Angiotensin type 2 receptor-mediated hypotension in angiotensin type-1 receptor-blocked rats.

The type-2 (AT(2)) angiotensin (Ang) II receptor has been characterized as potentially counterregulatory to the actions of Ang II at its type-1 (AT(1)) receptor. We investigated the effects of Ang II and CGP-42112A (CGP), a selective peptide AT(2) receptor agonist, on blood pressure (BP) in rats with or without pharmacological blockade of the AT(1) receptor with losartan (LOS) or valsartan (VAL). In anesthetized rats (n=5 per group) receiving normal sodium intake, Ang II (200 pmol/kg per minute IV) alone increased BP from a control of 112+/-3 to 168+/-7 mm Hg (P<0.001) and LOS (30 mg/kg) alone decreased BP to 89+/-7 mm Hg (P<0.0001 from control). Ang II administered together with LOS decreased BP further to 71+/-4 mm Hg (P<0.00001 from control and LOS alone). AT(2) receptor antagonist PD 123,319 (PD) completely blocked the hypotensive response to LOS combined with Ang II (P=NS from control). In conscious rats (n=5 per group) receiving normal sodium intake, VAL (10 mg/kg) alone decreased BP from a control of 98+/-5 to 86+/-3 mm Hg (P<0.00001). Ang II combined with VAL induced a consistent, highly significant decline in BP for 6 days to a nadir of 69+/-3 mm Hg (P<0.01 versus daily VAL alone). PD completely blocked the chronic hypotensive response to the combination of Ang II and VAL to control levels before VAL administration. In another study in conscious rats (n=5 per group), CGP (70 microg/kg per minute) also decreased BP in VAL-treated conscious rats. BP was 119+/-3 mm Hg during the control period, decreased to 86+/-6 mm Hg during 3 days of VAL alone, (P<0.00001) and decreased further to 65+/-7 mm Hg (P<0.001 from daily VAL alone) with 7 days of CGP in the presence of VAL. In the absence of VAL, CGP decreased BP for 4 consecutive days, and this response was blocked by PD. Also, the CGP-induced decrease in BP over a 7-day period was blocked by N(G)-nitro-L-arginine methyl ester, an inhibitor of NO synthase. The results strongly suggest that the AT(2) receptor induces a systemic vasodilator response mediated by NO that counterbalances the vasoconstrictor action of Ang II at the AT(1) receptor.

Renal interstitial cGMP mediates natriuresis by direct tubule mechanism.

The objective of this study was to test the hypothesis that renal interstitial (RI) cGMP is natriuretic in vivo. In conscious rats (n=8), urinary sodium excretion (U(Na)V) was significantly greater on days 3 and 4 of RI infusion of cGMP (1.17+/-0.14 and 1.61+/-0.11 mmol/24 h, respectively) than during vehicle infusion (0.56+/-0.15 and 0.70+/-0.17 mmol/24 h, respectively) (P<0.01). Similarly, U(Na)V was greater on days 3 and 4 of RI infusion of 8-bromo-cGMP (2.15+/-0.42 and 2.16+/-0.1 mmol/24 h, respectively). Protein kinase G inhibitor Rp-8-pCPT-cGMPS reduced cGMP-induced and 8-bromo-cGMP-induced U(Na)V to control levels. Acute RI infusion of L-arginine (L-Arg, 40 mg. kg(-1). min(-1)), but not D-arginine, caused an increase in U(Na)V from 1.65+/-0.11 to 4.07+/-0.1 micromol/30 min (P<0.01). This increase was blocked by RI infusion of N(G)-nitro-L-arginine methyl ester (100 ng. kg(-1). min(-1)) by the phosphodiesterase (PDE II) activator 5,6DMcBIMP (0.01 micromol/microL), by PDE II (0.03 U. kg(-1). min(-1)) itself, or by the soluble guanylyl cyclase inhibitor 1-H-[1,2,4]oxadiazolo-[4,2-alpha]quinoxalin-1-one (ODQ, 0.12 mg. kg(-1). min(-1)). The PDE II activator also blocked L-Arg-stimulated cGMP levels. The NO donor S-nitroso-N-acetylpenicillamine (SNAP, 0.12 micromol. L(-1). kg(-1). min(-1)) increased U(Na)V from 1.65+/-0.11 to 2.93+/-0.08 micromol/30 min (P<0.01), and this response was blocked completely by ODQ. Renal arterial but not RI administration of the heat-stable enterotoxin of Escherichia coli induced natriuresis. RA infusion of cGMP (3 microg/min) increased U(Na)V, renal blood flow (RBF), and glomerular filtration rate (GFR). Renal cortical interstitial cGMP infusion increased U(Na)V with no effect on total RBF, renal cortical blood flow, or GFR. Similarly, the natriuretic actions of renal interstitial L-Arg or SNAP were not accompanied by any change in RBF or GFR. Medullary cGMP infusion had no effect on U(Na)V, total RBF, or medullary blood flow. Texas red-labeled cGMP infused via the RI space was distributed exclusively to cortical renal tubular cells. The results demonstrate that RI cGMP inhibits renal tubular sodium absorption via protein kinase G independently of hemodynamic changes. These observations indicate that the cortical interstitial compartment provides a potentially important domain for cell-to-cell signaling within the kidney.

Angiotensin-converting enzyme inhibition potentiates angiotensin II type 1 receptor effects on renal bradykinin and cGMP.

Angiotensin (Ang) receptor blockers (ARBs) increase bradykinin (BK) by antagonizing Ang II at its type 1 (AT(1)) receptors and diverting Ang II to its counterregulatory type 2 (AT(2)) receptors. Because the effect of ARBs on BK is constrained by the short half-life of BK and because ACE inhibitors block the degradation of BK, this study was designed to test the hypothesis that an ACE inhibitor can potentiate ARB-induced increases in renal interstitial fluid (RIF) BK levels. We used a microdialysis technique to recover BK and cGMP in vivo from the RIF of sodium-depleted, conscious Sprague-Dawley rats infused for 60 minutes with the AT(1) receptor blocker valsartan (0.17 mg/kg per minute), with the active metabolite of the ACE inhibitor benazepril (benazeprilate, 0.05 mg/kg per minute), or with the specific AT(2) receptor blocker PD 123,319 (50 microg/kg per minute) alone or combined. Each animal served as its own control. RIF BK and cGMP levels increased significantly over 1 hour in response to valsartan, benazeprilate, or both but not to a vehicle control (P<0.01). The combined benazeprilate-valsartan effect was greater than the sum of their individual effects, suggesting potentiation rather than addition, and was abolished by PD 123,319. We demonstrate for the first time that an ACE inhibitor (benazepril) and an ARB (valsartan) potentiate each other, and we postulate that such combinations may be beneficial in clinical states marked by Ang II elevation, such as chronic heart failure, postinfarction left ventricular dysfunction, and hypertension.

Distribution of type-1 and type-2 angiotensin receptors in the normal human lung and in lungs from patients with chronic obstructive pulmonary disease.

This study was designed to examine the cellular distribution of the angiotensin II type-1 (AT1) and type-2 (AT2) receptors in the normal human and pathological human lung. Riboprobes were prepared against specific portions of each receptor DNA and labelled with FITC for detection using an anti-FITC antibody in combination with the alkaline phosphatase-anti-alkaline phosphatase technique and new Fuchsin. These were used to detect the presence of receptor mRNA in the lung. Specific antibodies were used to detect receptor protein in cells by immunocytochemistry. Image analysis was used in order to semi-quantify receptor density. AT1 receptor mRNA and protein were localised on vascular smooth muscle cells, macrophages and in the stroma underlying the airways epithelium probably relating to underlying fibroblasts. The AT1 receptor protein was not expressed in the epithelium although there was a low level of mRNA. In contrast, AT2 receptor RNA and protein was observed in the epithelium, with strong staining on the bronchial epithelial cell brush border and also on many of the underlying mucous glands. The AT2 receptor was also present on some endothelial cells. These findings were supported by the presence of mRNA in each case. In patients with chronic obstructive pulmonary disease, there was a five- to sixfold increase in the ratio of AT1 to AT2 receptors in the regions of marked fibrosis surrounding the bronchioles. This correlated well with the reduced lung function as expressed by the forced expiratory volume.

Role of the angiotensin AT2 receptor in blood pressure regulation and therapeutic implications.

The angiotensin (ANG) Type 2 (AT2) receptor is one of two major ANG II receptors that have been identified, cloned, and sequenced. Most of the biologic actions of ANG II are thought to be mediated by the AT1 receptor, but evidence is beginning to emerge that the AT2 receptor has a significant role in the regulation of blood pressure. In the adult rat, the AT2 receptor is expressed, albeit in low concentrations in kidney, mesenteric blood vessels, and heart. Most of the evidence suggests that the AT2 receptor stimulates a vasodilator signaling cascade that includes bradykinin, nitric oxide, and guanosine cyclic 3',5'-monophosphate. At lease some of the beneficial actions of AT1 receptor blockade are mediated by the AT2 receptor through this pathway. Several recent studies suggest that AT2 receptors may mediate vasodilation and hypotension. The AT2 receptor represents a potential therapeutic target for agonist action and a candidate molecule in the pathophysiology of hypertension.

Selective inhibition of the renal angiotensin type 2 receptor increases blood pressure in conscious rats.

The angiotensin II type 2 (AT(2)) receptor is present in rat kidney; however, its function is not well understood. The purpose of this study was to evaluate the role of the AT(2) receptor in blood pressure (BP) regulation. The effects of selective inhibition of the renal AT(2) receptor with phosphorothioated antisense oligodeoxynucleotide (AS-ODN) were examined in conscious uninephrectomized rats. Oligodeoxynucleotides (AS-ODN or scrambled [S-ODN]) were infused directly into the renal interstitial space by using an osmotic pump at 1 microL/h for 7 days. Texas red-labeled AS-ODN was distributed in renal tubules in the infused but not the contralateral kidney of normal rats. Continuous renal interstitial infusion of the AS-ODN, but not S-ODN, caused a significant (P<0.01) increase in BP 1 to 5 days after the initiation of the infusion. AS-ODN-treated rats experienced an increase in systolic BP from 109+/-4 to 130+/-4 mm Hg (n=8, P<0.01), whereas S-ODN-treated (n=8) and vehicle-treated (n=8) rats did not show any significant change in BP. On day 5 of the oligodeoxynucleotide infusion, AS-ODN-treated rats exhibited a greater pressor response to systemic angiotensin II infusion (30 ng/kg per hour) than did S-ODN-treated rats (P<0.01). Renal interstitial fluid cGMP decreased from 11.9+/-0.8 to 3.6+/-0.5 pmol/mL (P<0.001), and bradykinin decreased from 0.05+/-0.05 to 0.18+/-0.03 ng/mL (P<0.001) in response to AS-ODN, but they were not significantly changed in response to S-ODN. To evaluate the effects of AS-ODN and S-ODN on AT(2) receptor expression, Western Blot analysis was performed on treated kidneys. Kidneys treated with AS-ODN had approximately 40% less expression of AT(2) receptor than did kidneys treated with S-ODN or vehicle (P<0.05). These results suggest that AS-ODN directed selectively against the renal AT(2) receptor decreased receptor expression and caused an increase in BP. We conclude that the renal AT(2) receptor plays an important role in the regulation of BP via a bradykinin/cGMP vasodilator signaling cascade.

Angiotensin receptor blockers: evidence for preserving target organs.

Hypertension is a major problem throughout the developed world. Although current antihypertensive treatment regimens reduce morbidity and mortality, patients are often noncompliant, and medications may not completely normalize blood pressure. As a result, current therapy frequently does not prevent or reverse the cardiovascular remodeling that often occurs when blood pressure is chronically elevated. Blockade of the renin-angiotensin system (RAS) is effective in controlling hypertension and treating congestive heart failure. Both angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) inhibit the activity of the RAS, but these two classes of antihypertensive medications have different mechanisms of action and different pharmacologic profiles. Angiotensin-converting enzyme inhibitors block a single pathway in the production of angiotensin II (Ang II). In addition, angiotensin I is not the only substrate for ACE. The ACE inhibitors also block the degradation of bradykinin that may have potential benefits in cardiovascular disease. Bradykinin is, however, the presumed cause of cough associated with ACE inhibitor therapy. Data from clinical trials on ACE inhibitors serve to support the involvement of the RAS in the development of cardiovascular disease. Angiotensin receptor blockers act distally in the RAS to block the Ang II type 1 (AT1) receptor selectively. Thus, ARBs are more specific agents and avoid many side effects. Experimental and clinical trials have documented the efficacy of ARBs in preserving target-organ function and reversing cardiovascular remodeling. In some instances, maximal benefit may be obtained with Ang II blockade using both ARBs and ACE inhibitors. This review describes clinical trials that document the efficacy of ARBs in protecting the myocardium, blood vessels, and renal vasculature.

Angiotensin type 2 receptors: potential importance in the regulation of blood pressure.

The angiotensin type 2 receptor is one of two major angiotensin II receptors that has been identified, cloned and sequenced. The other major receptor, the angiotensin type 1 receptor, is thought to mediate most of the biological responses to the peptide. The angiotensin type 2 receptor is expressed heavily in fetal tissues, but only at a low level in the adult. Documented angiotensin type 2 receptor expression sites in the adult include kidney, heart and mesenteric blood vessels. The function of the angiotensin type 2 receptor is just beginning to be explored. Most of the evidence suggests that the angiotensin type 2 receptor mediates a vasodilator signalling cascade that includes bradykinin, nitric oxide and cyclic guanosine 5-monophosphate. At least some of the beneficial actions of angiotensin type 1 receptor blockade, such as hypotension, are mediated by stimulation of the angiotensin type 2 receptor. Several recent papers suggest that angiotensin type 2 receptors, presumably located in systemic blood vessels, mediate vasodilation and hypotension. The angiotensin type 2 receptor may be a new therapeutic target and candidate gene for the pathophysiology of hypertension.

Renal cyclic 3',5'-guanosine monophosphate and sodium excretion in Dahl salt-resistant and Dahl salt-sensitive rats: comparison of the roles of bradykinin and nitric oxide.

OBJECTIVE: The purpose of this study was to determine the relative importance of bradykinin and nitric oxide (NO) in mediating renal responses to altered sodium intake in Dahl salt-resistant (Dahl-SR) and salt-sensitive (Dahl-SS) rats. DESIGN AND METHODS: Dahl-SR and Dahl-SS rats consumed a diet containing 0.15% (low) or 4.0% (high) sodium chloride for 10 days. A microdialysis technique was then used to measure renal cortical interstitial fluid (RIF) cyclic 3',5'-guanosine monophosphate (cGMP) production in anesthetized rats, under baseline conditions and during acute cortical infusion of either the bradykinin B2 receptor antagonist icatibant or the NO synthase inhibitor nitro-L-arginine methyl ester (L-NAME). Urine sodium excretion was monitored simultaneously by ureter cannulation. Results Baseline sodium excretion was similar in the two types of rats, but RIF cGMP was significantly elevated in Dahl-SR compared to Dahl-SS rats on both low and high sodium diets. Icatibant infusion significantly reduced both RIF cGMP and sodium excretion in Dahl-SR rats during low sodium intake, but had no effect in Dahl-SS rats on either diet L-NAME infusion significantly reduced sodium excretion in Dahl-SR and Dahl-SS rats, during both low and high sodium intake. L-NAME infusion caused a significant reduction in RIF cGMP in Dahl-SR and Dahl-SS rats on low sodium diet, but reduced RIF cGMP only in Dahl-SR rats on high sodium diet. Conclusion These data suggest a potential role for cortical bradykinin, but not NO, in mediating the differences in the renal response to low sodium intake between Dahl-SR and Dahl-SS rats.

AT(1) and AT(2) receptors in the kidney: role in disease and treatment.

All components of the renin-angiotensin system (RAS) are present in the kidneys and constitute a functioning renal RAS. Angiotensin II (Ang II) receptor subtypes AT(1) and AT(2) have been identified in the afferent and efferent arterioles, glomeruli, mesangial cells, and proximal tubules. AT(1) receptors regulate vasoconstriction and sodium and water reabsorption, as well as promote cell growth, proliferation, and collagen matrix deposition. Recent animal studies are elucidating the role of the less well understood AT(2) receptors. The AT(2) receptors appear to counterbalance the AT(1) receptors by increasing the production of bradykinin, nitric oxide, and cyclic guanosine monophosphate-mediating vasodilation and by promoting cell differentiation, antiproliferation, and apoptosis. Ang II subtype 1 receptor blockers prevent Ang II activation of the AT(1) receptor while leaving the AT(2) receptor open to Ang II stimulation.

Update: role of the angiotensin type-2 (AT(2)) receptor in blood pressure regulation.

In the past, virtually all of the physiologic actions of angiotensin II (ANG II) were thought to be mediated by the type-1 ANG II receptor. However, there is now a compelling body of evidence suggesting that the type-2 (AT2) receptor is an important regulator of renal function and blood pressure (BP). The AT2 receptor stimulates a bradykinin (BK)-nitric oxide (NO)-cyclic GMP vasodilator cascade in blood vessels and in the kidney. Recent studies have shown that absence of the AT2 receptor lends to pressor and natriuretic hypersensitivity to ANG II. Furthermore, there is now excellent evidence that the AT2 receptor mediates pressure natriuresis. The AT2 receptor also stimulates the conversion of prostaglandin E2 (PGE2) to PGF2. In addition, it is now apparent that the therapeutic reduction in BP with AT1 receptor blockade (eg, losartan, valsartan, candesartan) is mediated by ANG II stimulation of the AT2 receptor, leading to increased levels of BK, NO, and cGMP. Current evidence predicts that AT2 receptor agonists would be beneficial in the treatment of hypertension.

The role of the AT2 receptor in hypertension.

The renin-angiotensin system (RAS) is integrally involved in maintaining the healthy body's hemodynamic status. It is also involved in many pathogenic situations. Angiotensin II (Ang II) is the major effector hormone of this system. Ang II subtype 1 receptor blockers (ARB), like angiotensin-converting enzyme (ACE) inhibitors, modulate the potent vasoconstricting and growth-promoting effects of Ang II. Thus, it is reasonable to assume that ACE inhibitors and ARB provide similar benefits in patients with hypertension and other diseases. There are salient differences, however, in that ARB antagonize Ang II at its AT1 receptor subtype but spare its AT2 receptor subtype, which has unique-and largely oppositional- effects on the blood vessels, kidneys, and adrenals. ACE inhibitors decrease the amount of Ang II available to its AT1 and AT2 receptors alike without totally suppressing its formation. This article reviews recent findings about the role of the AT2 receptor in both health and disease and the actions of ARB mediated by this receptor.

Angiotensin type 2 receptor mediates valsartan-induced hypotension in conscious rats.

Inhibition of the renin-angiotensin system is associated with vasodilation and reduction in blood pressure. We hypothesized that angiotensin type 1 (AT(1)) receptor (AT(1)R) blockade is associated with increased production of renal nitric oxide (NO) mediated by release of bradykinin (BK). By use of a microdialysis technique, changes in renal interstitial fluid (RIF) BK, NO end products nitrite and nitrate (NOX), and cGMP were monitored in response to intravenous infusion of the AT(1)R blocker valsartan (10 mg/kg), the angiotensin type 2 (AT(2)) receptor (AT(2)R) blocker PD123319 (50 microg x kg(-1) x min(-1)), and the BK B(2) receptor blocker icatibant (10 microg x kg(-1) x min(-1)) in conscious rats (n=10) during low sodium intake. RIF BK, NOX, and cGMP significantly increased during valsartan treatment, whereas AT(2)R blockade caused a significant decrease in these autacoids. During icatibant infusion, RIF NOX and cGMP decreased by 64% and 40%, respectively, whereas BK increased. Combined administration of valsartan and icatibant, of valsartan and PD123319, or of valsartan, PD123319, and icatibant prevented the increase in RIF cGMP and NOX in response to valsartan alone. These data demonstrate that AT(1)R blockade with valsartan is associated with release of renal BK, which in turn mediates NO production. The results suggest that increased angiotensin II, in response to sodium restriction and valsartan infusion, stimulates AT(2)R, which mediates a BK and NO cascade.

Age-related changes in renal cyclic nucleotides and eicosanoids in response to sodium intake.

The signaling molecules cGMP, cAMP, prostaglandin E(2) (PGE(2)), and prostaglandin F(2alpha) (PGF(2alpha)) play important roles in mediating the response of the kidney to changes in dietary sodium intake. We used a renal microdialysis technique in conscious rats to address the hypothesis that the renal ability to produce these mediators in response to dietary sodium intake is altered during maturation. Young (4-week-old) or adult (6-month-old) rats were studied after the consumption for 5 days of diets containing low (0. 04% NaCl), normal (0.28% NaCl), or high (4.0% NaCl) levels of sodium. Plasma renin activity was significantly increased by low-sodium diet and significantly decreased by high-sodium diet, with no significant difference between the responses of the 2 age groups. Renal interstitial fluid (RIF) levels of cGMP, cAMP, PGE(2), and PGF(2alpha) on normal-sodium diet were similar in the 2 age groups. Low-sodium diet caused a significant increase in RIF levels of all 4 mediators, with no significant differences between the responses of the 2 age groups. High-sodium diet also caused a significant increase in RIF levels of all 4 mediators. However, RIF production of cGMP, cAMP, and PGE(2) was significantly greater, and RIF PGF(2alpha) production was significantly lower, in young rats compared with adult rats. These data demonstrate that the kidneys of young and adult rats respond to dietary sodium restriction in a similar manner but that there are age-related changes in the renal response to sodium loading.

Nitric oxide: a physiological mediator of the type 2 (AT2) angiotensin receptor.

Virtually all of the biological actions of angiotensin II (ANG II) have been thought to be mediated by the type 1 (AT1) angiotensin receptor and the function of the type 2 (AT2) receptor is unknown. We now describe a novel physiological action of ANG II to release nitric oxide (NO) mediated by the AT2 receptor in both the kidney and gastrointestinal tract. We present an integrated model for a counter-regulatory protective action of the AT2 receptor mediated by nitric oxide. In the kidney, ANG II at the AT2 receptor stimulates a vasodilator cascade of bradykinin (BK), NO and cyclic GMP which is tonically activated only during conditions of increased ANG II, such as sodium depletion. In the absence of the AT2 receptor, pressor and antinatriuretic hypersensitivity to ANG II is associated with BK and NO deficiency. In angiotensin-dependent hypertension, the hypotensive effect at AT1 receptor blockade is due at least in part to AT2 receptor stimulation and consequent increased activity of the vasodilator cascade. In the gastrointestinal tract, physiological quantities of ANG II stimulate the AT2 receptor releasing NO and cGMP leading to increased sodium and water absorption. In conclusion, NO is an important physiological mediator of ANG II at the AT2 receptor.

Role of the angiotensin type 2 receptor in the regulation of blood pressure and renal function.

The renin-angiotensin system is a major physiological regulator of body fluid volume, electrolyte balance, and arterial pressure. Virtually all of the biological actions of the principle effector peptide angiotensin II (ANG II) have been attributed to an action at the type 1 (AT(1)) ANG receptor. Until recently, the functional role of the type 2 (AT(2)) receptor, if any, has been unknown, possibly because the AT(2) receptor has a low degree of expression compared with that of the AT(1) receptor. Evidence has now accumulated that the AT(2) receptor opposes functions mediated by the AT(1) receptor. Whereas the AT(1) receptor stimulates cell proliferation, the AT(2) receptor inhibits proliferation and promotes cell differentiation. These differences in growth responses have been ascribed to different cell signaling pathways in which the AT(1) receptor stimulates protein phosphorylation and the AT(2) receptor dephosphorylation. During the past 5 years, studies have demonstrated that the AT(2) receptor is responsible for vasodilation and natriuresis, thus opposing the vasoconstrictor and antinatriuretic effects of ANG II mediated through the AT(1) receptor. Work from our laboratory and others indicates that the AT(2) receptor stimulates vasodilation and natriuresis by an autocrine cascade including bradykinin, nitric oxide, and cyclic GMP. The AT(2) receptor also has been found to control vasodilator prostaglandins, which have a role in blood pressure regulation. The AT(2) receptor appears to play a counterregulatory protective role in the regulation of blood pressure and sodium excretion that opposes the AT(1) receptor.

Angiotensin II receptor blockers: review of the binding characteristics.

Several angiotensin II receptor blockers (ARBs), including candesartan cilexetil, irbesartan, losartan, telmisartan, and valsartan, are currently approved by the US Food and Drug Administration (FDA) for the treatment of patients with hypertension. These agents share a common mechanism of action-antagonism of the angiotensin type 1 (AT1) receptor-and as a result, they block a number of angiotensin II effects that are relevant to the pathophysiology of cardiovascular disease, including vasoconstriction, renal sodium reabsorption, aldosterone and vasopressin secretion, sympathetic activation, and vascular and cardiac hyperplasia and hypertrophy. Unlike the angiotensin converting enzyme (ACE) inhibitors, these new drugs block the effects of angiotensin II regardless of whether it is produced systemically in the circulation or locally via ACE- or non-ACE-dependent pathways in tissues. ARBs also block the angiotensin II-induced feedback regulation of renin release, resulting in an increase in angiotensin II levels. With the AT1 receptor blocked, angiotensin II is available to activate the angiotensin type 2 (AT2) receptor, which mediates several potentially beneficial effects in the cardiovascular system, including vasodilation, antiproliferation, and apoptosis. Thus, ARBs provide a highly selective approach for regulating the effects of angiotensin II.

Angiotensin II and nitric oxide: a question of balance.

The vasoconstrictor peptide angiotensin II (Ang II) and the endogenous vasodilator nitric oxide (NO) have many antagonistic effects, as well as influencing each other's production and functioning. In the short-term, Ang II stimulates NO release, thus modulating the vasoconstrictor actions of the peptide. In the long-term, Ang II influences the expression of all three NO synthase (NOS) isoforms, while NO downregulates the Ang II Type I (AT1) receptor, contributing to the protective role of NO in the vasculature. Within the cardiovascular system, Ang II and NO also have antagonistic effects on vascular remodeling and apoptosis. In the kidney, the distribution of the NOS isoforms coincides with the sites of the components of the renin-angiotensin system. NO influences renin secretion from the kidney, and NO-Ang II interactions are important in the control of glomerular and tubular function. In the adrenal gland, NO has been shown to affect Ang II-induced aldosterone synthesis, while in the brain NO appears to influence Ang II-induced drinking behavior, although conflicting data have been reported. In this review, we focus on the diverse ways in which Ang II and NO interact, and on the importance of maintaining a balance between these two important mediators.

The AT2 receptor: fact, fancy and fantasy.

The angiotensin AT2 receptor subtype was recently cloned and pharmacologically characterized but its function still remains elusive and controversial. It is a member of the G-protein coupled receptor superfamily with a minimal sequence homology with the AT1 receptor, responsible for the known effect of angiotensin II. The AT2 receptor displays a totally different signaling mechanisms from the AT1 receptor and involves various phosphatases. It is expressed at low density in adult tissues but up-regulated in pathological circumstances. Clearly, the AT2 receptor has antiproliferative properties and therefore opposes the growth promoting effect linked to the AT1 receptor stimulation. It is also reported that the AT2 receptor regulates ionic fluxes, affects differentiation and nerve regeneration, has anti-angiogenic and anti-fibrotic properties and stimulates apoptosis. However, the results, although suggestive, are sometimes equivocal. Obviously, the AT2 receptor plays a role in the pathogenesis and remodeling of cardiovascular and renal diseases. A more extensive knowledge of the AT2 receptor could therefore contribute to the understanding of the clincial beneficial effects of the AT1 receptor antagonists.