Converting enzyme inhibition modulates sympathetic neurotransmission in vivo via multiple mechanisms

1993 ◽  
Vol 264 (4) ◽  
pp. E631-E637 ◽  
Author(s):  
J. H. Schwieler ◽  
T. Kahan ◽  
J. Nussberger ◽  
P. Hjemdahl
Keyword(s):  
Receptor Antagonist ◽  
Ace Inhibition ◽  
Ang Ii ◽  
Converting Enzyme ◽  
Synthesis Inhibitor ◽  
Sympathetic Neurotransmission ◽  
Muscle Perfusion ◽  
Alpha Adrenoceptors ◽  
Hoe 140

We investigated the mechanism(s) by which angiotensin-converting enzyme (ACE) inhibition influences peripheral sympathetic neurotransmission. Thus effects of the angiotensin II (ANG II) receptor antagonist losartan (Du Pont 753) were compared with those of the ACE inhibitor benazeprilat on sympathetic neurotransmission in canine gracilis muscle in situ, with alpha-adrenoceptors either intact or irreversibly blocked by phenoxybenzamine. Furthermore, effects of the bradykinin receptor antagonist HOE 140 and the prostaglandin synthesis inhibitor diclofenac were studied after ACE inhibition. Losartan reduced the vasoconstrictor response to exogenous ANG II by 76 +/- 4% at the dose used and lowered muscle perfusion pressures. ACE inhibition by benazeprilat reduced plasma ANG-(1-8) octapeptide levels (from 8 +/- 2 to 2 +/- 1 pM), mean arterial pressure, and muscle perfusion pressures. After ACE inhibition, both HOE 140 (at a dose that reduced the vasodilatory response to exogenous bradykinin by 80 +/- 3%) and diclofenac elevated basal perfusion pressures. Losartan reduced the nerve stimulation-evoked overflow of endogenous norepinephrine (NE) (-14 +/- 6%) and vasoconstrictor responses (alpha-adrenoceptors intact). ACE inhibition increased NE overflow when alpha-adrenoceptors were intact (+12 +/- 5%) and tended to reduce it when alpha-adrenoceptors were blocked (-12 +/- 4%). During ACE inhibition, HOE 140 reduced and diclofenac enhanced the evoked NE overflow. In the absence of ACE inhibition, neither HOE 140 nor diclofenac influenced NE overflow. Our findings indicate that ACE inhibition influences sympathetic neurotransmission via reduced ANG II formation and enhanced bradykinin and prostaglandin accumulation. The effects of ANG II on sympathetic neurotransmission are, however, small under these in vivo conditions.

Role of angiotensin-converting enzyme and angiotensin II in development of hypoxic pulmonary hypertension

1995 ◽  
Vol 269 (4) ◽  
pp. H1186-H1194 ◽  
Author(s):  
N. W. Morrell ◽  
K. G. Morris ◽  
K. R. Stenmark
Keyword(s):  
Pulmonary Hypertension ◽  
Angiotensin Ii ◽  
Receptor Antagonist ◽  
Vascular Remodeling ◽  
Ace Inhibition ◽  
Protective Effects ◽  
Ang Ii ◽  
Converting Enzyme ◽  
Hypoxic Pulmonary Hypertension

Although angiotensin converting enzyme (ACE) inhibitors are known to attenuate the development of hypoxic pulmonary hypertension in rats, the precise mechanism of this protective effect remains unknown. Thus we utilized specific angiotensin II (ANG II)-receptor antagonists to investigate whether ANG II is involved directly in the hemodynamic and structural changes of pulmonary hypertension, and we tested whether the protective effects of ACE inhibition can be attributed partly to potentiation of bradykinin. During 14 days of hypobaric hypoxia, rats received, via intraperitoneal osmotic minipumps, either 1) the ACE inhibitor captopril, 2) captopril plus the bradykinin B2-receptor antagonist CP-0597, 3) the ANG II type 1 receptor antagonist losartan, 4) the ANG II type 2 receptor antagonist PD-123319, or 5) saline. At 14 days, mean pulmonary arterial pressure (MPAP) was reduced (P < 0.05) in hypoxic rats treated with captopril (26.6 +/- 0.8 mmHg) or losartan (24.4 +/- 1.0 mmHg) compared with saline (32.0 +/- 1.4 mmHg) but was unaffected by PD-123319 (29.5 +/- 1.7 mmHg). Right ventricular hypertrophy was reduced in hypoxic rats treated with captopril or losartan compared with saline-treated rats. Morphometry showed less medial thickening and peripheral muscularization of small pulmonary arteries in hypoxic animals treated with captopril or losartan. Coadministration of CP-0597 did not reverse the protective effects of captopril on pulmonary vascular remodeling. These results suggest a novel role for endogenous ANG II, acting through the type 1 receptor, in the vascular remodeling associated with hypoxic pulmonary hypertension. The beneficial effects of ACE inhibition in this model can be attributed to reduced ANG II production rather than potentiation of bradykinin.

ANG II is involved in the LPS-induced production of proinflammatory cytokines in dehydrated rats

2003 ◽  
Vol 284 (4) ◽  
pp. R1092-R1097 ◽  
Author(s):  
Michio Miyoshi ◽  
Katsumi Nagata ◽  
Toshiaki Imoto ◽  
Osamu Goto ◽  
Akiko Ishida ◽  
...  
Keyword(s):  
Plasma Concentration ◽  
Angiotensin Converting Enzyme ◽  
Receptor Antagonist ◽  
Proinflammatory Cytokines ◽  
Ace Inhibitor ◽  
Ang Ii ◽  
Converting Enzyme ◽  
Single Intravenous Injection

We have previously reported results that led us to speculate that ANG II is involved in the LPS-induced production of proinflammatory cytokines, especially under dehydrated conditions. To test this possibility, in this study we examined the effects of an angiotensin-converting enzyme (ACE) inhibitor and an antagonist of the type-1 ANG II receptor (AT1 receptor) on the LPS-induced production of the proinflammatory cytokines IL-1 and IL-6 in dehydrated rats. A single intravenous injection of LPS induced a marked increase in the expression of IL-1β mRNA in the liver, an effect that was significantly attenuated by pretreatment with the ACE inhibitor. Furthermore, the ACE inhibitor reduced the LPS-induced increase in the hepatic concentration of IL-1β protein. When the AT1-receptor antagonist was given intravenously before the LPS, the increase in the hepatic concentration of IL-1β was significantly reduced. Finally, the ACE inhibitor reduced the LPS-induced increase in the plasma concentration of IL-6. These results represent the first in vivo evidence that ANG II and its AT1 receptor play important roles in the production of proinflammatory cytokines that is induced by LPS under dehydrated conditions.

scholarly journals Effects of selected endothelium-dependent vasodilators on fetoplacental vasculature: physiological implications

1999 ◽  
Vol 277 (2) ◽  
pp. H842-H847
Author(s):  
Saral Amarnani ◽  
Belinda Sangrat ◽  
Gautam Chaudhuri
Keyword(s):  
Nitric Oxide ◽  
Nitric Oxide Synthase ◽  
Receptor Antagonist ◽  
Perfusion Pressure ◽  
Ang Ii ◽  
Hoe 140 ◽  
Oxide Synthase

The endothelium-dependent vasodilators ACh, histamine, and bradykinin were studied in the isolated, perfused human placental cotyledon. Histamine caused a decrease in perfusion pressure that was attenuated by cimetidine. Bradykinin, at lower concentrations (10−20 to 10−14 M), produced a concentration-dependent decrease in perfusion pressure, whereas at higher concentrations it produced an increase in perfusion pressure. ACh was without any effect. The decrease in perfusion pressure observed with bradykinin was potentiated by captopril and was significantly attenuated in the presence of HOE-140, the B2-receptor antagonist, or by pretreatment with an inhibitor of nitric oxide synthase, but not by an inhibitor of cyclooxygenase. The decrease in perfusion pressure observed with bradykinin was potentiated by ANG I but not by ANG II. It is concluded that endothelium-dependent vasodilation can be demonstrated with histamine and bradykinin in the fetoplacental vessels, and at least for bradykinin, this is partly mediated by release of nitric oxide. The potentiation of the bradykinin response in the presence of ANG I may serve to buffer the vasoconstriction produced by ANG II in the fetoplacental circulation.

Angiotensin-converting enzyme determination in plasma during therapy with converting enzyme inhibitor: two methods compared

1991 ◽  
Vol 37 (8) ◽  
pp. 1390-1393 ◽  
Author(s):  
T P Gorski ◽  
D J Campbell
Keyword(s):  
Angiotensin Converting Enzyme ◽  
Spectrophotometric Method ◽  
Enzyme Inhibitor ◽  
Ang Ii ◽  
Converting Enzyme ◽  
Fluorometric Method ◽  
Converting Enzyme Inhibitor ◽  
Ace Activity

Abstract For normal and above-normal concentrations of angiotensin-converting enzyme (ACE; EC 3.4.15.1) activity in plasma, results of a manual fluorometric method [with hippuryl-histidyl-leucine (HHL), 5 mmol/L, as substrate] correlated well with those of an automated spectrophotometric method [with 3-(2-furylacryloyl)-L-phenylalanyl-glycyl-glycine (FAPGG), 2 mmol/L, as substrate]. However, for patients receiving converting enzyme inhibitor (CEI) therapy, the spectrophotometric method showed much greater suppression of plasma ACE activity than did the fluorometric method. To determine which of the two methods provided a more reliable indication of ACE inhibition in vivo, we measured plasma ACE, angiotensin I (ANG I), and angiotensin II (ANG II) in patients receiving the CEI perindopril. During perindopril therapy, changes in the ratio of ANG II:ANG I, an index of ACE activity in vivo, showed a close agreement with changes in plasma ACE activity measured with FAPGG as substrate, but not with HHL as substrate. We conclude that measurement of ACE activity in vitro with FAPGG as substrate provides a reliable measure of changes in conversion of ANG I to ANG II in vivo during CEI therapy.

Angiotensin II induces apoptosis in human and rat alveolar epithelial cells

1999 ◽  
Vol 276 (5) ◽  
pp. L885-L889 ◽  
Author(s):  
Rongqi Wang ◽  
Alex Zagariya ◽  
Olivia Ibarra-Sunga ◽  
Claudia Gidea ◽  
Edmund Ang ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Epithelial Cells ◽  
Angiotensin Converting Enzyme ◽  
Enzyme Inhibitor ◽  
Alveolar Epithelial Cells ◽  
Receptor Subtypes ◽  
Ang Ii ◽  
Converting Enzyme ◽  
Alveolar Epithelial

Recent work from this laboratory demonstrated potent inhibition of apoptosis in human alveolar epithelial cells (AECs) by the angiotensin-converting enzyme inhibitor captopril [B. D. Uhal, C. Gidea, R. Bargout, A. Bifero, O. Ibarra-Sunga, M. Papp, K. Flynn, and G. Filippatos. Am. J. Physiol. 275 ( Lung Cell. Mol. Physiol. 19): L1013–L1017, 1998]. On this basis, we hypothesized that apoptosis in this cell type might be induced by angiotensin II (ANG II) through its interaction with the ANG II receptor. Purified ANG II induced dose-dependent apoptosis in both the human AEC-derived A549 cell line and in primary type II pneumocytes isolated from adult Wistar rats as detected by nuclear and chromatin morphology, caspase-3 activity, and increased binding of annexin V. Apoptosis also was induced in primary rat AECs by purified angiotensinogen. The nonselective ANG II-receptor antagonist saralasin completely abrogated both ANG II- and angiotensinogen-induced apoptosis at a concentration of 50 μg/ml. With RT-PCR, both cell types expressed the ANG II-receptor subtypes 1 and 2 and angiotensin-converting enzyme (ACE). The nonthiol ACE inhibitor lisinopril blocked apoptosis induced by angiotensinogen, but not apoptosis induced by purified ANG II. These data demonstrate the presence of a functional ANG II-dependent pathway for apoptosis in human and rat AECs and suggest a role for the ANG II receptor and ACE in the induction of AEC apoptosis in vivo.

Inactivation of Bradykinin and Angiotensin I Conversion in Conscious Rats with Two-Kidney, One-Clip Hypertension

1982 ◽  
Vol 63 (s8) ◽  
pp. 199s-201s ◽  
Author(s):  
Inge E. K. Trindade ◽  
Eduardo M. Krieger
Keyword(s):  
Enzyme Activity ◽  
Angiotensin Ii ◽  
Mean Arterial Pressure ◽  
Renal Artery ◽  
Ang Ii ◽  
Converting Enzyme ◽  
Hypertensive Rats ◽  
Angiotensin I ◽  
Parallel Increase

1. The extents of pulmonary degradation of bradykinin (BK) and angiotensin I (ANG I) to angiotensin II (ANG II) conversion were measured simultaneously to determine whether converting enzyme activity, in vivo, is altered in two-kidney, one-clip hypertensive rats (15, 60 and 180 days after renal artery clipping). 2. Inactivation of BK (estimated by comparing equipressor doses injected intravenously and intra-aortically) was markedly increased in these hypertensive rats: 98.5% (15 days), 98.4% (60 days) and 99.5% (180 days) vs 95.6% in control rats. All groups of hypertensive rats exhibited hyper-reactivity to intra-aortic BK, requiring doses 14–38 times smaller than the control rats to produce the same depressor response. 3. The percentage of ANG I conversion (calculated from equipressor doses of ANG I and ANG II injected intravenously) was elevated after 15 days (46.0% vs 28.1% in control rats), unchanged after 60 days (27.7%) and slightly elevated after 180 days (36.0%). Hyporeactivity to ANG II was observed 15 and 180 days after renal artery clipping (doses six times were needed to produce a standard increase in mean arterial pressure). No alterations were found in the rats at 60 days after artery clipping. 4. The increased degradation of BK cannot be explained solely by elevation of converting enzyme activity since no parallel increase in ANG I conversion was observed, indicating that other bradykininases in the lung may be involved.

scholarly journals The role of angiotensin II in the early stages of bovine ovulation

Reproduction ◽  
2007 ◽  
Vol 134 (5) ◽  
pp. 713-719 ◽  
Author(s):  
Rogério Ferreira ◽  
João Francisco Oliveira ◽  
Rafael Fernandes ◽  
José Ferrugem Moraes ◽  
Paulo Bayard Gonçalves
Keyword(s):  
Receptor Antagonist ◽  
Gnrh Agonist ◽  
Saline Solution ◽  
Critical Role ◽  
Renin Angiotensin System ◽  
Ovulation Rate ◽  
Receptor Subtype ◽  
Ang Ii

There is evidence that the renin–angiotensin system plays an important role in ovulation in cattle. Using anin vivomodel, we investigated the role of angiotensin (Ang) II in bovine ovulation by injecting Ang II receptor antagonists into ovulatory follicles. Animals (n= 102) were pre-synchronized and, when the follicles reached 12 mm, they were given the respective treatment and the cows received GnRH agonist (i.m.) to induce ovulation. The ovulation rate was significantly lower when 100μM saralasin (Ang II receptor antagonist) was intrafollicularly injected (14.3%) in comparison with saline solution (83.3%). Based on these results, a second experiment was carried out to determine the timing of Ang II’s critical role in ovulation. Saralasin inhibited ovulation only when applied at 0 and 6 h (16.7 and 42.9% ovulation rate in the 0- and 6-h groups respectively), but not at 12 h (100%) following GnRH agonist treatment. To investigate the subtypes of Ang II receptors implicated in the LH-induced ovulation, losartan (LO; AT1-Ang II receptor antagonist), PD123 319 (AT2-Ang II receptor antagonist), LO+PD123 319, or saline were intrafollicularly injected when the cows were challenged with GnRH agonist. Ovulation was inhibited by PD123 319 and LO+PD123 319 (50.0 and 33.3% on ovulation rate respectively), but not by LO or saline solution (100% ovulation in both groups). From these results, we suggest that Ang II plays a pivotal role in the early mechanism of bovine ovulation via the AT2receptor subtype.

Effect of ANG II receptor antagonist on albuminuria and renal function in passive Heymann nephritis

1992 ◽  
Vol 263 (2) ◽  
pp. F311-F318
Author(s):  
F. N. Hutchinson ◽  
S. K. Webster
Keyword(s):  
Blood Pressure ◽  
Receptor Antagonist ◽  
Enzyme Inhibitor ◽  
Pressor Response ◽  
Plasma Renin ◽  
Angiotensin Converting Enzyme Inhibitors ◽  
Ang Ii ◽  
Converting Enzyme ◽  
Converting Enzyme Inhibitors ◽  
Heymann Nephritis

Angiotensin-converting enzyme inhibitors reduce albuminuria in nephrotic subjects, but the hormonal mechanism of this effect is not known. To determine whether specific inhibition of angiotensin (ANG) II activity would decrease albuminuria as occurs after converting enzyme inhibition, rats with passive Heymann nephritis received enalapril or the ANG II receptor antagonist losartan (6 mg.kg-1.day-1) for 4 days. Enalapril reduced both albuminuria (from 583 +/- 53 to 286 +/- 55 mg/day, P less than 0.001) and the fractional clearance of albumin (FCAlb) each day after starting treatment but did not affect glomerular filtration rate (GFR). Losartan reduced albuminuria significantly only after 4 days of treatment, but this value was not different from controls. GFR significantly increased with losartan (from 1.24 +/- 0.09 to 1.73 +/- 0.21 ml/min, P less than 0.05) so that FCAlb was reduced (from 0.0134 +/- 0.0027 to 0.0080 +/- 0.0018, P less than 0.05). Blood pressure decreased only in the enalapril group. Although plasma renin activity increased and the pressor response to ANG I was inhibited by both enalapril and losartan, suggesting effective peripheral blockade of ANG II activity, a third group of nephrotic rats was treated with losartan (18 mg.kg-1.day-1) to ensure that adequate ANG II blockade was achieved. Blood pressure decreased 10 mmHg, GFR increased from 1.35 +/- 0.14 to 1.79 +/- 0.12 ml/min (P less than 0.01), but albuminuria and FCAlb did not change. Urinary total kallikrein excretion was increased only in nephrotic rats treated with enalapril. Although both enalapril and losartan reduce ANG II activity, only the converting enzyme inhibitor reduces albuminuria.(ABSTRACT TRUNCATED AT 250 WORDS)

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