Differential Angiotensin-Converting Enzyme Inhibition in Brain after Oral Administration of Perindopril Demonstrated by Quantitative in vitro Autoradiography

Sakaguchi, Keiji; Chai, Siew Yeen; Jackson, Bruce; Johnston, Colin I.; Mendelsohn, Frederick A.O.

doi:10.1159/000125015

Cited by 39 publications

(12 citation statements)

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“…Studies with the ACE inhibitor ceronapril showed no inhibition of brain ACE, but inhibition in the circumventricular organs, with results after 2 weeks of chronic dosing being essentially the same as those obtained after a single dose [24]. However, large doses of perindopril (up to 16 mg/kg) did progressively inhibit ACE in brain structures, including the basal ganglia [25]. Given that vasopeptidase inhibitors will be used for long periods of time clinically, further studies are needed in order to assess more precisely their effects on cellular structures within the brain and outside the blood-brain barrier.…”

Section: Discussionmentioning

confidence: 77%

Differential tissue and enzyme inhibitory effects of the vasopeptidase inhibitor omapatrilat in the rat

et al. 2003

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Vasopeptidase inhibitors simultaneously inhibit angiotensin-converting enzyme (ACE) and neutral endopeptidase (NEP). The present study characterized the tissue distributions of ACE and NEP, and assessed the effects of the vasopeptidase inhibitor omapatrilat on ACE and NEP in rat tissues. In vivo ACE and NEP inhibition was studied by in vitro autoradiography and using the ACE inhibitor radioligand (125)I-MK351A and the NEP inhibitor radioligand (125)I-RB104 in rats that received oral omapatrilat (40 mg x day(-1) x kg(-1)) for 3 days. In vitro autoradiography was used to examine the distribution of ACE and NEP in the kidney, aorta, heart, adrenal gland, lung, intestine, liver, spleen and brain, and to assess enzyme inhibition after oral omapatrilat. Omapatrilat inhibited plasma ACE and increased plasma renin activity (P <0.01). Tissue ACE was inhibited by 70-95% (P <0.01), except in the brain, where ACE was not inhibited. NEP was inhibited by 87% in the kidney and by 20-40% in atria, aorta, adrenal gland, lung, liver and intestine; it was not inhibited in the brain, the ventricle or the spleen. Omapatrilat is a potent vasopeptidase inhibitor that significantly inhibits tissue ACE and NEP, with the degree of inhibition varying according to the enzyme and the tissue under assessment. The degree and site of tissue enzyme inhibition by vasopeptidase inhibitors may be relevant to end-organ protection as well as to the side-effect profiles of these agents.

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Section: Discussionmentioning

confidence: 77%

Differential tissue and enzyme inhibitory effects of the vasopeptidase inhibitor omapatrilat in the rat

et al. 2003

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“…36 It is proposed that due to the high concentration of the enzyme in this area, 36 the activity of ACE is not effectively blocked by this dose of perindopril, allowing local conversion of Ang I to II and potent stimulation of drinking. 37 It has also been noted that rats treated long term with an AT-1 receptor antagonist have increased urinary volume and increased water intake.…”

Section: Discussionmentioning

confidence: 99%

Selective reduction in body fat mass and plasma leptin induced by angiotensin-converting enzyme inhibition in rats

et al. 2008

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Objective: There is emerging evidence that angiotensin stimulates adipocyte differentiation and lipogenesis. This study tested the hypothesis that inhibition of angiotensin II by treatment with an angiotensin-converting enzyme inhibitor, perindopril, would reduce fat mass in rats. Design: After a 12-day baseline, rats were divided into two groups: one was untreated and the other received perindopril (1.2 mg kg À1 per day) in drinking water for 26 days. Subjects: In total, 16 male Sprague-Dawley rats aged 10 weeks at the start of the study. Measurements: Plasma leptin was measured in samples collected at baseline, half-way through and at the end of treatment. Body weight, food and water intake were measured daily throughout the experiment. Body fat mass, bone and lean mass were determined by dual energy X-ray absorptiometry (DEXA) at the end of the treatment period. Results: Daily food intake was the same in both groups throughout the study. By the end of treatment, animals receiving perindopril showed a modest reduction in weight gain relative to the untreated animals (62.4 ± 5.0 g vs 73.0 ± 4.0 g; Po0.05). DEXA analysis showed that body composition was greatly altered and the perindopril-treated group had 26% less body fat mass than the untreated group (61.0 ± 5.2 g vs 44.4 ± 4.2 g; Po0.01). The reduction in body fat mass was correlated with reductions in the weight of both the epididymal and retroperitoneal fat pads (Po0.001). Similarly, plasma leptin was reduced by perindopril treatment (4.64 ± 0.56 ng ml À1 ) compared to the untreated group (8.27 ± 1.03 ng ml À1 ; Po0.001). In contrast, there were no differences in lean or bone mass between the two groups. Conclusion: Oral treatment with perindopril selectively reduced body fat mass without influencing daily food intake. In contrast, there were no differences in lean or bone mass between the two groups.

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“…Furthermore, they cross the blood-brain barrier (Evered et al, 1980;Sakaguchi et al, 1988;Sica, 2003) and reduce the levels of AII. Because AII induces striatal DA release, acute administration of ACEIs, such as Captopril, inhibits DA neurotransmission in the central nervous system (Jenkins et al, 1997;Tsuda et al, 1998).…”

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Angiotensin‐converting enzyme inhibition reduces oxidative stress and protects dopaminergic neurons in a 6‐hydroxydopamine rat model of Parkinsonism

Lopez-Real

Rey

Soto‐Otero

et al. 2005

J of Neuroscience Research

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It is now established that the brain possesses a local renin-angiotensin system and that angiotensin II exerts multiple actions in the nervous system, including regulation of striatal dopamine release. Furthermore, angiotensin activates NADPH-dependent oxidases, which are a major source of superoxide, and angiotensin-converting enzyme inhibitors, commonly used in the treatment of hypertension and chronic heart failure, have shown antioxidant properties in several tissues. Oxidative stress is a key contributor to the pathogenesis and progression of Parkinson's disease. In the present study, we treated rats with intraventricular injections of the dopaminergic neurotoxin 6-hydroxydopamine and subcutaneous injections of the angiotensin-converting enzyme inhibitor Captopril to study the possible neuroprotective effect of the latter on the dopaminergic system and on 6-hydroxydopamine-induced oxidative stress. Rats treated with Captopril and 6-hydroxydopamine showed significantly less reduction in the number of dopaminergic neurons (i.e., immunoreactive to tyrosine hydroxylase) in the substantia nigra and in the density of striatal dopaminergic terminals than 6-hydroxydopamine-lesioned rats not treated with Captopril. In addition, Captopril reduced the levels of major oxidative stress indicators (i.e., lipid peroxidation and protein oxidation) in the ventral midbrain and the striatum of 6-hydroxydopamine-lesioned rats. Our results suggest that angiotensin-converting enzyme inhibitors may be useful for treatment of Parkinson's disease and that further investigation should focus on the neuroprotective capacity of these compounds.

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Differential Angiotensin-Converting Enzyme Inhibition in Brain after Oral Administration of Perindopril Demonstrated by Quantitative in vitro Autoradiography

Cited by 39 publications

References 5 publications

Differential tissue and enzyme inhibitory effects of the vasopeptidase inhibitor omapatrilat in the rat

Differential tissue and enzyme inhibitory effects of the vasopeptidase inhibitor omapatrilat in the rat

Selective reduction in body fat mass and plasma leptin induced by angiotensin-converting enzyme inhibition in rats

Angiotensin‐converting enzyme inhibition reduces oxidative stress and protects dopaminergic neurons in a 6‐hydroxydopamine rat model of Parkinsonism

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