Captopril

Captopril is an inhibitor of Angiotensin-I-converting enzyme (ACE) with IC50 value of 6nM [1].

Captopril is an old drug with antihypertensive efficacy commonly used in the control of blood pressure. Captopril is found to be an ACE inhibitor in all species studied. Administration of captopril inhibits the pressor response to intravenously administered angiotensin I but not that induced by angiotensin II both in normal human beings and in conscious normotensive rabbits. Captopril is proven to be a useful alternative to combination antihypertensive therapy in

the patients with resistant hypertension [2].

Captopril is also found to have anticancer activity. It can significantly reduce tumor growth without toxicity in athymic mice bearing LNM35 human lung cells xenografts. It is proven that captopril affects cell growth through inducing apoptosis [3].

References:
[1] FitzGerald RJ, Meisel H. Milk protein-derived peptide inhibitors of angiotensin-I-converting enzyme. Br J Nutr. 2000 Nov;84
[2] Bravo EL, Tarazi RC. Converting enzyme inhibition with an orally active compound in hypertensive man. Hypertension. 1979 Jan-Feb;1(1):39-46.
[3] Attoub S, Gaben AM, Al-Salam S, Al Sultan MA, John A, Nicholls MG, Mester J, Petroianu G. Captopril as a potential inhibitor of lung tumor growth and metastasis. Ann N Y Acad Sci. 2008 Sep;1138:65-72.

Captopril apparently increase and cisplatin apparently decrease human albumin concentration in artificial urinary solutions.[Pubmed:28217897]

J Clin Lab Anal. 2017 Nov;31(6).

BACKGROUND: Measurement of urinary albumin (HSA) is very important in diagnostic of kidney diseases. Much less is known about the possible impact of substances present in urine together with albumin on the results of measurements. METHODS: We investigated the effect of the presence of Captopril and cisplatin in the solution on the result of the determination of HSA by native polyacrylamide gel electrophoresis. Protein conformation in the absence and presence of the drugs was examined using Fourier Transform Infrared Spectroscopy (FTIR). RESULTS: The presence of Captopril apparently increases HSA concentration while cisplatin causes an apparent decrease in the HSA concentration. The presence of both drugs also influence the secondary structure forms of HSA albumin investigated by FTIR. CONCLUSION: Both drugs tested in the concentration of human use can have an impact on the results of determination of albumin in urine which can influence clinical decision.

Effect of ivabradine, captopril and melatonin on the behaviour of rats in L-nitro-arginine methyl ester-induced hypertension.[Pubmed:28195070]

J Physiol Pharmacol. 2016 Dec;67(6):895-902.

Cardiovascular diseases including hypertension are often associated with behavioural alterations. The aim of this study was to show, whether ivabradine, the blocker of If-channel in sinoatrial node, is able to modify the behaviour of rats in L-nitro-arginine methyl ester (L-NAME)-induced hypertension and to compare the effect of ivabradine with Captopril and melatonin. 12-week-old male Wistar rats were divided into the following groups: controls, ivabradine (10 mg/kg/24 h), L-NAME (40 mg/kg/24 h), L-NAME + ivabradine, L-NAME + Captopril (100 mg/kg/24 h), L-NAME + melatonin (10 mg/kg/24 h). Systolic blood pressure (SBP) and heart rate (HR) were measured by tail-cuff method once a week. The behaviour of rats was investigated during 23-hours in the phenotyper after four weeks of the treatment. Chronic administration of L-NAME induced hypertension without a change in HR. All tested substances partly prevented the increase of SBP, while ivabradine and melatonin also reduced HR. Ivabradine, Captopril and melatonin reduced daily food intake, slightly decreased daily water intake and attenuated body weight gain. In L-NAME group, locomotor activity was enhanced by ivabradine, whereas exploratory behaviour was increased by melatonin and Captopril. In conclusion, ivabradine, besides its potentially protective hemodynamic actions, does not seem to exert any disturbing effects on behaviour in L-NAME-induced hypertension in rats, while some of its effects were similar to Captopril or melatonin. It is suggested that ivabradine used in cardiovascular indications is harmless regarding the effect on behaviour.

Effect of captopril on radiation-induced TGF-beta1 secretion in EA.Hy926 human umbilical vein endothelial cells.[Pubmed:28209920]

Oncotarget. 2017 Mar 28;8(13):20842-20850.

The pathophysiological mechanism involved in the sustained endothelial secretion of cytokines that leads to fibrosis 6-16 months after radiotherapy remains unclear. Angiotensin II (Ang II) is produced by the endothelium in response to stressing stimuli, like radiation, and may induce the synthesis of TGF-beta, a profibrotic cytokine. In this study we tested the hypothesis that Captopril, an angiotensin-converting enzyme (ACE) inhibitor, inhibits or attenuates radiation-induced endothelial TGF-beta1 secretion. The human endothelial hybrid cell line EA.HY926 was irradiated with split doses of x-rays (28 Gy delivered in 14 fractions of 2 Gy). TGF-beta1 mRNA, TNF-alpha mRNA and TGF-beta1 protein levels were evaluated by RT-PCR and western blotting each month until the fifth month post radiation. Ang II was detected using radioimmunoassays, NF-kappaB activity was examined using EMSA, and western blotting was used to detect the expression of Ikappa-Balpha. To explore the role of Ang II on radiation-induced TGF-beta1 release and Ikappa-Balpha expression, Captopril was added to cultured cells before, during, or after irradiation. Sustained strong expression of TGF-beta1 was observed after conventional fractionated irradiation. TNF-alpha, Ang II, and NF-kappaB activity were also increased in EA.Hy926 cells after radiation. Captopril decreased Ang II expression, inhibited the NF-kappaB pathway and reduced TGF-beta1 expression. These data suggest that Captopril might protect the endothelium from radiation-induced injury.

Captopril does not Potentiate Post-Exercise Hypotension: A Randomized Crossover Study.[Pubmed:28219104]

Int J Sports Med. 2017 Apr;38(4):270-277.

To evaluate whether Captopril (3x50 mg/day) potentiates post-resistance exercise hypotension (PREH) in hypertensives (HT), 12 HT men received Captopril and placebo for 4 weeks each in a double-blinded, randomized-crossover design. On each therapy, subjects underwent 2 sessions: Control (C - rest) and Resistance Exercise (RE - 7 exercises, 3 sets to moderate fatigue, 50% of 1 RM -repetition maximum). Measurements were taken before and after 30-60 min (Post1) and 7 h (Post2), and ambulatory blood pressure (BP) was monitored for 24 h. There were no differences in PREH characteristics and mechanisms between the placebo and Captopril periods. At Post1, systolic/diastolic BP decreased significantly and similarly after RE with both therapies (Placebo=-13+/-2/-9+/-1 mmHg vs. Captopril=-12+/-2/-10+/-1 mmHg, P<0.05). RE reduced cardiac output in some subjects and systemic vascular resistance in others. Heart rate and cardiac sympathetic modulation increased, while stroke volume and baroreflex sensitivity decreased after RE (Placebo: +13+/-2 bpm, +21+/-5 nu, -11+/-5 ml, -4+/-2 ms/mmHg; Captopril: +13+/-2 bpm, +35+/-4 nu, 17+/-5 ml, -3+/-1 ms/mmHg, P<0.05). At Post2, all variables returned to pre-intervention values. Ambulatory BP was similar between the sessions. Thus, Captopril did not potentiate the magnitude and duration of PREH in HT men, and it did not influence PREH mechanisms.

LKPNM: a prodrug-type ACE-inhibitory peptide derived from fish protein.[Pubmed:10604535]

Immunopharmacology. 1999 Oct 15;44(1-2):123-7.

It has been previously documented that the thermolysin-digest of "Katsuo-bushi", a Japanese traditional food processed from dried bonito possesses potent inhibitory activity against angiotensin I-converting enzyme (ACE). The present authors isolated eight kinds of ACE-inhibitory peptides from it. Of these isolated peptides, LKPNM (IC50 = 2.4 microM) was found to be hydrolyzed by ACE to produce LKP (IC50 = 0.32 microM) with 8-fold higher ACE-inhibitory activity relative to the parent peptide or LKPNM, suggesting that LKPNM can be regarded as a prodrug-type ACE-inhibitory peptide. For assessment of relative antihypertensive activities of LKPNM and LKP to that of Captopril, they were orally administered to SHR rats to monitor time-course changes of blood pressures, whereby it was evidenced that both LKPNM and Captopril showed maximal decrease of blood pressure 4 h after oral administration and their efficacies lasted until 6 h post-administration. In sharp contrast, however, maximal reduction of blood pressure occurred as early as 2 h after administration of LKP. Minimum effective doses of LKPNM, LKP and Captopril were 8, 2.25 and 1.25 mg/kg, respectively. When compared on molar basis, antihypertensive activities of LKPNM and LKP accounted for 66% and 91% relative to that of Captopril, respectively, whereas in vitro ACE-inhibitory activities of LKPNM and LKP were no more than 0.92% and 7.73% compared with that of Captopril (IC50 = 0.022 microM). It is of interest to note that both of these peptides exert remarkably higher antihypertensive activities in vivo despite weaker in vitro ACE-inhibitory effects, which was ascertained by using Captopril as the reference drug.

Effects of early captopril treatment and its removal on plasma angiotensin converting enzyme (ACE) activity and arginine vasopressin in hypertensive rats (SHR) and normotensive rats (WKY).[Pubmed:8869001]

Clin Exp Hypertens. 1996 Feb;18(2):201-26.

The purpose of this study was to evaluate the effects of early administration and removal of the ACE inhibitor, Captopril (CAP) on the plasma ACE activity, AVP levels, and mean arterial pressure (MAP) in groups of rats, control and CAP treated SHR and WKY (SHR, WKY SHRCAP, WKYCAP, respectively and in SHR taken off CAP (OFFCAP) and their progeny (2nd generation, 2ndG). Plasma ACE activity in SHRCAP (54.8 +/- 2.1 mU/ml/min) was significantly greater than in SHR (25.96 +/- 0.34 mU/ml/min) and their offspring (OFFCAP, 26.32 +/- 2.71 and 2ndG, 17.62 +/- 2.47 mU/ml/min, P < 0.001, respectively). Plasma level of AVP in SHR (14.18 +/- 0.98 pg/ml) were greater than in SHRCAP (9.1 +/- 1.01 pg/ml, P < 0.01). A decrease in plasma AVP levels were also noted in OFFCAP (10.48 +/- 0.51 pg/ml) and their offspring 2ndG (10.34 +/- 0.46 pg/ml). Our results did not show a relationship between plasma ACE activity and blood pressure reduction. However, treatment of SHR with Captopril produced a decrease in plasma AVP levels which may participate in its antihypertensive mechanism of action.

Inhibition of leukotriene A4 hydrolase/aminopeptidase by captopril.[Pubmed:1885582]

J Biol Chem. 1991 Sep 5;266(25):16507-11.

Captopril ((2S)-1-(3-mercapto-2-methyl-propionyl)-L-proline) inhibited the bifunctional, Zn(2+)-containing enzyme leukotriene A4 hydrolase/aminopeptidase reversibly and competitively with Ki = 6.0 microM for leukotriene B4 formation and Ki = 60 nM for L-lysine-p-nitroanilide hydrolysis at pH 8. Inhibition was independent of pH between pH 7 and 8, the optimum range for each catalytic activity. Half-maximal inhibition of leukotriene B4 formation by intact erythrocytes and neutrophils required 50 and 88 microM Captopril, respectively. In neutrophils and platelets neither 5(S)-hydroxyeicosatetraenoic acid, 12(S)-hydroxyeicosatetraenoic acid, nor leukotriene C4 formation were reduced, indicating selective inhibition of leukotriene A4 hydrolase/aminopeptidase, not 5-lipoxygenase, 12-lipoxygenase, or leukotriene C4 synthase. In whole blood, Captopril inhibited leukotriene B4 formation with an accompanying redistribution of substrate toward formation of cysteinyl leukotrienes. The decrease in leukotriene B4 was more substantial than the corresponding increase in cysteinyl leukotrienes suggesting that nonenzymatic hydration predominates over transcellular metabolism of leukotriene A4 by platelets during selective inhibition of leukotriene A4 hydrolase. Enalapril dicarboxylic acid and Glu-Trp-Pro-Arg-ProGln-Ile-Pro-Pro which inhibit angiotensin-converting enzyme: angiotensin I, bradykinin, and N-[3-(2-furyl)acryloyl]Phe-Gly-Gly which are substrates; and chloride ions which activate angiotensin-converting enzyme did not modulate leukotriene A4 hydrolase/aminopeptidase activity. The results indicate that: (i) the sulfhydryl group of Captopril is an important determinant for inhibition of leukotriene A4 hydrolase/aminopeptidase, probably by binding to an active site Zn2+; (ii) aminopeptidase and leukotriene A4 hydrolase display differential susceptibility to inhibition; (iii) there is minimal functional similarity between angiotensin-converting enzyme (peptidyl dipeptidase) and leukotriene A4 hydrolase/aminopeptidase; (iv) Captopril may be a useful prototype to identify more potent and selective leukotriene A4 hydrolase inhibitors.