR and western blot were used to investigate if angiotensin-generating components are present in the mouse pancreatic islets, which are subject to regulation by islet transplantation. The localisation of AT₁-receptors in islets was investigated by immunohistochemistry. Batch-type incubations of isolated islets were applied for studying the influence of angiotensin II on the glucose-stimulated insulin release, glucose oxidation and (pro)insulin, and total protein biosynthesis.Results Major components, namely angiotensinogen, ACE, AT ₁ - and AT ₂ -receptors, were expressed in endogenous islets. AT₁-receptors were localised to pancreatic beta cells. Exposure of the isolated islets to angiotensin II induced a dose-dependent inhibition of glucose-stimulated insulin release and inhibited (pro)insulin biosynthesis. This inhibitory action was fully preventable by pretreatment of the islets with losartan, an AT₁-receptor antagonist. We also investigated if the expression of these components was changed after islet transplantation. Notably, a markedly increased expression of mRNA for the AT ₁ -receptor was observed in islets retrieved from 4-week-old syngeneic islet transplants, a finding that was confirmed at the protein level.Conclusion/interpretation These data indicate the existence of an islet angiotensin-generating system of potential importance in the physiological regulation of glucose-induced insulin secretion, thus diabetes mellitus. The increased expression of the AT₁-receptor in islet transplants could have relevance to islet-graft function.Abbreviations Ang II Angiotensin II - AT₁ angiotensin II receptor type 1 - AT₂ angiotensin II receptor type 2 - Ao angiotensinogen - RAS Renin-angiotensin system - KRBB Krebs-Ringer bicarbonate buffer     

Comparison of the effects of AT1 receptor blockade and angiotensin converting enzyme inhibition on atherosclerosis

Angiotensin converting enzyme (ACE) inhibitors reduce the development of atherosclerosis in hypercholesterolemic animals across a wide range of species. Although the mechanism for these effects has not been well delineated, it has been assumed generally that both angiotensin II suppression and interference with the breakdown of bradykinin are involved. To determine whether angiotensin II receptor blockade provides similar effects as those observed with ACE inhibition, we examined the influence of irbesartan, an AT₁ receptor antagonist, on aortic atherosclerosis in Watanabe heritable hyperlipidemic rabbits using the identical protocol that was employed in our earlier studies involving ACE inhibitors. At a dose of irbesartan (30 mg/kg/day), which was selected because it appeared to block most of the pressor effects of infused angiotensin in rabbits, no effect on atherosclerosis was observed. However, a higher dose of irbesartan (75 mg/kg/day) caused reductions in blood pressure and aortic atherosclerosis similar to those seen in earlier studies with ACE inhibitors. The decrease in aortic intimal surface involvement with irbesartan was from 38.9 ± 3.8% in controls to 24.1 ± 3.0% in the treated group (P < .01). Aortic cholesterol content was also significantly reduced in those animals (P < .02). The findings indicate that suppression of the renin-angiotensin system by AT₁ receptor blockade in a genetically hypercholesterolemic rabbit model causes comparable inhibition of aortic atherosclerosis as that achieved by ACE inhibition, and that a mild reduction of blood pressure induced by both classes of agents may contribute to their antiatherosclerotic action in this model.     

In hypertension, the kidney breaks your heart

The renin-angiotensin system (RAS) is a master regulator of blood pressure and fluid homeostasis. Because RAS components are expressed in several tissues that may influence blood pressure, studies using conventional gene targeting to globally interrupt the RAS have not determined the contributions of angiotensin II receptor type 1 (AT₁) receptors in specific tissue pools to blood pressure regulation and tissue injury. Recent experiments using kidney cross-transplantation and mice lacking the dominant murine AT₁ receptor isoform, AT 1A, have demonstrated that 1) AT₁ receptors inside and outside the kidney make equivalent contributions to normal blood pressure homeostasis, 2) activation of renal AT 1 receptors is required for the development of angiotensin II-dependent hypertension, and 3) this blood pressure elevation rather than activation of AT₁ receptors in the heart drives angiotensin II-induced cardiac hypertrophy. These findings, together with previous experiments, confirm the kidney’s critical role in the pathogenesis of hypertension and its complications.     

Role of the renin-angiotensin-aldosterone system and proinflammatory mediators in cardiovascular disease

Inflammation is a key mechanism in the initiation, progression, and clinical sequelae of cardiovascular diseases (CVDs), including atherosclerosis, nephropathy, and cardiomyopathy. Angiotensin II, the major effector peptide of the renin-angiotensin-aldosterone system (RAAS), plays a significant role in the advent and perpetuation of these inflammatory diseases, most notably in atherogenesis. Consequently, suppression of the influence of angiotensin II by angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers may reduce or potentially reverse atherosclerosis and other inflammation-associated CVDs. Angiotensin II receptor blockers and angiotensin-converting enzyme inhibitors exert anti-inflammatory actions and prevent or reduce the development of atherosclerosis in animal models. Clinically, RAAS suppression reduces common carotid and femoral artery intima-media thickness, thus indicating moderation of the vascular disease process. These clinical benefits likely involve restraint of the deleterious effects of angiotensin II in addition to, or independent of, lowering blood pressure. Increasing evidence that the detection and monitoring of vascular inflammation are important tools in the management of atherosclerosis also implicates the RAAS in this pathogenic process. Inflammatory molecules such as intercellular adhesion molecule-1, vascular cell adhesion molecule-1, monocyte chemoattractant protein-1, tumor necrosis factor-alpha, and C-reactive protein have potential diagnostic and prognostic values in CVD and are modified by angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers. Monitoring these markers may be crucial for determining which agents, or combinations of agents, will result in the most clinically beneficial outcomes for patients. Large-scale trials are still required to determine the effects of the long-term suppression of inflammation on CVDs through the use of RAAS modulating agents, as well as to determine how closely markers of inflammatory activity may correlate with CVD outcomes.     

Direct regulation of insulin secretion by angiotensin II in human islets of Langerhans

Aims/hypothesis This study aimed to identify the expression of angiotensin II receptors in isolated human islets and beta cells and to examine the functional consequences of their activation. Materials and methods Single-cell RT-PCR was used to identify whether human islet cells express mRNA for type 1 angiotensin II receptors (AT₁), and western blotting was used to determine AT₁ protein expression by human islets and MIN6 beta cells. We measured changes in intracellular calcium by microfluorimetry using Fura 2-loaded MIN6 cells and human islet cells. Dynamic insulin secretory responses were determined by RIA following perifusion of human islets and MIN6 cells. Results Human islets expressed mRNAs for both the angiotensin precursor, angiotensinogen, and for angiotensin-converting enzyme. In addition, human and mouse beta cells expressed AT₁. These were functionally coupled to increases in intracellular calcium, which occurred at least in part through phospholipase-C-sensitive mechanisms and calcium influx through voltage-operated calcium channels. Short-term exposure of human islets and MIN6 cells to angiotensin II caused a rapid, short-lived initiation of insulin secretion at 2 mmol/l glucose and potentiation of insulin secretion induced by glucose (at 8 and 16.7 mmol/l). Conclusions/interpretation These data demonstrate that the AT₁ is expressed by beta cells and that angiotensin II effects a short-lived and direct stimulation of human and mouse beta cells to promote insulin secretion, most probably through elevations in intracellular calcium. Locally produced angiotensin II may be important in regulating a coordinated insulin secretory response from beta cells.