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Thomas Unger

Publications and source records attributed to Thomas Unger.

72 records · Page 4Linked to original sources
PubMed2003

Kinins are involved in the antiproteinuric effect of angiotensin-converting enzyme inhibition in experimental diabetic nephropathy.

The present study examined non-insulin-treated streptozotocin (STZ)-induced diabetic rats to determine the role of kinins in diabetic nephropathy. Their involvement in the renoprotective effect of the angiotensin-converting enzyme inhibitor (ACEI) ramipril was investigated using the bradykinin (BK) B(2)-receptor antagonist, icatibant (HOE 140), or a combination of the two drugs.Although, none of the treatments prevented the decline of the glomerular filtration rate (GFR) in diabetic rats, ramipril (3 mg/kg/day), but not icatibant (HOE 140; 500 microg/kg/day), prevented proteinuria in these animals. However, the antiproteinuric effect of ramipril was reduced by 45% when combined with icatibant. To explore whether the renal kallikrein-kinin system (KKS) belongs to the underlying mechanisms of these findings, we also determined urinary BK levels, renal kallikrein (KLK) and angiotensin-converting enzyme (ACE) activity as well as renal cortical mRNA levels of neutral endopeptidase 24.11 (NEP) and low-molecular weight (LMW) kininogen. STZ led to a reduction of renal KLK and ACE activity and NEP expression and to a three-fold increase of urinary BK excretion and renal kininogen expression. Icatibant given alone had no effect on these parameters. In contrast, ramipril treatment normalized urinary protein and BK excretion as well as kininogen mRNA expression without affecting NEP mRNA expression or KLK and ACE activity. Our data demonstrate that renal BK is increased in severe STZ-induced diabetes mellitus, but may affect glomerular regulation only to a minor degree under this condition. However, kinins are partly involved in the antiproteinuric action of ACEI at this stage of diabetic nephropathy.

Actins↗
PubMed2003

Contribution of bradykinin and nitric oxide to AT2 receptor-mediated differentiation in PC12 W cells.

We investigated the effect of angiotensin II on intracellular cyclic GMP content and neurite outgrowth as an indicator of cell differentiation in PC12 W cells. Neurite outgrowth was examined by phase-contrast microscopy. Outgrown neurites were classified as small, medium and large, and were expressed as neurites per 100 cells. Angiotensin II (10-7 m) increased the outgrowth of medium and large neurites by mean +/- SEM 20.2 +/- 2.3 and 6.6 +/- 1.4 compared with 1.66 +/- 0.5 and 0.1 +/- 0.06 neurites per 100 cells in control. Cellular cyclic GMP content increased by 50-250% with angiotensin II at concentrations of 10-6-10-4 m. Both blockade of AT2 receptors and of nitric oxide synthase markedly reduced angiotensin II-induced neurite outgrowth and cyclic GMP production. In contrast, B2 receptor blockade had no effect or even increased these angiotensin II effects. Sodium nitroprusside and 8-bromo-cyclic GMP both mimicked the effects of angiotensin II on cell differentiation. The protein kinase G inhibitor KT-5823 inhibited the neurite outgrowth induced by both angiotensin II and 8-bromo-cyclic GMP. Our results demonstrate that angiotensin II can stimulate cell differentiation in PC12 W cells by nitric oxide-related and cyclic GMP-dependent mechanisms. The effects of angiotensin II on cell differentiation and cyclic GMP production were mediated via the AT2 receptor and further enhanced by bradykinin B2 receptor blockade.

Alkaloids↗
PubMed2003

Angiotensin AT1/AT2 receptors: regulation, signalling and function.

Angiotensin II (Ang II), the biologically active component of renin-angiotensin system (RAS), acts through two receptor subtypes, the AT1 and the AT2 receptor. All classic physiological effects of Ang II, such as vasoconstriction, aldosterone and vasopressin release, sodium and water retention and sympathetic facilitation, are mediated by the AT1 receptor. Ang II, via its AT1 receptor, is also involved in cell proliferation, left ventricular hypertrophy, nephrosclerosis, vascular media hypertrophy, endothelial dysfunction, neointima formation and processes leading to athero-thrombosis. Recent investigations have established a role for the AT2 receptor in cardiovascular, brain and renal function as well as in the modulation of various biological processes involved in development, cell differentiation, tissue repair and apoptosis. This review summarizes new insights in the regulation, signalling and (patho-) physiological functions of AT1 and AT2 receptors. An extensive review on angiotensin receptors has been published recently (de Gasparo M et al., Pharmacol Rev 2000; 52: 415-72).

Angiotensin II Type 1 Receptor Blockers↗
PubMed2003

Blood pressure lowering and renin-angiotensin system blockade.

Angiotensin II (ANG II), the main effector peptide of the renin-angiotensin system (RAS), is implicated in the development of vascular, cardiac and renal pathologies. Considered to be central to the whole cardiovascular continuum, recent investigations have also established a role for ANG II in the recovery of the brain after cerebral insult. ANG II exerts its actions through two receptors: ANG II type 1 (AT1) and type 2 (AT2). Characterization of these receptors and their functions has led to an understanding of the role that ANG II plays in the body and has opened new avenues for therapeutic research. Investigations in animal models of hypertension, endothelial dysfunction, myocardial infarction, left ventricular hypertrophy and stroke have established the part that the ANG II receptors play in vascular, cardiac and cerebral pathologies using selective inhibitors of AT1 and AT2 receptors. The AT1 receptor mediates most of the deleterious effects of ANG II, such as vasoconstriction, endothelial damage and cell growth. Selective inhibition of the AT1 receptor not only inhibits these effects, but also leaves the AT2 receptor open to stimulation by ANG II. Among the many potential effects mediated by stimulation of the AT2 is the neuronal regeneration after injury and inhibition of pathological growth. Thus, AT1 receptor blockade appears to offer both active and passive therapeutic benefits. With high penetration through the blood-brain barrier, effective and selective inhibition of the AT1 receptor and prolonged duration of the receptor blockade for more than 24 h, telmisartan is strongly placed for the emerging therapeutic opportunities.

Animals↗
PubMed2003

Chronic pretreatment with candesartan improves recovery from focal cerebral ischaemia in rats.

OBJECTIVE: In the present study, we investigated whether systemic pretreatment with the AT1 receptor antagonist, candesartan, reduces neuronal injury after cerebral ischaemia in rats. DESIGN AND METHODS: Focal cerebral ischaemia in male, normotensive Wistar rats was induced by 90 min middle cerebral artery occlusion (MCAO) followed by reperfusion. Experiment 1: Candesartan was injected intravenously (i.v.) at doses of 0.1 or 0.3 mg/kg, 4 h prior to ischaemic injury. Experiment 2: Rats were treated with candesartan [0.1 mg/kg, subcutaneously (s.c.) twice daily], on 5 consecutive days prior to ischaemia. The last injection was administered 12 h before MCAO. Mean arterial pressure (MAP) was measured before, during and after ischaemic injury. Twenty-four hours after ischaemia, neurological outcome, infarct volume and brain oedema were evaluated. RESULTS: Acute i.v. pretreatment with candesartan, 0.1 and 0.3 mg/kg, dose-dependently decreased MAP before, during and after ischaemic injury but did not improve recovery from brain ischaemia. Systemic long-term s.c. pretreatment with 0.1 mg/kg candesartan, reduced MAP during and after ischaemia to the same extent as did the i.v. dose of 0.1 mg administered 4 h before MCAO, but significantly improved neurological outcome and reduced infarction size and oedema of the ipsilateral hemisphere when compared with the vehicle-treated group. CONCLUSION: Long-term blockade of AT1 receptors improves neurological outcome of focal cerebral ischaemia and protects brain tissue against ischaemic injury.

Angiotensin II Type 1 Receptor Blockers↗
PubMed2003

Neurological protection provided by candesartan: reviewing the latest study results.

Arterial hypertension is closely correlated with the occurrence of stroke and also with the loss of cognitive function and dementia. The results of several trials, including Syst-Eur, PROGRESS, and the preliminary findings from SCOPE open the way to the possible prevention of dementia by antihypertensive treatment. In this respect, candesartan seems to be a promising drug as it has been shown to have neuroprotective effects in animal models of cerebral ischaemia and can prevent non-fatal strokes in elderly subjects with arterial hypertension.

Aged↗
PubMed2003

Drug interactions with angiotensin receptor blockers: a comparison with other antihypertensives.

The ever-increasing introduction of new therapeutic agents means that the potential for drug interactions is likely to escalate. Numerous different classes of drugs are currently used to treat hypertension. The angiotensin receptor blockers offer one of the newest approaches to the management of patients with high blood pressure. Compared with other classes of antihypertensive agents, the angiotensin receptor blockers appear overall to have a low potential for drug interactions, but variations within the class have been detected. Losartan and irbesartan have a greater affinity for cytochrome p450 (CYP) isoenzymes and, thus, are more likely to be implicated in drug interactions. There is pharmacokinetic evidence to suggest that such interactions could have a clinical impact. Candesartan cilexetil, valsartan and eprosartan have variable but generally modest affinity and telmisartan has no affinity for any of the CYP isoenzymes. In vitro studies and pharmacokinetic/pharmacodynamic evaluation can provide evidence for some interactions, but only a relatively small number of drug combinations are usually studied in this way. The absence of any pharmacokinetic evidence of drug interaction, however, should not lead to complacency. Patients should be made aware of possible interactions, especially involving the concurrent use of over-the-counter products, and it may be prudent for all patients receiving antihypertensive treatment to be monitored for possible drug interactions at their regular check-ups. The physician can help by prescribing agents with a low potential for interaction, such as angiotensin receptor blockers.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed2003

Reduction (TELMAR) as assessed by magnetic resonance imaging in patients with mild-to-moderate hypertension--a prospective, randomised, double-blind comparison of telmisartan with metoprolol over a period of six months rationale and study design.

The Telmisartan Effectiveness on Left ventricular MAss Reduction (TELMAR) trial will assess the effect of the angiotensin II (Ang II) receptor blocker, telmisartan, on left ventricular hypertrophy (LVH) compared with the b-blocker, metoprolol, at similar antihypertensive doses. The rationale is that antihypertensives reduce LVH, a cardiac adaptation to pressure overload, principally by pressure-related effects. Ang II plays a key role in pressure-independent mechanisms causing LVH, and angiotensin-converting enzyme (ACE) inhibitors induce more pronounced LVH regression than some other antihypertensives. Blocking Ang II Type 1 receptors may be more effective than ACE inhibition in reducing LVH. TELMAR is a prospective, randomised, double-blind, double-dummy, parallel-group trial. A total of 140 patients (age 18 80 years) with uncontrolled essential hypertension (mean daytime systolic blood pressure [SBP] >140 mmHg or diastolic blood pressure [DBP] >90 mmHg and/or night-time SBP >120 mmHg or DBP >70 mmHg, measured by ambulatory blood pressure monitoring [ABPM]) and left ventricular mass index related to height (LVMI) >0.8 g/cm for females, >1.1 g/cm for males (defined by magnetic resonance imaging [MRI]) will be randomised to once-daily telmisartan or metoprolol. The telmisartan dose will be 40 mg for the first two weeks, 80 mg for 5.5 months and 40 mg for the last two weeks. Metoprolol will be given at a dose of 47.5 mg for two weeks, 95 mg for 5.5 months and 47.5 mg for two weeks. Concomitant add-on medication with hydrochlorothiazide and amlodipine will be allowed. The primary endpoint is the percentage change in LVMI at treatment end versus baseline, using MRI. Secondary variables include blood pressure changes and response rates assessed by ABPM and manual cuff sphygmomanometry, and end-systolic wall stress, systolic left ventricular function (LVF) and diastolic LVF determined by MRI. A separate study was performed prior to the main trial to define the normal range of MRI data in an age-matched population.

Adrenergic beta-Antagonists↗
PubMed2002

Calcium channel blockade limits transcriptional, translational and functional up-regulation of the cardiac calpain system after myocardial infarction.

Abnormal Ca(2+) inward current through cardiac Ca(2+) channels during ischemia has been shown to be an initial signal for activation of myocardial Ca(2+)-dependent enzymes. This study investigated the contribution of cardiac L- and T-type Ca(2+) channels in the calpain-mediated myocardial damage following myocardial infarction. Myocardial infarction was induced by permanent ligation of the left coronary artery. Infarcted rats were orally treated with placebo, amlodipine (L-channel blockade; 4 mg/kg/day) or mibefradil (L-/T-channel blockade; 10 mg/kg/day) beginning 7 days before induction of myocardial infarction. Gene expression, protein levels and enzyme activity of calpains I and II were measured 1, 3, 7 and 14 days postcoronary occlusion in the noninfarcted and infarcted myocardium. Infarct size, left ventricular dilation and interstitial collagen volume fraction were determined in picrosirius red-stained hearts. Myocardial infarction induced an up-regulation of calpain I mRNA, protein and activity in the noninfarcted myocardium (maximum 14 days postinfarction), whereas mRNA, protein and activity of calpain II were maximally increased in the infarcted myocardium 3 days postinfarction. Fourteen days postinfarction, infarct size was 49%, the left ventricle was dilated and interstitial collagen volume fraction was increased. Amlodipine-inhibited mRNA, protein and activity up-regulation of calpain I decreased interstitial collagen volume fraction and infarct size. Mibefradil-attenuated mRNA, protein and activity up-regulation of calpain II at all four time points measured and of calpain I at 7 and 14 days postinfarction reduced infarct size and prevented left ventricular dilation. Infarction-induced cardiac hypertrophy was accompanied by an up-regulation of calpain I, whereas calpain II was up-regulated in the infarcted myocardium. Cardiac L- and T-type Ca(2+) channel blockade differentially reduced postinfarction remodeling associated with selective inhibition of cardiac calpains I and II, respectively.

Animals↗
PubMed2002

Rats with chronic spinal cord transection as a possible model for the at-level pain of paraplegic patients.

Patients with complete spinal cord injury (SCI) often suffer from chronic pain which is perceived around the segment of the lesion. The present study tests the hypothesis that chronic SCI pain is due to pathophysiological neuronal activity in the spinal segment just rostral to the SCI. In an animal model with complete chronic SCI, the impulse activity of single dorsal horn neurones was recorded in the segment rostral to the lesion. Following SCI, the neurones exhibited a higher background activity. Some neurones showed an abnormal type of activity which was not present under control conditions. The results support the hypothesis that increased and altered background activity just rostral to the lesion contributes to chronic at-level pain of paraplegic patients.

Animals↗
PubMed2002

Identification of a zinc finger homoeodomain enhancer protein after AT(2) receptor stimulation by differential mRNA display.

Using differential mRNA display, we isolated differentially expressed genes after stimulation of angiotensin II (Ang II) type 2 (AT(2)) receptors in PC12w cells. Among the polymerase chain reaction products isolated, we identified Zfhep, a zinc finger homoeodomain enhancer-binding protein and the angiotensin AT(2) receptor itself, both implicated in developmental processes. In the presence of epidermal growth factor (EGF) a concordant expression pattern of Zfhep and AT(2) mRNA was observed with marked downregulation 6 hours after stimulation with EGF+Ang II. In quiescent PC12w cells, Zfhep mRNA was time-dependently induced by Ang II (10(-7) mol/L) up to 3 hours, an effect that was blocked by the selective AT(2) antagonist PD123177 (10(-6) mol/L). We extended our studies on Zfhep mRNA expression to cells of vascular origin (coronary endothelial cells [CECs]), that express AT(1) and AT(2) receptors, and that respond differently to Ang II dependent on which receptor subtype is stimulated. In CECs, Zfhep mRNA expression was induced up to 3 hours after AT(2) stimulation. Interestingly, this Zfhep induction was observed only when the AT(1) receptor was blocked by using the selective AT(1) receptor antagonist, losartan (10(-5) mol/L), suggesting a negative-regulatory influence of AT(1) receptors on AT(2)-induced Zfhep mRNA induction. In conclusion, Zfhep not only represents a suitable marker for AT(2) receptor activation, but it may also link AT(2) signaling and downstream events involved in the proposed function of the AT(2) receptor in development and regeneration.

Angiotensin Receptor Antagonists↗
PubMed2002

The role of the renin-angiotensin system in the development of cardiovascular disease.

A direct, continuous, and independent relation between blood pressure and the incidence of various cardiovascular events, such as stroke and myocardial infarction, is now well accepted. The increase in risk can be attributed to structural and functional changes in target organs. Central to many of these pathophysiologic processes is the renin-angiotensin system (RAS), specifically, angiotensin II. Binding of angiotensin II to angiotensin II type-1 (AT(1)) receptors produces acute vasoconstriction, leading to an increase in blood pressure. AT(1) receptor activation also contributes independently to chronic disease pathology by promoting vascular growth and proliferation, and endothelial dysfunction. These negative consequences of angiotensin II are partly counteracted by angiotensin II type-2 (AT(2)) receptor stimulation, which has favorable effects on tissue growth and repair processes. Thus, the use of selective AT(1) receptor antagonists in the treatment of hypertension has a 2-fold rationale: (1) selective AT(1) receptor blockade targets the final common pathway for all major detrimental cardiovascular actions of angiotensin II, and (2) circulating angiotensin II levels (which increase during AT(1) receptor antagonist treatment) will be free to act only at unopposed AT(2) receptors, potentially providing additional end-organ protection. Angiotensin-converting enzyme (ACE) inhibitors interrupt the RAS by preventing the conversion of angiotensin I to angiotensin II. They also increase plasma levels of bradykinin, which possesses vasodilatory and tissue-protective properties. The combination of an AT(1) receptor antagonist with an ACE inhibitor represents an appealing therapeutic strategy, because it should produce more complete blockade of the RAS, while preserving the beneficial effects mediated by AT(2) receptor stimulation and increased bradykinin levels.

Angiotensin II↗
PubMed2002

Pathophysiologic and therapeutic importance of tissue ACE: a consensus report.

Angiotensin-converting enzyme (ACE) activation and the de novo production of angiotensin II contribute to cardiovascular disease through direct pathological tissue effects, including vascular remodeling and inflammation, as well as indirect action on nitric oxide bioavailability and its consequences. The endothelium plays a pivotal role in both vascular function and structure; thus, the predominant localization of ACE to the endothelium has implications for the pathobiology of vascular disease, such as coronary artery disease. Numerous experimental studies and clinical trials support the emerging realization that tissue ACE is a vital therapeutic target, and that its inhibition may restore endothelial function or prevent endothelial dysfunction. These effects exceed those attributable to blood pressure reduction alone; hence, ACE inhibitors may exert an important part of their effects through direct tissue action. Pharmacologic studies show that while ACE inhibitors may differ according to their binding affinity for tissue ACE the clinical significance remains to be determined.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed2002

Activity profile of calpains I and II in chronically infarcted rat myocardium--influence of the calpain inhibitor CAL 9961.

1. The calpains have been proposed to be activated following cardiac ischaemia and to contribute to myocyte damage after myocardial infarction (MI). In this study, the activity of calpains I and II in the infarcted and non-infarcted rat myocardium and the action of the selective calpain inhibitor, CAL 9961, has been investigated. 2. MI was induced by permanent ligation of the left coronary artery. One, 3, 7 and 14 days post MI, the enzymes calpain I and II were separated from homogenates of the interventricular septum (IS) and left ventricular free wall (LVFW) by chromatography on DEAE-Sepharose. The activity of the calpains was measured in sham-operated and MI animals chronically treated with placebo or CAL 9961 (15 mg kg(-1) d(-1) s.c.) in a synthetic substrate assay. Treatment was started 3 days before MI induction. 3. Calpain I activity reached highest values in IS 14 days post MI, whereas maximum activity of calpain II was measured in LVFW 3 days post MI. In experiments in vitro, CAL 9961 completely inhibited both calpains. In vivo, chronic treatment of MI animals with CAL 9961 partially prevented the increase in calpain I activity in IS and reduced calpain II activity in LVFW to sham levels. 4. Our findings demonstrate that calpains I and II are activated after MI, however, both enzymes differ in their regional and temporal activation within the infarcted myocardium. Chronic inhibition of these enzymes with CAL 9961 might limit the calpain-induced myocardial damage and preserve cardiac structural integrity post MI.

Animals↗
PubMed2002

Effects of orally applied candesartan cilexetil on central responses to angiotensin II in conscious rats.

OBJECTIVE: In the present study, we investigated the ability of the peripherally administered angiotensin II type 1 (AT1) receptor antagonist, candesartan cilexetil, to block central effects of angiotensin II (Ang II) in conscious rats. DESIGN AND METHODS: Candesartan cilexetil was administered orally by gavage at doses of 0.1, 1, 10 and 30 mg/kg. Drinking response, pressor response and release of vasopressin into the circulation following intracerebroventricular (i.c.v.) Ang II (10 or 100 ng) were measured at 0.5, 2, 4 and 24 h following the drug application. The same parameters were measured after chronic treatment with candesartan cilexetil for 1 week. In a separate experiment, the release of vasopressin induced by microinjection of Ang II (100 ng) into the paraventricular nucleus (PVN) was determined 4 h after oral administration of candesartan cilexetil (1 mg/kg) or vehicle. RESULTS: Oral treatment with candesartan cilexetil inhibited all central responses to i.c.v. Ang II in a dose- and time-dependent manner. The Ang II-induced responses were inhibited 4 h after acute or chronic treatment with 0.1 mg/kg candesartan cilexetil, but had returned to control levels 24 h after drug application. In contrast, the highest dose of candesartan cilexetil (30 mg/kg) nearly abolished the central responses to Ang II for 24 h. Candesartan cilexetil completely blocked vasopressin release into the circulation induced by Ang II microinjection into the PVN. CONCLUSIONS: Our results demonstrate that the AT1 receptor antagonist, candesartan cilexetil, very effectively inhibits the centrally mediated effects of Ang II upon peripheral application.

Administration, Oral↗
PubMed2002

Angiotensin AT2 receptor ligands: do they have potential as future treatments for neurological disease?

In addition to the systemic renin-angiotensin system (RAS), a local RAS has been identified. Recent research has focused on this latter system and has investigated the effects of locally generated angiotensin II, especially in the kidney, heart and CNS. In the mammalian brain, all components of the RAS are present including angiotensin AT(1) and AT(2) receptor subtypes. While the AT(1) receptor is responsible for the classical effects of angiotensin II, it has been found that the AT(2) receptor displays totally different signalling mechanisms and this has revealed hitherto unknown functions of angiotensin II. AT(2) receptors are expressed at low density in many healthy adult tissues, but are up-regulated in pathological circumstances, e.g. stroke or nerve lesion. Evidence has now emerged that the actions of angiotensin II that are exerted via the AT(2) receptor are directly opposed to those mediated by the AT(1 )receptor. For example, the AT(2) receptor has antiproliferative properties and therefore opposes the growth-promoting effect linked to AT(1) receptor stimulation. It has been reported that the AT(2) receptor regulates several functions of nerve cells, e.g. ionic fluxes, cell differentiation and axonal regeneration, but also modulates programmed cell death. It is possible that a more extensive knowledge of the AT(2) receptor could contribute to the understanding of the clinically beneficial effects of AT(1) receptor antagonists, as this treatment may unmask AT(2) receptor activity. This review presents selected aspects of advances in AT(2) receptor pharmacology, molecular biology and signal transduction with particular reference to possible novel therapeutic options for CNS diseases.

Angiotensin II↗
PubMed2002

[Pathophysiological and clinical implications of AT(1)/AT(2) angiotensin II receptors in heart failure and coronary and renal failure].

The octapeptide angiotensin II (Ang II), the potent effector molecule of the renin-angiotensin-aldosterone system (RAAS), is involved in the control of blood pressure, cardiac and vascular function as well as sodium and water homeostasis. Because Ang II has also been implicated in the pathophysiology of cardiovascular diseases and renal failure, it has been of increasing interest to inhibit the RAAS at the level of its enzymes such as renin and angiotensin-converting enzyme (ACE) and receptors. At least two subtypes of angiotensin receptors have been identified: AT(1) and AT(2). The AT(1 )receptor mediates all of the known actions of Ang II in the cardiovascular system, such as vasoconstriction, increasing cardiac contractility and renal tubular sodium reabsorption, as well as vascular and cardiac hypertrophy. In contrast, less is known regarding the function of the AT(2) receptor. Evidence suggests that the AT(2) receptor inhibits cell proliferation and induces differentiation, apoptosis and regeneration. The AT(2) receptor has been shown to reverse AT(1) receptor-mediated hypertrophy, suggesting that these receptors exert opposing effects in the cardiovascular system. While renin and ACE inhibitors block the RAAS at the enzymatic level, AT receptor antagonists specifically inhibit the RAAS at the receptor site. AT(1 )receptor antagonists induce a dose-dependent blockade of Ang II-induced effects, resulting in a reduction in blood pressure, cardiac and vascular hypertrophy, proteinuria and glomerular sclerosis. It is postulated that AT(1) receptor antagonists may provide end-organ protection by blocking Ang II via the AT(1) receptor, yet leaving the AT(2) receptor unopposed. These substances have been shown to decrease morbidity and mortality of patients with heart failure and renal disease associated with diabetes.

Angiotensin Receptor Antagonists↗