Oral Administration Of Captopril Research Articles

Transdermal delivery of captopril using poly(vinyl pyrrolidone)/poly(vinyl alcohol)-based dissolving and hydrogel-forming microneedles: A proof of concept

Captopril (CAP) is an angiotensin-converting enzyme (ACE) inhibitor that has been widely used to treat hypertension. Oral administration of CAP has been associated with bioavailability and frequency issues, affecting patient compliance. Thus, it is essential to investigate an alternative route for overcoming those problems, namely transdermal. Microneedles is a promising strategy to enhance skin permeation of hydrophilic drugs, such as CAP. This research aimed to develop poly(vinyl pyrrolidone)/poly(vinyl alcohol)-based dissolving microneedles (DMN) and hydrogel-forming microneedles (HFMN) with film reservoirs for delivering CAP transdermally. HFMNs were manufactured using poly(vinyl pyrrolidone) K-29/32 (PVP K-29/32), poly(vinyl alcohol) (PVA), and citric acid anhydrous. CAP was formulated into DMNs and film reservoirs (FD). CAP-loaded DMNs were manufactured using PVP K-29/32 and PVA. Meanwhile, CAP-containing FDs were prepared using PVP K-29/32, PVP K-90, and glycerol. The manufactured polymeric microneedles were evaluated in terms of their mechanical properties and the ability to deliver CAP in an in vitro study using Franz diffusion cells. Based on the in vitro studies, both HFMNs integrated with FDs (FD-1) and DMN-1 successfully delivered the CAP with the cumulative amount of drug permeated were 9.90 ± 0.31 mg and 7.49 ± 0.17 mg, respectively. Results revealed that both HFMN and DMN were able to deliver more than 50 % of CAP loaded. This research presents a novel insight, for the first time, by showcasing DMNs and HFMN as promising approaches for delivering CAP transdermally.

52. SUBLINGUAL VERSUS ORAL CAPTOPRIL FOR BLOOD PRESSURE REDUCTION IN HYPERTENSION URGENCY: A SYSTEMATIC REVIEW AND META-ANALYSIS

Background: The use of sublingual captopril has been suggested in hypertension urgency on the assumption of faster absorption and thus more rapid effect on blood pressure than with the oral route. But there are still confusing data regarding the preferential route in literature. Objective: This study aimed to compare the effect of sublingual and oral captopril to reduce blood pressure in hypertension urgency patients. Method: We systematically searched the relevant studies from date of inception to January 2021. Outcomes of interest were blood pressure reduction at 10, 30, and 60 minutes after 25 mg sublingual and oral captopril administration. Results: One RCT and two observational studies comprising 353 patients were included. Systolic blood pressure (SBP) was significantly reduced faster in sublingual group at 10 minutes (mean difference 6.65 [95% CI 1.21, 12.09]; p = 0.02; I 2: 89%) and 30 minutes (mean difference 2.54 [95% CI 0.76, 4.32]; p = 0.005; I 2: 0%) compared to oral group. Mean arterial pressure (MAP) was also reduced more rapidly at 10 minutes (mean difference 3.62 [95% CI 2.78, 4.46]; p < 0.00001; I 2: 0%) and 30 minutes (mean difference 2.12 [95% CI 0.88, 3.36]; p = 0.0008; I 2: 0%) in sublingual group. Our meta-analysis showed no significant difference in blood pressure reduction at 60 minutes between two groups. Conclusion: Sublingual captopril can reduce SBP and MAP more rapidly compared to oral captopril in the first 30 minutes after administration, but the effect was similar at 60 minutes.

Cardio-protective and antioxidant properties of caffeic acid and chlorogenic acid: Mechanistic role of angiotensin converting enzyme, cholinesterase and arginase activities in cyclosporine induced hypertensive rats

Caffeic acid (CAA) and chlorogenic acid (CHA) are important members of hydroxycinnamic acid with natural antioxidant and cardio-protective properties. The present study aimed to determine the effect of CAA and CHA on systolic blood pressure, heart rates (HR) as well as on the activity of the angiotensin-1-converting enzyme (ACE), acetylcholinesterase (AChE), butrylcholinesterase (BChE) and arginase in cyclosporine-induced hypertensive rats. Experimental rats were distributed into 7 groups (n = 6): normotensive control rats; hypertensive rats (induced rats) as well as hypertensive- treated groups with captopril (10 mg/kg/day), CAA (10 and 15 mg/kg/day) and CHA (10 and 15 mg/kg/day), respectively. The experiment lasted for 7 days and the systolic blood pressure (SBP) and heart rates were recorded using tail-cuff method. Oral administration of captopril, caffeic acid and chlorogenic acid normalized hypertensive effect caused by cyclosporine administration. CAA and CHA significantly (P < 0.05) reduced SBP and HR, activity of ACE, AChE, BChE and arginase in the treated hypertensive rats compared with cyclosporine induced-hypertensive rats. Likewise, CAA and CHA improved nitric oxide (NO) bioavailability, increased catalase activity and reduced glutathione content while malondialdehyde (MDA) level was reduced compared with cyclosporine hypertensive rats. Findings from this study shows that CAA and CHA exhibited blood pressure lowering properties and reduced activities of key enzymes linked to the pathogenesis of hypertension in cyclosporine-induced rats. These might be some of the possible mechanisms of action by which their cardio-protective properties are exhibited.

The Effects of Captopril Treatment and Exercise and Blood Pressure, Endothelium Function and Gene Expression of the Renin Angiotensin System in the Spontaneously Hypertensive Rat

Angiotensin converting enzyme inhibitors (ACE‐I) have been show to prevent impairment of endothelial cell function in the Spontaneously Hypertensive Rat (SHR). The purpose of this study was to examine the combined effects of long‐term exercise training and ACE‐I treatment on blood pressure, vascular reactivity and gene expression of the Renin Angiotensin System (RAS), in the SHR. Three groups of male SHR were studied: 1) untreated SHR; 2) exercise trained (35 cm/s) for 60 minutes/day, for 3 days/week (SHREX); 3) exercised trained + captopril treated (50 mg/kg/day), treatment was initiated at four weeks of age and continued for 16 weeks (CAPEX). N = 8, for all three groups. At 20 weeks of age, systolic blood pressure (via tail cuff) in the untreated SHR was 190±11 mmHg. Exercise treatment in the SHR significantly decrease MAP in the SHREX was 151±7 mmHg). The combination of exercise and oral administration of captopril was associated with a significant decrease in systolic blood pressure (130±3 mmHg) compared to untreated SHR and SHREX. Isolated 3mm aortic ring segments were suspended in tissue chambers for measurement of isometric force. Ring segments were exposed to cumulative concentrations of serotonin (3× 10−9 – 3 × 10−5M). Preliminary data from aortic rings from SHR demonstrated increased responsiveness to serotonin induced contraction in comparison to aortic rings from the SHREX and CAPEX group. Endothelium‐dependent relaxation to acetylcholine was dramatically impaired in the SHR. Harvested tissue samples from the brain, kidney liver and blood will be used to examine gene expression of the renin angiotensin system using Next Generation RNA Sequencing.Support or Funding InformationMini Grant Award from the Office of Research and Graduate School, Prairie View A&amp;M University

Early co-expression of cyclooxygenase-2 and renin in the rat kidney cortex contributes to the development of N(G)-nitro-L-arginine methyl ester induced hypertension.

We investigated the involvement of cyclooxygenase-2 (COX-2) and the renin-angiotensin system in N(G)-nitro-L-arginine methyl ester (L-NAME)-induced hypertension. Male Wistar rats were treated with L-NAME (75.0 mg·(kg body mass)(-1)·day(-1), in their drinking water) for different durations (1-33 days). COX-2 and renin mRNA were measured using real-time PCR in the renal cortex, and prostanoids were assessed in the renal perfusate, whereas angiotensin II (Ang II) and Ang (1-7) were quantified in plasma. In some rats, nitric oxide synthase inhibition was carried out in conjunction with oral administration of captopril (30.0 mg·kg(-1)·day(-1)) or celecoxib (1.0 mg·kg(-1)·day(-1)) for 2 or 19 days. We found a parallel increase in renocortical COX-2 and renin mRNA starting at day 2 of treatment with L-NAME, and both peaked at 19-25 days. In addition, L-NAME increased renal 6-Keto-PGF(1α) (prostacyclin (PGI2) metabolite) and plasma Ang II from day 2, but reduced plasma Ang (1-7) at day 19. Captopril prevented the increase in blood pressure, which was associated with lower plasma Ang II and increased COX-2-derived 6-Keto-PGF(1α) at day 2 and plasma Ang (1-7) at day 19. Celecoxib partially prevented the increase in blood pressure; this effect was associated with a reduction in plasma Ang II. These findings indicate that renal COX-2 expression increased in parallel with renin expression, renal PGI2 synthesis, and plasma Ang II in L-NAME-induced hypertension.

22-Year-old patient with malignant hypertension associated with primary aldosteronism

A 22-year-old male patient with no known history of hypertension was admitted to the emergency unit of the regional hospital in March 2011 with signs of pulmonary oedema and was found to have blood pressure (BP) of 220/140 mm Hg. Before hospitalization the patient reported progressive shortness of breath for 2 days. His BP was reduced by oral administration of captopril within few hours to 170/100 mm Hg. In addition, the patient was put on amlodipine 20 mg per day and bispoprolol 10 mg per day. After the patient was stabilized, he was transferred to the Department of Hypertension, Institute of Cardiology, Warsaw.

The Effects of Captopril Treatment and Exercise Training on Blood Pressure and Endothelium Function in the Spontaneously Hypertensive Rat

Angiotensin converting enzyme inhibitors (ACE‐I) have been show to prevent impairment of endothelial cell function in the Spontaneously Hypertensive Rat (SHR). The purpose of this study was to examine the combined effects of long‐term exercise training and ACE‐I treatment on blood pressure and vascular reactivity in the SHR. Four groups of male SHR were studied: 1) untreated SHR; 2) exercise trained (35 cm/s) for 60 minutes/day, for 5 days/week (SHREX); 3) captopril treated (50 mg/kg/day), treatment was initiated at four weeks of age and continued for 12 weeks (CAP); and 4) captopril treated + exercise (CAPEX). N = 8, for all four groups. All rats were studied at 16–18 weeks of age. Mean arterial pressure (MAP) in the untreated SHR was 130±5 mmHg. Exercise treatment in the SHR significantly decrease MAP in the (SHREX – 114±7 mmHg). Oral administration of captopril was associated with a significant decrease in MAP (97±3 mmHg) compared to untreated SHR and SHREX. Further, captopril treatment + exercise significantly lowered MAP in the CAPEX group (107±6mmHg, vs. SHR). Isolated aortic ring segments were suspended in tissue chambers for measurement of isometric force. Ring segments were exposed to cumulative concentrations of serotonin (3× 10−9 − 3 × 10−5M). Aortic rings from SHR demonstrated increased responsiveness to serotonin induced contraction in comparison to aortic rings from the CAP and CAPEX group. Endothelium‐dependent relaxation to acetylcholine was dramatically impaired in the SHR. Endothelium‐dependent relaxation was markedly greater in both the CAP and CAPEX group. These findings suggest that early long‐term treatment of captopril coupled to exercise training can prevent alterations in endothelial function observed in the SHR….

Effects of subacute oral administration of captopril (SQ 14,255) on the renin-angiotensin system in spontaneously hypertensive rats.

Effects of subacute oral administration of captopril (SQ 14,255) on the renin-angiotensin system in spontaneously hypertensive rats.

Effects of Captopril and Telmisartan on Matrix Metalloproteinase-2 and -9 Expressions and Development of Left Ventricular Fibrosis Induced by Isoprenaline in Rats

The aim of this study was to clarify the effects of renin-angiotensin system (RAS) blockade by captopril, an angiotensin converting enzyme inhibitor, and telmisartan, an angiotensin II type 1 receptor antagonist, on matrix metalloproteinase (MMP)-2 and MMP-9 expressions and development of left ventricular (LV) fibrosis induced by isoprenaline in rats. Rats were treated with subcutaneous injection of isoprenaline (5 mg/kg/d) and with oral administration of captopril (30 mg/kg/d) or telmisartan (3 mg/kg/d) for 1 or 7 d. Hearts were excised at the day 2 and day 8. Degree of fibrosis was evaluated by Azan staining. MMP-2 and MMP-9 expressions were analyzed by Western blotting. Localization of MMP-9 expression in LV section was detected by immunohistochemical staining. At the day 8, myocardial fibrosis was observed in LV section from isoprenaline-treated rats. Captopril but not telmisartan significantly enhanced the isoprenaline-induced myocardial fibrosis. MMP-9 expression at the day 2 and MMP-2 expression at the day 8 increased significantly in LV from isoprenaline-treated rats. Captopril had no influence on the MMP-2 expression, but significantly augmented the isoprenaline-induced MMP-9 expression. Telmisartan had no effect on the isoprenaline-induced MMP-2 and MMP-9 expressions. In immunohistochemical staining, MMP-9 positive-interstitial cells were extensively observed in LV sections from isoprenaline + captopril-treated rats at the day 2. The present study reveals that RAS blockade by captopril and telmisartan does not have suppressive effects on isoprenaline-induced MMP-2 and MMP-9 expressions as well as LV fibrosis. Furthermore, captopril may enhance LV fibrosis through promoting isoprenaline-induced MMP-9 expression in cardiac interstitial cells.

Cardiac infarcts increase sodium transporter transcripts (rBSC1) in the thick ascending limb of Henle

Enhanced expression of the kidney-specific sodium transporter, rBSC1, in the thick ascending limb of Henle (TAL) and of the renal water channel, aquaporin-2 (AQP2), in collecting duct has been identified in rats with congestive heart failure (CHF) as a cause for enhanced sodium and water retention in this condition. However, the mechanism of impaired urinary sodium excretion observed even in rats with mild cardiac dysfunction remains unknown. Male Sprague-Dawley rats with myocardial infarctions measuring 15 to 30% of the left ventricular circumference with no overt CHF were prepared. We measured the amount of rBSC1 or AQP2 mRNA using competitive polymerase chain reaction (PCR) by inducing a point mutation at the middle of the PCR product for rBSC1 or by deleting 180 bp from the 760 bp PCR product for AQP2, respectively. The results were confirmed by in situ hybridization. rBSC1 protein expression was examined by immunohistochemistry and Western blot analysis using a specific antibody against rBSC1. Although plasma renin activity was slightly elevated in rats with myocardial infarction (MI), no significant differences in lung weight or plasma concentrations for aldosterone and atrial natriuretic peptide were observed between control rats and MI rats. Competitive PCR showed a significant increase in rBSC1 mRNA in the renal outer medulla and cortex of MI rats, which was confirmed by in situ hybridization. However, the AQP2 mRNA of these rats remained unchanged throughout the kidney. Renin-angiotensin II blockade by oral captopril administration did not influence the alteration in rBSC1 mRNA induced by myocardial infarction. Immunohistochemistry and Western blots showed the enhanced expression of rBSC1 protein in TAL of rats with small to moderate cardiac infarcts. rBSC1 is up-regulated even in rats with small to moderate myocardial infarctions, which may enhance the sodium transport in the TAL in this pathophysiologic condition.

Nephrotic-range proteinuria in patients with renovascular disease

PURPOSE: Proteinuria is usually considered a manifestation of glomerular disease. We sought to describe the characteristics of patients with nephrotic-range proteinuria resulting from renovascular disease and to compare them with those of patients who had glomerulonephritis. SUBJECTS AND METHODS: We identified 14 patients with nephrotic-range proteinuria and renovascular disease and compared them with 14 patients who had nephrotic-range proteinuria and biopsy-proven glomerulonephritis, matched for sex, age, and glomerular filtration rate. RESULTS: Patients with renovascular disease were more likely to have known atherosclerotic vascular disease [13 of 14 (93%) vs 3 of 14 (21%), P <0.0001] and were usually smokers [12 of 14 (85%) vs 3 of 14 (21%), P <0.0001]. They also had a greater mean (± SD) difference between the lengths of their kidneys (29 ± 10 vs 5 ± 5 mm, P <0.001); greater systolic blood pressure (203 ± 22 vs 174 ± 25 mm Hg, P <0.005), plasma renin activity (17 ± 19 vs 2 ± 2 ng/mL/h, P = 0.005), and plasma aldosterone concentration (40 ± 23 vs 11 ± 10 ng/dL, P = 0.0001); and lower serum potassium levels (3.3 ± 0.5 vs 3.8 ± 0.5, P <0.05). Effective renal plasma flow was lower (139 ± 68 vs 307 ± 185 mL/min/1.73 m 3) and filtration fraction was markedly greater (0.28 ± 0.04 vs 0.15 ± 0.07, P = 0.0001) in the patients with renovascular disease. After the oral administration of captopril, blood pressure, effective renal plasma flow, and glomerular filtration rate decreased only among patients with renovascular disease. Of the 14 patients with renovascular disease, 13 had evidence of renal artery thrombosis seen at angiography; 2 patients required dialysis, and 3 others died during follow-up. CONCLUSION: Our findings suggest that the patients with nephrotic-range proteinuria resulting from renovascular disease have distinct characteristics and a poor prognosis.

Evidence that brain angiotensin II is involved in both thirst and sodium appetite in baboons.

The roles of ANG II in the brain mechanisms subserving thirst and Na appetite in baboons were investigated by chronic intracerebroventricular infusions of ANG II and AT1-receptor antagonists using subcutaneous miniosmotic pumps and by oral administration of captopril. ANG II at 3 or 5 micrograms/h for 7 days increased water intake from 2,455 +/- 107 to 7,052 +/- 562 ml/day by day 6 and 300 mM NaCl intake from 8.3 +/- 1.1 to 275 +/- 87 mmol/day by day 5. Concurrent intracerebroventricular losartan (300 micrograms/h) did not substantially reduce these responses, but they were abolished by intracerebroventricular ZD-7155 (50 micrograms/h). The increase of 300 mM NaCl intake when it was offered after intramuscular injection of furosemide, 2 mg . kg-1 . day-1 for 3 days, was unaltered by intracerebroventricular losartan (300 micrograms/h) but was reduced by intracerebroventricular ZD-7155 (50 micrograms/h) infused throughout Na depletion/repletion; oral captopril (1 g, 3 and 18 h before access to 300 mM NaCl) also reduced NaCl intake. Restriction of water intake to 25% of daily intake for 3 days caused a high intake of water on day 4, and this was reduced by intracerebroventricular losartan (300 micrograms/h) infused throughout the period of water restriction/rehydration. These novel results in a primate species suggest that brain ANG II is involved in both thirst and Na appetite, acting via AT1 receptors.

Angiotensin converting enzyme inhibitors suppress production of tumor necrosis factor-α in vitro and in vivo

It has been reported that angiotensin converting enzyme (ACE) inhibitors have beneficial effects on insulin resistance and congestive heart failure, in which elevations of serum tumor necrosis factor-α (TNF-α) level have been indicated. Therefore, in this study, we examined effect of ACE inhibitors on TNF-α production both in vitro and in vivo by using human blood mononuclear cells and mice, respectively. LPS (20 μg/ml)-induced in vitro TNF-α production, measured by bioassay and enzyme-linked immunosorbent assay, was significantly inhibited with captopril, delapril and cilazapril in a concentration of 10−3 mol/l. A single, oral administration of captopril, delapril and cilazapril at more than 10-fold doses of common clinical use in man significantly inhibited LPS (2 mg/kg)-induced serum TNF-α activity in Balb/c mice. These results indicate that ACE inhibitors such as captopril, delapril and cilazapril have an inhibitory effect on TNF-α production not only in vitro as previously reported, but also in vivo, although relatively high concentrations and large doses were required in this study.

Effect of Angiotensin Converting Enzyme Inhibitor (ACEI) on Glucose Intolerance in OLETF Rats

Using three month-old Otsuka Long-Evans Tokushima Fatty (OLETF) rats as a NIDDM model and Long-Evans Tokushima Otsuka (LETO) rats as the control, we examined the effect of ACEI on the onset of diabetes mellitus. Oral administration of captopril (ACEI) was started from the age of 13 to 32 weeks (A group) and from the age of 25 to 32 weeks (B group). Oral GTT (oGTT) was performed at 4-week intervals from 12 weeks to 32 weeks of the age in OLETF and LETO rats. Body weights did not change significantly in either the A or B groups, compared with that in the control group. In oGTT for OLETF rats at 28 and 32 weeks of age, blood glucose levels in the A group were lower at 120 min after glucose administration than those in the B and control groups. In LETO rats, there were no significant changes in blood glucose levels in oGTT in any group. GLUT4 protein concentrations in the skeletal muscle and adipocytes were not significantly changed in any group. These data suggest that ACEI improves the glucose intolerance in NIDDM model rats through some factor other than changes in GLUT4 concentrations.

A Case of Renin-producing Juxtaglomerular Tumor: Effect of ACE Inhibitor or Angiotensin II Receptor Antagonist

Kashiwabara H, Inaba M, Itabashi A, Ishii J, Katayama S. A case of renin-producing juxtuglomerular tumor: effect of ACE inhibitor or angiotensin II receptor antagonist.We report a case of a renin-producing juxtaglomerular cell tumor and the effects of angiotensin-converting enzyme (ACE) inhibitor captopril or angiotensin II receptor antagonist TCV-116. xsA 19-year-old female visited our clinic because of hypertension (162/122 mmHg). Plasma renin activity (PRA) was 25 ng/ml/h and plasma aldosterone concentration (PAC) was 880 pg/ml. Abdominal sonography revealed a low echoic tumor in the center of the right kidney. The mass was shown to have isodensity on a computed tomography scan, iso- or slightly lower intensity on T1–weighted magnetic resonance imaging (MRI), and low intensity on T2-weighted MRI. Renal angiography disclosed a hypovascular tumor. Plasma renin activity was not decreased in response to oral administration of captopril (50 mg) or TCV-116 (4 mg), which is associated with a marked decrease in PAC and blood pressure. The average of the mean blood pressure determined by an ambulatory monitoring system every hour for 24 h was lowered from 118–t 10.6 (SD) to 85 t 11.4 mmHg by TCV-116. Plasma renin activity did not show any difference between the right and left renal vein. Removal of the tumor successfully decreased PRA to 0.3 ng/ml/h and PAC to 33 pg/ml, resulting in a decrease in 24–h average of the mean blood pressure to 78 ± 16.9 mmHg. The tumor was well capsulated and stained with an antibody against mouse renin. In the tumor, but not normal tissues, renin mRNA was detected at 1.6 kb using rat renin cDNA. The content of active renin in the tumor amounted to 182pg/g tissue, which is 109 times higher than that in normal tissue. The plasma- or tumor-inactive renjn concentration was 3.6- or 1.8-fold the active renin concentration, respectively. These results suggest that the juxtaglomerular tumor had an MRI image of iso- to low intensity on TI and low intensity on T2, and that renin secretion from the tumor may be due mainly to the constitutive pathway and angiotensin II receptor antagonist, as well as to ACE inhibitors, and may be very effective for lowering the blood pressure.

Effect on insulin sensitivity of angiotensin converting enzyme inhibitors with or without a sulphydryl group: bradykinin may improve insulin resistance in dogs and humans

The present study compared the effect on insulin sensitivity of ACE inhibitors with a sulphydryl group (captopril) or those without a sulphydryl group (delapril and enalapril) during the hyperinsulinaemic euglycaemic clamp test in both animal and clinical experiments. A possible contribution of bradykinin to the improvement of insulin sensitivity by ACE-inhibition was also studied. In healthy control and depancreatized dog experiments, administration of captopril either intravenously (3.0 mmol · kg−1) or orally (5.0 mmol · kg−1) increased insulin sensitivity indices and plasma bradykinin concentrations. In comparison, intravenous administration of an active metabolite of delapril (3.0 mmol · kg−1) and oral administration of either delapril or enalapril (5.0 mmol · kg−1) showed slight, but not significant increases in insulin sensitivity indices and plasma bradykinin concentrations. Infusion of a bradykinin antagonist (N-α-adamantaneacetyl-d-Arg-[Hyp3, Thi5,8,d-Phe7]-bradykinin) (0.5 nmol · kg−1 · min−1) abolished the effect of captopril on insulin sensitivity. Furthermore, intravenous administration of bradykinin (0.1 nmol · kg−1 · min−1) increased insulin sensitivity indices. In clinical experiments, insulin sensitivity indices decreased in the following order: normotensive healthy subjects, hypertensive non-diabetic patients, normotensive NIDDM patients and hypertensive NIDDM patients. In these four groups, oral administration of captopril (2.0 mmol · kg−1) significantly increased insulin sensitivity indices, and a concomitant increase in plasma bradykinin concentrations was observed. By contrast, oral administration of enalapril or delapril showed slight, but not significant effects on insulin sensitivity indices and plasma bradykinin concentrations. From these studies, it is concluded that ACE inhibitors with a sulphydryl group have more potent action on the improvement in insulin sensitivity than those without a sulphydryl group. Bradykinin may also possibly be involved in the mechanism underlying the improvement in insulin sensitivity associated with ACE-inhibition.

Effect on insulin sensitivity of angiotensin converting enzyme inhibitors with or without a sulphydryl group: Bradykinin may improve insulin resistance in dogs and humans

The present study compared the effect on insulin sensitivity of ACE inhibitors with a sulphydryl group (captopril) or those without a sulphydryl group (delapril and enalapril) during the hyperinsulinaemic euglycaemic clamp test in both animal and clinical experiments. A possible contribution of bradykinin to the improvement of insulin sensitivity by ACE-inhibition was also studied. In healthy control and depancreatized dog experiments, administration of captopril either intravenously (3.0 mmol.kg-1) or orally (5.0 mmol.kg-1) increased insulin sensitivity indices and plasma bradykinin concentrations. In comparison, intravenous administration of an active metabolite of delapril (3.0 mmol.kg-1) and oral administration of either delapril or enalapril (5.0 mmol.kg-1) showed slight, but not significant increases in insulin sensitivity indices and plasma bradykinin concentrations. Infusion of a bradykinin antagonist (N-alpha-adamantane-acetyl-D-Arg-[Hyp3,Thi5,8,D-Phe7]-b bradykinin) (0.5 nmol.kg-1 x min-1) abolished the effect of captopril on insulin sensitivity. Furthermore, intravenous administration of bradykinin (0.1 nmol.kg-1 x min-1) increased insulin sensitivity indices. In clinical experiments, insulin sensitivity indices decreased in the following order: normotensive healthy subjects, hypertensive non-diabetic patients, normotensive NIDDM patients and hypertensive NIDDM patients. In these four groups, oral administration of captopril (2.0 mmol.kg-1) significantly increased insulin sensitivity indices, and a concomitant increase in plasma bradykinin concentrations was observed. By contrast, oral administration of enalapril or delapril showed slight, but not significant effects on insulin sensitivity indices and plasma bradykinin concentrations. From these studies, it is concluded that ACE inhibitors with a sulphydryl group have more potent action on the improvement in insulin sensitivity than those without a sulphydryl group.(ABSTRACT TRUNCATED AT 250 WORDS)

The Effects of Chronic Administration of Captopril on the Mouse Subfornical Organ and Area Postrema

We have studied by morphometric procedures the chronic effect of captopril on the subfornical organ (SFO) and area postrema (AP) of the adult mouse. Oral administration of captopril does not produce any change in the size of individual nuclei of the ependymocytes and neurons in both centers. However, there are other quantitative effects of captopril on the global volume of the SFO and on the neuropil and vascular elements of both the SFO and AP which present a significant increase. It is suggested that this increase is due to metabolic processes at the level of both circumventricular organs.

Improved flow injection analysis (FIA) method for determining selenium in biological samples, and the effect of captopril administration on selenium levels and glutathione peroxidase activity in rat.

An improved flow injection analysis (FIA) method has been developed for the determination of trace selenium in biological samples, and this method has been applied to investigate the effect of captopril, an antihypertensive drug having a thiol group, on selenium concentrations in the rat blood, liver and urine. After oral administration of captopril, selenium levels in the blood decreased, while those in the liver increased significantly. However, no pronounced effect was observed on the urinary excretion rate. The glutathione peroxidase activities in the blood and the liver were comparable to the changes in the selenium levels.

Acute hemodynamic effects of captopril in children with a congestive or restrictive cardiomyopathy.

The acute hemodynamic effects of captopril were evaluated at cardiac catheterization in 16 children (age, 0.3-18 years) with cardiomyopathy. Twelve children had congestive cardiomyopathy, whereas four had restrictive cardiomyopathy. Hemodynamic measurements were obtained 30 and 60 minutes after the oral administration of captopril (0.5 mg/kg). Blood pressures were measured in the aorta, pulmonary artery, right atrium, and pulmonary capillary wedge position; cardiac outputs were measured by the thermodilution technique. Hemodynamic data could not be obtained after the administration of captopril in one child with congestive cardiomyopathy because of an immediate, severe hypotensive response. In 11 of 12 children with congestive cardiomyopathy, cardiac index increased by 22%, from 2.3 to 2.8 l/min/m2 (p less than 0.05), and stroke volume increased by 22%, from 23 to 28 ml/m2 (p less than 0.05). Systemic vascular resistance decreased from 32 to 21 units.m2 (p less than 0.01), but the mean aortic pressure did not change significantly. In contrast, four children with restrictive cardiomyopathy had no change in cardiac output after captopril, but there was a trend toward significant arterial hypotension (mean aortic pressure decreased from 78 to 59 mm Hg). Thus, captopril acutely reduced systemic vascular resistance and increased both cardiac output and stroke volume in children with congestive cardiomyopathy. In children with restrictive cardiomyopathy, however, captopril did not affect cardiac output, but it did decrease aortic pressure. These data indicate that captopril may benefit children with a congestive cardiomyopathy but that captopril probably should not be used in children with restrictive disease.