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PubMed1993

Evidence that [Sar1]angiotensin II behaves differently from angiotensin II at angiotensin AT1 receptors in rabbit aorta.

Three peptide analogues, [Sar1]angiotensin II, angiotensin II and [Asn1, Val5]angiotensin II, that act at angiotensin AT1 receptors were compared in an isolated rabbit aorta assay. Significant differences have been found among them in agonist profiles and agonist-antagonist interactions with losartan, a nonpeptide antagonist selective for AT1 receptors. Most significantly, underestimation of the antagonist potency for losartan with a flat Schild plot was obtained with [Sar1]angiotensin II. These findings were confirmed in further examinations with representative peptide antagonists including [Sar1,Ala8]angiotensin II. The failure of PD123177, a nonpeptide antagonist selective for AT2 binding sites, to induce any significant difference in the complex antagonism of [Sar1,Phe(Br5)8]angiotensin II to angiotensin II appeared to rule out significant involvement of AT2 binding sites in the differences observed among the agonists, as well as in the complex antagonism. On the basis of the present findings it is speculated that either a saturable agonist removal process or heterogeneous sub-populations of AT1 receptors may be involved.

Angiotensin II↗

PubMed1986

Inhibition of angiotensin-converting enzyme by des-Leu10-angiotensin I: a potential mechanism of endogenous angiotensin-converting enzyme regulation.

Des-Leu10-angiotensin I is a nonapeptide generated from angiotensin I by the action of carboxypeptidase-like activities residing in the human platelet and mast cell. This nonapeptide was found to inhibit rabbit lung angiotensin-converting enzyme (peptidyl-dipeptide hydrolase, EC 3.4.15.1) with a Ki of 3.1 X 10(-7) M. The mechanism of inhibition was competitive. Inhibition of human serum angiotensin-converting enzyme by des-Leu10-angiotensin I was comparable in magnitude to inhibition by bradykinin and angiotensin III. These results suggest that limited proteolysis of angiotensin I by cells resident in vascular tissue may result in the generation of an endogenous inhibitor of angiotensin-converting enzyme. Such pathways may play roles in controlling levels of vasoactive peptides at local vascular sites.

Angiotensin I↗

PubMed1993

Renal tissue angiotensin II: response to infusions of angiotensin I and an angiotensin-converting enzyme inhibitor.

A procedure for the collection, processing, extraction, separation, and measurement of renal tissue angiotensin II [ANG-(1-8)] is described. The arterial plasma and renal tissue concentrations of ANG-(1-8) were examined in anesthetized Sprague-Dawley male rats (10 to 12 weeks of age) given an intravenous saline infusion (group 1; n = 6), an intravenous bolus infusion of 0.5 microgram angiotensin I (group 2; n = 6), or an intravenous bolus of an angiotensin-converting enzyme inhibitor (group 3; n = 6). Plasma and renal tissue were collected at the peak mean arterial pressure (MAP) response. The mean (+/- SEM) concentration of ANG-(1-8) in the group given the saline vehicle was 12 +/- 2 fmol/mL in the plasma and 2.4 +/- 0.3 pmol/g in the renal tissue. The angiotensin I bolus significantly increased MAP by 40%. Following the angiotensin I infusion, at the time of peak MAP response, the concentration of the circulating and renal tissue ANG-(1-8) were 12-fold and twofold higher, respectively, compared with the saline vehicle. The angiotensin-converting enzyme inhibitor significantly decreased MAP by 10% and decreased the circulating and renal tissue ANG-(1-8) levels by 75% and 62.5%, respectively, compared with the saline vehicle. The rapid conversion of exogenous angiotensin I to ANG-(1-8) in renal tissue provides direct evidence that renal tissue can generate de novo ANG-(1-8) from a circulating precursor. Furthermore, plasma and renal tissue respond similarly to acute angiotensin-converting enzyme inhibition.

Angiotensin I↗

PubMed1992

Effects of the angiotensin II receptor antagonist Losartan (DuP 753/MK 954) on arterial blood pressure, heart rate, plasma concentrations of angiotensin II and renin and the pressor response to infused angiotensin II in the salt-deplete dog.

1. The blood pressure, heart rate, hormonal and pressor responses to constant rate infusion of various doses of the angiotensin (type 1) receptor antagonist Losartan (DuP 753/MK 954) were studied in the conscious salt-deplete dog. 2. Doses in the range 0.1-3 micrograms min-1 kg-1 caused no change in blood pressure, heart rate or pressor response to angiotensin II (54 ng min-1 kg-1), and a dose of 10 micrograms min-1 kg-1 had no effect on blood pressure, but caused a small fall in the pressor response to angiotensin II. Infusion of Losartan at 30 micrograms min-1 kg-1 for 3 h caused a fall in mean blood arterial pressure from baseline (110.9 +/- 11.2 to 95.0 +/- 12.8 mmHg) and a rise in heart rate (from 84.6 +/- 15.1 to 103 +/- 15.2 beats/min). Baseline plasma angiotensin II (42.5 +/- 11.8 pg/ml) and renin (64.5 +/- 92.7 mu-units/ml) concentrations were already elevated in response to salt depletion and rose significantly after Losartan infusion to reach a plateau by 70 min. The rise in mean arterial blood pressure after a test infusion of angiotensin II (35.3 +/- 11.6 mmHg) was reduced at 15 min (11.8 +/- 6.8 mmHg) by Losartan and fell progressively with continued infusion (3 h, 4.3 +/- 3.3 mmHg). The peak plasma angiotensin II concentration during infusion of angiotensin II was unaffected by Losartan, but the rise in plasma angiotensin II concentration during infusion was reduced because of the elevated background concentration. Noradrenaline infusion caused a dose-related rise in mean blood arterial pressure (1000 ng min-1 kg-1, +19.9 +/- 8 mmHg; 2000 ng min-1 kg-1, +52.8 +/- 13.9 mmHg) with a fall in heart rate (1000 ng min-1 kg-1, -27.9 +/- 11.5 beats/min; 2000 ng min-1 kg-1, -31.2 +/- 17.3 beats/min).(ABSTRACT TRUNCATED AT 250 WORDS)

Angiotensin II↗

PubMed1980

A comparison of the ability of two angiotensin II receptor blocking drugs, 1-Sar; 8-Ala angiotensin II and 1-Sar, 8-Ile angiotensin II, to modify the regulation of glomerular filtration rate in the cat.

1 Modest stimulation of the renal nerves in the anaesthetized unilaterally nephrectomized cat resulted in a 15% fall in renal blood flow, no change in glomerular filtration rate and significant falls in both the absolute and fractional rates of sodium excretion.2 The haemodynamic responses to nerve stimulation were not modified by angiotensin II blockade with 1-Sar, 8-Ala angiotensin II although the fall in absolute, but not fractional sodium excretion was significantly larger. In contrast, stimulation of renal nerves following administration of 1-Sar, 8-Ileangiotensin II caused a significant fall in glomerular filtration rate. The reductions in both absolute and fractional sodium were of the same magnitude as in the absence of drug.3 Both renal blood flow and glomerular filtration rate were autoregulated during the reduction of renal perfusion pressure and this was associated with reductions in both absolute and fractional sodium excretions.4 In the presence of 1-Sar, 8-Ala angiotensin II, the haemodynamic and sodium excretory responses to reductions in renal perfusion pressure were not significantly different from those recorded in the absence of drug. However, following administration of 1-Sar, 8-Ile angiotensin II, renal blood flow but not glomerular filtration rate, was autoregulated during reduction in renal perfusion pressure. The falls in absolute and fractional sodium excretions caused by this manoeuvre were of similar magnitude to those obtained in the absence of drug.5 The results obtained using the 1-Sar, 8-Ile angiotensin II are consistent with angiotensin II having an important intra-renal site of action to regulate glomerular filtration rate, possibly via an action at the efferent arteriole. Administration of 1-Sar, 8-Ala angiotensin II was without effect on the regulation of renal haemodynamics which it is suggested reflects a limitation in the use of this particular compound as an intrarenal angiotensin II antagonist.

1-Sarcosine-8-Isoleucine Angiotensin II↗

PubMed1975

Synthesis and evaluation of (Des-Asp1)angiotensin I as a precursor for (Des-Asp1)angiotensin II ("Angiotensin III").

The nonapeptide [des-Asp1]angiotensin I (IV), synthesized by Merrifield's solid-phase procedure, was tested as a possible substrate for the converting enzymes from porcine lung and plasma. IV, [des-Asp1]angiotensin II (III), [des-(Asp1,Arg2)]angiotensin II (V), [des-(Asp1,Arg2,Val3)]angiotensin II (VI), [Sar1,Ile8]angiotensin II (VII), and [des-Asp1,Ile8]angiotensin II (VIII) possessed 0.5, 20, 2, 0 less than 0.1, and less than 0.01% of the inotropic activity (rabbit atria), 1, 15, 5, 0, 3, and 0% secretory activity of the cat adrenal medulla, and 0.0, 150, 0.5, 3, and 10% of the adrenal steroidogenic activity of angiotensin II, respectively. When tested for their antagonistic activity in the above tissues, only VII and VIII were found to inhibit responses to angiotensin II. The pA2 values for VII and VIII were 8.31 and 10.0 in the adrenal cortex and 9.31 and 9.16 in the adrenal medulla, respectively. All these peptides were also tested as product inhibitors for the plasma and lung converting enzymes. With the plasma enzyme, the ID50 values were II, 1.6 X 10(-4) M; III, 5 X 10(-5) M; V, 1.2 X 10(-4) M; VI 5 X 10(-4) M; VII 5 X 10(-5) M; VIII, 5 X 10(-4) M. Thus, IV is a good substrate for converting enzymes from lung and plasma while all other compounds were inhibitors of these enzymes. The most potent inhibitors of converting enzyme were III followed by VII and VIII. With the exception of II and III, all the other analogs had very low intrinsic activities, per se. These results suggest (a) an alternate pathway for the formation of heptapeptide III, viz., by the action of converting enzyme on the nonapeptide IV, and (b) that III may also be acting as inhibitor of the converting enzyme by the feedback mechanism.

Angiotensin II↗

PubMed1975

Effect of angiotensin II and of an angiotensin II analogue (Sar1-Ile8-angiotensin II) on blood pressure, plasma aldosterone and plasma renin activity in the dog.

1. The effect of infusions of equimolar doses of angiotensin II (AII) and of the angiotensin analogue Sar1-Ile8-angiotensin II on arterial blood pressure, plasma aldosterone and plasma renin activity were compared in normal anaesthetized dexamethasone suppressed dogs. 2. Angiotensin II induced a significant increase of blood pressure and of plasma aldosterone whereas plasma renin activity decreased. The blood pressure was only slightly affected by large doses of the analogue. Plasma aldosterone, however, increased and plasma renin activity decreased. These changes were significant but less pronounced than after the infusions of angiotensin II. Plasma aldosterone remained high and renin activity low for 40 min after the infusions of the analogue. 3. The results suggest a strong agonistic potency of Sar1-Ile8-angiotensin II at the adrenal and renal angiotensin receptors, and that it is almost ineffective at the vascular receptors. The inhibition of renin secretion by angiotensin seems not be related to its vasoconstrictive activity.

Aldosterone↗

PubMed1976

Blood pressure and plasma angiotensin II concentration after renal artery constriction and angiotensin infusion in the dog. (5-Isoleucine)angiotensin II and its breakdown fragments in dog blood.

We measured arterial plasma angiotensin II concentration, renal blood flow, and arterial blood pressure in six conscious dogs during intravenous infusion of angiotensin II (5, 10, and 20 ng/kg per min). The same measurements were made on a different occasion in the same six animals, while they were conscious, before and during constriction of a main renal artery. Arterial blood pressure and plasma angiotensin II rose and renal blood flow decreased in both experiments. The similarity of regressions for plasma angiotensin II concentration and arterial blood pressure in the two experiments strongly suggests that the rise of circulating angiotensin II after renal artery constriction is sufficient to account for the hypertension by its direct pressor action. As discussed, a different mechanism seems likely to be involved in the later stages of renal hypertension. Angiotensin II is more likely to be in the 5-isoleucine form than in the 5-valine form in the dog. In contrast to the rat, plasma concentrations of the heptapeptide (angiotensin III), hexapeptide, and pentapeptide fragments of angiotensin II are low in the dog.

Amino Acids↗

PubMed1977

Effect of angiotensin-converting enzyme inhibitor (SQ 20881) on the plasma concentration of angiotensin I, angiotensin II, and arginine vasopressin in the dog during hemorrhagic shock.

The effect of an angiotensin-converting enzyme inhibitor on the circulating levels of angiotensin I, angiotensin II, and arginine vasopressin was studied in dogs subjected to hypotensive hemorrhagic shock. In dogs subjected to hemorrhage but not given the inhibitor, angiotensin II rose 20-fold (from 69 to 1,343 pg/ml of plasma), whereas in dogs subjected to hemorrhage but pretreated with the inhibitor, angiotensin II rose only 2-fold (from 92 to 171 pg/ml of plasma). In the pretreated dogs angiotensin I rose 30-fold (from 108 to 3,232 pg/ml of plasma). There was no statistically significant difference between the vasopressin levels found in the untreated dogs and the levels found in dogs given the inhibitor (1,016 and 1,095 pg/ml of plasma). Of the 15 dogs in the untreated group, five died before retransfusion was completed (four of cardiac failure and one of cardiac arrhythmia); none of the 10 dogs in the inhibitor-treated group died. These observations suggest that the very high levels of angiotensin II observed following severe hemorrhage do not contribute significantly to the increased secretion of vasopressin and that the inhibitor protects against death, possibly by suppressing the very high blood levels of angiotensin II observed following this type of experimental hemorrhagic shock.

Angiotensin II↗

PubMed1998

Effects of MDL 100,240, a dual inhibitor of angiotensin-converting enzyme and neutral endopeptidase on the vasopressor response to exogenous angiotensin I and angiotensin II challenges in healthy volunteers.

MDL 100,240, a dual inhibitor of angiotensin-converting enzyme (ACE) and neutral endopeptidase (NEP), was administered intravenously to two panels of four healthy males in a four-period, dose-increasing (0, 1.56, 6.25, and 25 mg, and 0, 3.13, 12.5, and 50 mg, respectively) double-blind, placebo-controlled study. Plasma ACE activity and blood-pressure response to exogenous angiotensin I and angiotensin II i.v. challenges and safety and tolerance were assessed over a 24-h period. MDL 100,240 induced a rapid, dose-related, and sustained inhibition of ACE (>70% over 24 h at doses > or =12.5 mg). The time integral of ACE inhibition was related to the dose but with near-maximal values already attained at doses > or =12.5 mg. Systolic and diastolic blood-pressure responses to exogenous angiotensin I challenges were inhibited in a dose-dependent fashion, whereas the effects of angiotensin II remained unaffected. Mean supine blood pressure decreased transiently (3 h) at doses > or =3.125 mg and < or =24 h with the 25- and 50-mg doses, but not significantly. MDL 100,240 was well tolerated. In healthy subjects, MDL 100,240 exerts a dose-dependent and long-lasting ACE-blocking activity, also expressed by the inhibition of the pressor responses to exogenous angiotensin I challenges. The baroreceptor reflex, assessed by the response to exogenous angiotensin II challenge, remains unaltered.

Adult↗

PubMed2000

Renal protective effects of blocking the intrarenal renin-angiotensin system: angiotensin II type I receptor antagonist compared with angiotensin-converting enzyme inhibitor.

The present study compared renoprotective effects of angiotensin II type I receptor antagonist (AT1RA) with angiotensin converting enzyme inhibitor (ACEI), and their influence on the renin-angiotensin-system (RAS). Experimental nephrotic syndrome was induced in SD rats by repeated peritoneal injections of puromycin. Twenty-eight rats were randomly divided into four groups: normal control, nephrotic control, ACEI-treated, and AT1RA-treated groups. Serum, urine, and renal tissue were collected for study at the end of 12 weeks. Compared with those of the nephrotic control group, urinary protein was less and renal function was better in both treated groups. The glomerular and interstitial damage indexes of both ACEI- and AT1RA-treated rats were lower than those of nephrotic control rats, with no significant difference observed between the two treated groups. Local renal ACE activity and angiotensin II concentration were elevated in nephrotic rats (p< 0.01). However, there is no significant difference in circulating RAS, renal tissue renin, and aldosterone between the normal control and nephrotic control rats. As expected, enalapril inhibited the local renal ACE activity and significantly decreased angiotensin II (p< 0.01). Intrarenal ACE activity and angiotensin concentration returned to normal levels after treatment with irbesartan (p< 0.01). In conclusion, AT1RA and ACEI have comparable renal protective effects, and these protective effects were associated with the inhibition of intrarenal ANG II.

Angiotensin Receptor Antagonists↗

PubMed1990

Discrimination of two angiotensin II receptor subtypes with a selective agonist analogue of angiotensin II, p-aminophenylalanine6 angiotensin II.

Angiotensin II receptor binding sites in rat liver and PC12 cells differ in their affinities for a nonpeptidic antagonist, DuP 753, and p-aminophenylalanine6 angiotensin II. In liver, which primarily contains the sulfhydryl reducing agent-inhibited type of angiotensin II receptor, which we refer to as the AII alpha subtype, DuP 753 displays an IC50 of 55 nM, while p-aminophenylalanine6 angiotensin II displays an IC50 of 8-9 microM. In PC12 cells, which primarily contain the angiotensin II receptor type whose binding affinity is enhanced by sulfhydryl reducing agents (AII beta), DuP 753 displays an IC50 in excess of 100 microM, while p-aminophenylalanine6 angiotensin II displays an IC50 of 12 nM. p-Aminophenylalanine6 angiotensin II binding affinity in liver is decreased in the presence of guanosine 5'-O-(3-thiotriphosphate) (GTP gamma S) suggesting that this analogue is an agonist.

Adrenal Gland Neoplasms↗

PubMed2004

Renin-angiotensin system blockade at the level of the angiotensin converting enzyme or the angiotensin type-1 receptor: similarities and differences.

The development of drugs which block the renin-angiotensin system (RAS) has been proven a major advance in cardiovascular medicine. Angiotensin converting enzyme (ACE) inhibitors, which block the formation of angiotensin II from the inactive angiotensin I, are widely used as first line treatment in hypertension, heart failure and diabetic nephropathy. More recently, selective antagonists of the angiotensin type-1 receptor (AT1R) have become available for clinical use. Accumulating evidence suggests that AT1R antagonists have similar effects to ACE inhibitors in hypertension, heart failure and diabetic nephropathy. Although ACE inhibitors and AT1R antagonists block the same system, experimental evidence suggest that their mechanisms of action differ in several respects, such as increased bradykinin and angiotensin 1-7 levels with ACE inhibitors and AT2R activation with AT1R antagonists. Nevertheless, the clinical significance of these differences remains largely unknown and, in practice, the only clear advantage of AT1R antagonists over ACE inhibitors is the absence of cough as a side effect. Recent clinical data suggest that combined ACE inhibition and AT1R antagonism offer additive effects in reducing blood pressure in hypertension, in reducing proteinuria in nephropathy and in improving prognosis in heart failure. Further evidence suggests that some hypertensive patients may have a good antihypertensive response with ACE inhibition but not with AT1R antagonism, or the reverse. These data suggest that these two drug classes have important similarities, because they act on the same system, but they also appear to have important differences, which are not only of theoretical but also of clinical importance.

Angiotensin II Type 1 Receptor Blockers↗

PubMed1975

Angiotensin III: (DES-Aspartic Acid-1)-Angiotensin II. Evidence and speculation for its role as an important agonist in the renin - angiotensin system.

Evidence is reviewed that three and possibly four peptides formed from renin substrate have biological activity that merits their recognition as agonists. The decepeptide angiotensin I affects sites in the central nervous system and adrenal medulla. The octapeptide angiotensin II affects vascular and cardiac sites that mediate acute pressor responses, and also causes direct feedback inhibition of renin release. The heptapeptide (des-asp-1)-angiotensin II ("angiotensin III") stimulates aldosterone release.. It may exert its effects intracellularly at the adrenal glomerulosa and other sites. The fourth candidate is the (des-asp-1)-angiotensin I nonapeptide, but nothing is known of its activity or circulating levels. This formulation of the angiotensin reaction sequence and the effects of its individual congeners suggests several experiments. It also permits simple explanations for previously confusing data, such as the inability of immunization and anti-angiotensin II to prevent aldosterone responses, and the paradoxical preservation of adrenal responsiveness in Bartter's syndrome.

Adrenal Cortex↗

PubMed1980

Adrenal angiotensin II receptors and vascular reactivity to angiotensin II in the rat during continuous inhibition of angiotensin converting enzyme.

1. The effect of continuous infusion of captopril (80 microgram/h) for up to 5 days on blood pressure, adrenal angiotensin II receptors and vascular reactivity exogenous angiotensin II, arginine vasopressin and noradrenaline was studied in the rat. 2. In treated rats, blood pressure decreased transiently to a minimum after 2 days (-18 mmHg). Vascular reactivity to angiotensin II, but not to arginine vasopressin, was also increased significantly after 2 days, but vascular reactivity to noradrenaline decreased. After 5 days, vascular reactivity to angiotensin II had returned to normal and was similar to that of sham-treated controls. Adrenal angiotensin II receptor concentrations decreased significantly after 1 and 2 days, but at 5 days were again similar to controls There was no change in receptor affinity. 3. Converting enzyme inhibition with captopril causes transient specific changes in adrenal angiotensin II receptors and vascular reactivity. The receptor and vascular effects may facilitate and oppose, respectively, the early changes in blood pressure with captopril, but a long-term contribution from either is unlikely.

Adrenal Glands↗

PubMed1997

Effects of angiotensin-converting enzyme inhibitors and angiotensin II type 1 receptor antagonists in rats with heart failure. Role of kinins and angiotensin II type 2 receptors.

Angiotensin-converting enzyme inhibitors (ACEi) improve cardiac function and remodeling and prolong survival in patients with heart failure (HF). Blockade of the renin-angiotensin system (RAS) with an angiotensin II type 1 receptor antagonist (AT1-ant) may have a similar beneficial effect. In addition to inhibition of the RAS, ACEi may also act by inhibiting kinin destruction, whereas AT1-ant may block the RAS at the level of the AT1 receptor and activate the angiotensin II type 2 (AT2) receptor. Using a model of HF induced by myocardial infarction (MI) in rats, we studied the role of kinins in the cardioprotective effect of ACEi. We also investigated whether an AT1-ant has a similar effect and whether these effects are partly due to activation of the AT2 receptor. Two months after MI, rats were treated for 2 mo with: (a) vehicle; (b) the ACEi ramipril, with and without the B2 receptor antagonist icatibant (B2-ant); or (c) an AT1-ant with and without an AT2-antagonist (AT2-ant) or B2-ant. Vehicle-treated rats had a significant increase in left ventricular end-diastolic (LVEDV) and end-systolic volume (LVESV) as well as interstitial collagen deposition and cardiomyocyte size, whereas ejection fraction was decreased. Left ventricular remodeling and cardiac function were improved by the ACEi and AT1-ant. The B2-ant blocked most of the cardioprotective effect of the ACEi, whereas the effect of the AT1-ant was blocked by the AT2-ant. The decreases in LVEDV and LVESV caused by the AT1-ant were also partially blocked by the B2-ant. We concluded that (a) in HF both ACEi and AT1-ant have a cardioprotective effect, which could be due to either a direct action on the heart or secondary to altered hemodynamics, or both; and (b) the effect of the ACEi is mediated in part by kinins, whereas that of the AT1-ant is triggered by activation of the AT2 receptor and is also mediated in part by kinins. We speculate that in HF, blockade of AT1 receptors increases both renin and angiotensins; these angiotensins stimulate the AT2 receptor, which in turn may play an important role in the therapeutic effect of the AT1-ant via kinins and other autacoids.

Angiotensin Receptor Antagonists↗

PubMed2004

Hematocrit-lowering effect following inactivation of renin-angiotensin system with angiotensin converting enzyme inhibitors and angiotensin receptor blockers.

Several clinical and experimental observations suggest that an intact and activated renin-angiotensin system (RAS) may be an important determinant of erythropoiesis in a variety of clinical conditions, including hypertension, chronic renal insufficiency or failure, chronic obstructive pulmonary disease, and congestive heart failure. Accordingly, RAS inactivation may confer susceptibility to the hematocrit-lowering effects of angiotensin-converting enzyme inhibitors or angiotensin receptor blockers. Indeed, a dose-dependent decrease in hematocrit is observed within the first month of such therapy. In the majority of patients with hypertension decreases in hematocrit values after RAS inactivation are small and not clinically important. In extreme conditions, however, such as erythrocytosis after successful renal transplantation, secondary polycythemia of chronically hypoxemic COPD patients, erythrocytosis associated with renovascular hypertension, severe cardiac or renal failure, the hematocrit-lowering effect of angiotensin-converting enzyme inhibitors and angiotensin receptor blocker may be profound and even lead to or worsen anemia. Hematocrit reaches its nadir value within three months, and then it remains stable during long-term observations. After discontinuation of RAS blockade, hematocrit values rise gradually over the next three to four months towards the pretreatment levels. The mechanism(s) related to this phenomenon is not yet fully understood, but angiotensin II seems to be responsible for inappropriately sustaining secretion of erythropoietin despite hematocrit elevation and capable to directly stimulate the erythroid progenitors in bone marrow to produce erythrocytes.

Angiotensin Receptor Antagonists↗

PubMed2000

A novel angiotensin-converting enzyme-related carboxypeptidase (ACE2) converts angiotensin I to angiotensin 1-9.

ACE2, the first known human homologue of angiotensin-converting enzyme (ACE), was identified from 5' sequencing of a human heart failure ventricle cDNA library. ACE2 has an apparent signal peptide, a single metalloprotease active site, and a transmembrane domain. The metalloprotease catalytic domains of ACE2 and ACE are 42% identical, and comparison of the genomic structures indicates that the two genes arose through duplication. In contrast to the more ubiquitous ACE, ACE2 transcripts are found only in heart, kidney, and testis of 23 human tissues examined. Immunohistochemistry shows ACE2 protein predominantly in the endothelium of coronary and intrarenal vessels and in renal tubular epithelium. Active ACE2 enzyme is secreted from transfected cells by cleavage N-terminal to the transmembrane domain. Recombinant ACE2 hydrolyzes the carboxy terminal leucine from angiotensin I to generate angiotensin 1-9, which is converted to smaller angiotensin peptides by ACE in vitro and by cardiomyocytes in culture. ACE2 can also cleave des-Arg bradykinin and neurotensin but not bradykinin or 15 other vasoactive and hormonal peptides tested. ACE2 is not inhibited by lisinopril or captopril. The organ- and cell-specific expression of ACE2 and its unique cleavage of key vasoactive peptides suggest an essential role for ACE2 in the local renin-angiotensin system of the heart and kidney. The full text of this article is available at http://www. circresaha.org.

Adult↗