Contribution by bradykinin to the natriuretic response to the angiotensin converting enzyme inhibitor ramiprilat in spontaneously hypertensive rats

Summary It is well documented that angiotensin converting enzyme inhibitors decrease blood pressure, which is associated with natriuresis in humans and certain animal models of hypertension. However, it is not clear whether these beneficial effects are due solely to blockade of angiotensin-II production and/or also involves any contribution by kinins. The present study was performed in Inactin^® (5-ethyl-5-(1-methylpropyl)-2-thio-barbiturate sodium)-anesthetized spontaneously hypertensive rats aged 10–13 wks to examine the relative influence of the angiotensin receptor antagonist losartan (2-n-butyl-4-chloro-5-hydroxymethyl-1- [(2-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl] imidazole potassium salt) and the bradykinin receptor 2 antagonist HOE 140 (D-Arg-[Hyp3, Thi5, D-Tic7, Oic8] bradykinin) on renal and hemodynamic responses to the angiotensin converting enzyme inhibitor ramiprilat. We found that ramiprilat (1 mg/kg, i.v.) caused sustained reduction in mean blood pressure, marked increases in urine output and urinary sodium excretion without alteration in glomerular filtration rate. In a separate group of animals, it was found that losartan (1 mg/kg, i. v.) decreased blood pressure to a similar degree as ramiprilat and the magnitude of blood pressure fall seen following the combined administration of ramiprilat and losartan was similar to that caused by either compound alone. However, the increase in urinary sodium excretion seen following losartan administration was significantly smaller than that following ramiprilat or ramiprilat plus losartan. It was also found that HOE 140 (50 g/kg, i.v.), which did not significantly affect both hemodynamic and renal parameters when administered alone, significantly attenuated the natriuretic and diuretic, but not the antihypertensive effect of ramiprilat. These results indicate that inhibition of angiotensin II formation accounts for the major portion of antihypertensive, diuretic and natriuretic effects of ramiprilat and that the accumulation of kinins contributes significantly to renal but not the acute antihypertensive effects of ramiprilat. Correspondence to: M. F. Lokhandwala at the above address     

Inhibition of canine lung angiotensin converting enzyme by substance P

We have studied inhibition of purified canine angiotensin converting enzyme by substance P and its nonapeptide derivative using Hip-His-Leu as the substrate. Kinetic studies indicated that both substance P and its nonapeptide derivative inhibited the hydrolysis of Hip-His-Leu at different concentrations. The mode of inhibition was competitive with a Ki of 1.15 microM for substance P. These results indicate that substance P is a potent inhibitor of angiotensin converting enzyme in vitro.     

喘息患儿ACE基因多态性、家族聚集性的表达

目的观察喘息患儿血管紧张素转换酶(ACE)基因多态性分布、家族聚集倾向。方法对哮喘、喘憋性肺炎、肺炎三组的149、108、121例患儿,经PCR检测ACE基因I/D多态性分布;对54例哮喘患儿作外周血总IgE(TIgE)检测。结果三种基因型插入型纯合子(II)、缺失插入型纯合子(ID)、缺失型纯合子(DD)表达例数分别为:哮喘组42、36、71例;喘憋性肺炎组34、26、48例;肺炎组61、30、30例。I、D等位基因频率三组分别为152、90和94例和122、120、178例。哮喘组与肺炎组,喘憋性肺炎组与肺炎组,D、I等位基因优势比分别为2.51和2.19,有显著性差异。哮喘组一级、二级亲属有哮喘史83例,无哮喘史66例,II、ID、DD表达例数分别为16、23、44例和26、13、27例,有显著性差异。喘憋性肺炎组一级、二级亲属有哮喘史46例,无哮喘史62例,II、ID、DD表达例数分别为12、12、22例和22、14、26例,无显著性差异。对分别表达为II、ID、DD的17、19、18例哮喘患儿测定TIgE,分别为(849.08±350.65)KU/L、(744.09±440.62)KU/L、(863.67±647.46)KU/L,无显著性差异。结论哮喘患儿ACE基因I/D多态性分布中以DD为多见,且存在家族聚集倾向。     

Regulation of uterine smooth muscle bradykinin receptors by bradykinin levels and angiotensin converting enzyme inhibitor in the rat

1. Bradykinin infusion (0.1 microgram/min i.v.) decreased the number of uterine bradykinin receptors by 20% at Day 2. Bradykinin receptors returned to control levels at Day 7. 2. Captopril infusion (1.7 micrograms/min i.v.) induced prolonged decreases in the number of uterine bradykinin receptors of 15% at Day 2 and of 13% at Day 7, respectively. 3. The number of uterine bradykinin receptors was increased in two-kidney, one clip hypertensive rats by 19%. 4. These results suggest that endogenous bradykinin participates in the regulation of uterine bradykinin receptors. 5. Decreased uterine bradykinin receptors induced by captopril might reflect increased endogenous bradykinin.     

Effects of angiotensin I and angiotensin II in blood vessels: greater influence of converting enzyme activity in the rabbit basilar artery

We investigated the constrictor effects of Angiotensin I (Ang I) and Angiotensin II (Ang II) on rabbit peripheral (aorta, carotid artery, mesenteric artery, saphenous artery) and cerebral (basilar artery) vessels and in rat aorta in functional organ bath studies. The effect of angiotensin converting enzyme (ACE) inhibition by captopril was also assessed in these preparations. Ang II elicited concentration-dependent contractions with comparable potency in rabbit and rat endothelium-free vascular rings (pD₂ about 8.5) which indicates a lack of species and regional variation in the contractile responses to Ang II. The responses to Ang II were reduced by the presence of a functional endothelium in rabbit mesenteric artery and in rat aorta. Since ACE determines the plasma and tissue conversion of Ang I to active Ang II, we calculated the ratio R (EC₅₀ Ang I-induced contraction: EC₅₀ Ang II-induced contraction) as an indicator of the tissue ACE effectiveness. In the aorta without endothelium, Ang I was found to be much less potent than Ang II in the rabbit (R = 44) compared with the rat (R = 3.5). This species difference in the aortic conversion of Ang I to Ang II was confirmed by the use of captopril. Captopril (10^–6M) shifted the Ang I concentration/response curve by 2- and 14-fold to the right in rabbit and rat respectively. In other rabbit blood vessels, the rank order of potency to Ang I in endothelium denuded rings was basilar artery carotid artery aorta saphenous artery. In addition, the R value was the lowest for the basilar artery (R = 2.5). This is in agreement with the highest rightward shift (78-fold) of the Ang I concentration/response curve by captopril for basilar artery in comparison with only 3-, 8- and 3-fold shifts observed in carotid artery, saphenous artery and aorta respectively. In conclusion, our data provide evidence for a greater influence of ACE in rabbit basilar artery than in peripheral vessels.     

The effect of the converting enzyme inhibitor HOE 498 on the renin angiotensin system of normal volunteers

Summary The converting enzyme inhibitor HOE 498 was evaluated in 12 normotensive male volunteers aged 21 to 26. The efficacy of single 5, 10 or 20 mg oral doses in blocking the pressor response to exogenous angiotensin I was tested in 3 of the subjects. All 3 doses of HOE 498 reduced the pressor response to exogenous angiotensin I to below 50% of control within 1,5 h following administration of the drug. Plasma renin and converting enzyme activity, blood angiotensin I, as well as plasma angiotensin II and aldosterone were measured serially before and up to 72 h following oral administration of a single dose of 2.5, 5, 10 or 20 mg of HOE 498 to groups of 5 volunteers each. As expected, blood angiotensin I levels and plasma renin activity rose while plasma converting enzyme activity, plasma angiotensin II and aldosterone concentration fell after administration of the drug. While the dose of 2.5 mg did not reduce plasma converting enzyme activity below 20% of control, the higher doses all resulted in plasma converting enzyme inhibition exceeding 90%. No side-effects were observed. It is concluded that in normal volunteers HOE 498 is an effective potent and long-acting converting enzyme inhibitor. Based on these preliminary findings it is expected that 5 mg HOE 948 will turn out to be adequate for therapeutic use.     

AngⅡ受体阻断剂与ACEI对肾性高血压大鼠血以及血浆和组织AngⅡ含量变化的影响

目的明确血管紧张素转换酶抑制剂(ACEI)卡托普利与血管紧张素Ⅱ(AngⅡ)受体阻断剂洛沙坦二类药物的药效和作用特点。方法本实验采用①离体血管环微量生物反应测定法检测AngⅡ引起的血管收缩反应;②建立两肾一夹型高血压大鼠模型;利用颈动脉插管法和鼠尾测压计检测血压,观测急性与慢性血压的变化;③用放射免疫法检测高血压大鼠血浆与肾组织中的AngⅡ含量。结果①离体血管环实验:AngⅡ能引起剂量依赖性的血管收缩反应,卡托普利(0.1 mg/kg)对低剂量AngⅡ收缩反应有轻度的抑制效应;随着外源性AngⅡ量增多,其抑制血管收缩作用明显减弱。同样条件下洛沙坦却能完全抑制AngⅡ所引起的血管收缩反应。②在体急性降压实验:最大有效剂量的卡托普利使模型鼠的平均动脉压由(18.4±3.9)kPa降为(8.7±1.2)kPa,降压幅度达到9.6 kPa,之后给洛沙坦最大降压有效剂量(2 mg/kg),血压未再下降;改变给药顺序,平均动脉压由(16.8±1.1)kPa降为(11.4±2.4)kPa,降压幅度为5.30 kPa,然后给最大有效降压剂量的卡托普利,血压持续降为(9.3±1.8)kPa,幅度达2.12 kPa,差异具有明显的统计学意义(P<0.05)。③慢性降压实验:高血压大鼠模型给予实验因素干预后,卡托普利组平均动脉压由(18.9±2.5)kPa降为(11.8±1.6)kPa,洛沙坦平均动脉压由(19.7±2.4)kPa降为(11.7±2.0)kPa,降压幅度分别为7.19 kPa和7.93 kPa,与对照组比较差异无统计学意义。④放射免疫实验:血浆中AngⅡ含量卡托普利组为(376±72)ng/L,明显低于对照组的(526±77)ng/L,而洛沙坦组为(1 036±159)ng/L,明显高于对照组(P<0.01),二者差异具有统计学意义。肾组织中AngⅡ含量,卡托普利组(392±81)pg/g,较对照组的(431±80)pg/g降低8.9%,洛沙坦组为(294±86)pg/g,较对照组降低32.4%(P<0.05)。结论①洛沙坦是通过阻断AngⅡ受体而发挥作用,而卡托普利只能够减少内源性AngⅡ的生成,离体状态下药效弱于洛沙坦。②急性在体实验卡托普利的最大降压效应强于洛沙坦;慢性在体实验二者药效差异无统计学意义。③长期作用下,肾组织的AngⅡ水平对调节血管张力起主要的作用,血浆中AngⅡ辅助起作用。     

血管紧张素转换酶抑制剂治疗慢性充血性心力衰竭有效剂量探讨

目的探讨不同剂量血管紧张素转换酶抑制剂（ACEI）卡托普利治疗慢性充血性心力衰竭（CHF）疗效。方法CHF患者56例，随机分为卡托普利高剂量组n=28，150mg／d，低剂量组n=28，25mg／d，疗程24周。观察治疗前后两组临床症状、超声心动图心功能指标并记录不良反应发生情况。结果高剂量组总有效率89．3％，明显优于低剂量组60．7％（P〈0．01），左心室功能指标每搏量（SV）、心排出量（CO）、射血分数（EF）、左室短轴缩短率（FS）治疗后与治疗前比较，高剂量组有显著改善（P〈0．01），低剂量组变化不大（P〉0．05）。结论大剂量（目标剂量）ACEI较小剂量更有效改善心功能。     

Angiofensin converting enzyme density is increased in temporal cortex from patients with Alzheimer's disease

The present study assesses the binding density of the selective angiotensin converting enzyme (ACE) radioligand [³H]ceranapril in brain tissue homogenates derived from patients with Alzheimer's disease and those from age-, sex- and post-mortem delay-matched neurologically normal patients. Saturation studies with [³H]ceranapril identified that the specific binding (defined by captopril, 10 μM) was homogenous and of high affinity. ACE inhibitor recognition site density was higher by some 70% in the temporal cortex (Brodmann area 22) from Alzheimer's patients whereas densities were similar in frontal cortex and cerebellum when compared to control tissue. It is unknown whether this apparently selective alteration in ACE density is directly related to. or a compensatory effect of the disease, but it provides additional support for the development of compounds which interact with the central angiotensin system as novel therapies for cognitive dysfunction.     

Importance of intracellular angiotensin II in vascular smooth muscle cell apoptosis: inhibition by the angiotensin AT1 receptor antagonist irbesartan

The intracellular uptake of Angiotensin II has been described, although its physiological role is not yet understood. We aimed to study the role of Angiotensin II internalization in Angiotensin II-induced apoptosis. Vascular smooth muscle cells were cultured from male Wistar-Kyoto rats and treated with Angiotensin II (1 microM, 48 h). Apoptosis was assessed by DNA fragmentation, cell cytometry and caspase-3 activity. The Angiotensin AT(1) receptor antagonist irbesartan (0.1-10 microM) and the inhibitors of Angiotensin II internalization phenylarsine oxide (PAO, 20 microM), but not the AT(2) receptor antagonist PD123319 (S-(+)-1-[(4-(Dimethylamino)-3-methylphenyl)methyl]-5-(diphenylacetyl)-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-6-carboxylic acid di(trifluoroacetate) salt), decreased Angiotensin II-mediated apoptosis. Pre-treatment with irbesartan, but not with PD123319, blocked Angiotensin II internalization. We found a strong correlation between intracellular Angiotensin II staining and Angiotensin II-induced apoptosis for all compared groups. We therefore conclude that internalization of Angiotensin II is involved in apoptosis of vascular smooth muscle cells induced by this peptide.     

Study on pharmacokinetics of a new biliary excreted oral angiotensin converting enzyme inhibitor,temocapril (CS-622) in humans

Despite the usefulness of angiotensin converting enzyme (ACE; EC 3.4.15.1) inhibitors for patients with renal insufficiency, some hesitation has been exercised in applying ACE inhibitors to the treatment of such patients because most ACE inhibitors are excreted mainly into the urine. In this context, development of an ACE inhibitor which is excreted into the bile has been sought. The pharmacokinetic properties of the novel ACE inhibitor, temocapril hydrochloride (temocapril HCl; CS-622), were investigated in six healthy volunteers. This drug is excreted mainly into the bile in animal studies. Temocapril HCl was given in a single dose of 0.5, 1.0, and 2.0 mg, and 36, 44, and 38 per cent of the administered drug was excreted in the feces and 17, 19, and 24 per cent in the urine as the de-esterified active diacid form (the diacid metabolite) within 48 h, respectively. The plasma ACE activity was markedly inhibited. No abnormal clinical findings suggestive of side-effects were observed. Thus, from the pharmacokinetic standpoint, temocapril HCl is expected to be a useful drug for patients with renal dysfunction.     

Dose-finding study of imidapril,a novel angiotensin converting enzyme inhibitor,in patients with stable chronic heart failure

Objective: To study the haemodynamic profile and tolerability of imidapril, a new long-acting ACE inhibitor, and to investigate the effect of inhibition of circulating ACE on blood pressure in patients with stable chronic heart failure. Methods: Twenty-four patients with stable, chronic heart failure (New York Heart Association (NYHA) functional Class II–III) were randomised to receive either 2.5 mg or 5 mg imidapril. Other vasodilators were withheld for ≥ 5 half-lives. Blood pressure and ACE activity were carefully monitored for 24 h after dosing. Results: Both 2.5 mg and 5 mg imidapril decreased systolic blood pressure, while diastolic blood pressure fell only after 5 mg imidapril. The two doses produced a significant and similar inhibition of circulating (serum) ACE. No serious adverse effects were observed, although symptomatic hypotension occurred in 1 patient (5 mg). The decrease in blood pressure was not related to baseline ACE activity, serum sodium or serum creatinine concentration. Conclusions: Imidapril significantly lowered systolic blood pressure and was well tolerated. The difference in the first dose response to the two doses with respect to diastolic blood pressure suggests that this haemodynamic effect of ACE-inhibition is not related to inhibition of circulating ACE. Received: 21 April 1995/Accepted in revised form: 15 December 1995     

Enalapril, a new nonsulfhydryl angiotensin converting enzyme inhibitor, does not potentiate morphine analgesia

Sprague-Dawley rats received oral doses of enalapril maleate (5 mg/kg), a potent, nonsulfhydryl, angiotensin converting enzyme inhibitor, or saline. Sixty min later, morphine sulfate, 5 mg/kg, or saline was injected subcutaneously. Response to a thermal stimulus was monitored before and up to 5 h ter morphine injection using the rat tail flick test. Serum ACE activity was greater than 90% inhibited by enalapril throughout the experiment. Enalapril did not exhibit analgesic activity nor did it potentiate morphine analgesia.     

Adverse drug reaction monitoring with angiotensin converting enzyme inhibitors: A prospective, randomized, open-label, comparative study

Objectives:

Angiotensin converting enzyme inhibitors (ACEIs) are known to possess different chemical structures, and change in structure of a drug can bring about change in its adverse drug reaction (ADR) profile. The study aims to observe the incidence and severity of ADRs between the di-carboxyl group containing ACEIs (d-ACEIs) versus phosphonate group containing ACEIs (p-ACEIs), in patients suffering from essential hypertension.

Materials and Methods:

One hundred and twenty patients with essential hypertension were randomized into four groups receiving enalapril, lisinopril, ramipril, and fosinopril. They were followed up for four months, to observe the clinical efficacy along with the associated ADRs.

Results:

Mild, dry brassy cough (% incidence; 95% CI) was observed with d-ACEIs (6.6%; 0 to 15.6) versus p-ACEI (20%; 5.7 to 34.3), in which the cough observed was moderate-to-severe in intensity and two patients required treatment discontinuation (P < 0.05). No cases of hypotension were observed with the use of d-ACEIs, whereas, two patients on p-ACEI (6.6%; 0 to15.6) had hypotension (P < 0.05). Three patients (10%; 0 to 20.7) on d-ACEIs had nausea, which was not observed with p-ACEI treatment (0%) (P < 0.05).

Conclusions:

The phosphonate group in p-ACEIs may have a probable relationship with increase in the incidence and severity of ADRs such as dry brassy cough and hypotension. The di-carboxyl group in d-ACEIs may have a probable relationship with increase in the incidence of ADRs like nausea.     

缬沙坦对自发性高血压大鼠肾脏和脑组织中血管紧张素转化酶2表达的影响

目的 研究缬沙坦对自发性高血压大鼠肾脏和脑组织中血管紧张素转化酶2(ACE2)表达的影响,探讨ACE2对肾脏及脑组织中的保护作用.方法 选取24只(♂)12周龄的自发性高血压大鼠(SHR),随机均分为缬沙坦组和SHR组;选取12只正常♂ Wistar大鼠做为对照组.缬沙坦组大鼠ig给予缬沙坦30 mg·kg-1 ·d-1,而SHR组及对照组均给予等量0.9％氯化钠溶液.10周后处死大鼠,取出肾脏及脑组织,HE染色法观察各组大鼠肾脏及脑组织的病理变化,免疫组织化学法和逆转录聚合酶链反应(RT-PCR)法测各组大鼠肾脏及脑组织中ACE2的表达差异.结果 与正常大鼠相比,缬沙坦组、SHR组大鼠肾脏及脑组织中ACE2的表达明显减低(P＜0.05);与缬沙坦组相比,SHR组大鼠组织中ACE2的表达较低(P＜0.05).结论 缬沙坦能够上调自发性高血压大鼠肾脏及脑组织中ACE2的表达,并对肾脏及脑组织起保护作用,可能为血管紧张素Ⅱ受体拮抗剂类药物降压的新机制.     

Sequential development of angiotensin receptors and angiotensin I converting enzyme during angiogenesis in the rat subcutaneous sponge granuloma

1. The vasoconstrictor peptide antiotensin II (AII) can stimulate angiogenesis, an important process in wound healing, tumour growth and chronic inflammation. To elucidate mechanisms underlying AII-enhanced angiogenesis, we have studied a subcutaneous sponge granuloma model in the rat by use of ¹³³Xe clearance, morphometry and quantitative in vitro autoradiography.
2. When injected directly into the sponge, AII (1 nmol day⁻¹) increased ¹³³Xe clearance from, and fibrovascular growth in sponge granulomas, indicating enhanced angiogenesis 6 to 12 days after implantation. This AII-enhanced angiogenesis was inhibited by daily doses (100 nmol/sponge) of the specific but subtype non-selective AII receptor antagonist (Sar¹, Ile⁸)AII, and by the selective non-peptide AT₁ receptor antagonists losartan and DuP 532. In contrast, AII-enhanced neovascularization was not inhibited by the AT₂ receptor antagonist PD123319, nor was it mimicked by the AT₂ receptor agonist CGP42112A (each at 100 nmol/sponge day⁻¹).
3. AI (1 nmol/sponge day⁻¹), the angiotensin converting enzyme (ACE) inhibitors captopril (up to 100 μg/sponge day⁻¹) and lisinopril (40 μg/sponge day⁻¹), or AII receptor antagonists did not affect angiogenesis in the absence of exogenous AII.
4. [¹²⁵I]-(Sar¹, Ile⁸)AII binding sites with characteristics of AT₁ receptors were localized to microvessels and to non-vascular cells within the sponge stroma from 4 days after implantation, and were at higher density than in skin throughout the study.
5. [¹²⁵I]-(Sar¹, Ile⁸)AII binding sites with characteristics of AT₂ receptors were localized to non-vascular stromal cells, were of lower density and appeared later than did AT₁ sites.
6. The ACE inhibitor [¹²⁵I]-351A bound to sites with characteristics of ACE, 14 days after sponge implantation. [¹²⁵I]-351A bound less densely to sponge stroma than to skin.
7. We propose that AII can stimulate angiogenesis, acting via AT₁ receptors within the sponge granuloma. AT₁ and AT₂ receptors and ACE develop sequentially during microvascular maturation, and the role of the endogenous angiotensin system in angiogenesis will depend on the balanced local expression of its various components. Pharmacological modulation of this balance may provide novel therapeutic approaches in angiogenesis-dependent diseases.

     

Pharmacokinetics of temocapril hydrochloride,a novel angiotensin converting enzyme inhibitor,in renal insufficiency

Summary The pharmacokinetics of temocapril hydrochloride, a novel prodrug-type angiotensin-I converting enzyme (ACE) inhibitor, has been studied in patients with mild (Group II) to severe (Group III) renal insufficiency in comparison with subjects with normal renal function (Group I).The pharmacokinetic parameters of the active diacid metabolite, including C_max, AUC and half-life (t_1/2), showed only slight changes between the three groups: AUC (0–) was significantly larger in Group III than Group I, and t1/2 tended to be prolonged in Group III, but the change was not significant.The urinary recovery of the diacid was significantly decreased in Group III. (Group I, 28.1 %, Group II, 21.6 %, Group III, 12.8 %). Compared with other ACE inhibitors, which are mainly excreted through the kidney, the plasma concentration of the active diacid metabolite was hardly influenced by renal function. It was speculated that lowering of the dose of temocapril might be recommended only in patients with severe renal insufficiency.     

Discovery of new angiotensin converting enzyme (ACE) inhibitors from medicinal plants to treat hypertension using an in vitro assay

Background and purpose of the study

Angiotensin converting enzyme (ACE) inhibitors plays a critical role in treating hypertension. The purpose of the present investigation was to evaluate ACE inhibition activity of 50 Iranian medicinal plants using an in vitro assay.

Methods

The ACE activity was evaluated by determining the hydrolysis rate of substrate, hippuryl-L-histidyl-L-leucine (HHL), using reverse phase high performance liquid chromatography (RP-HPLC). Total phenolic content and antioxidant activity were determined by Folin-Ciocalteu colorimetric method and DPPH radical scavenging assay respectively.

Results

Six extracts revealed > 50% ACE inhibition activity at 330 μg/ml concentration. They were Berberis integerrima Bunge. (Berberidaceae) (88.2 ± 1.7%), Crataegus microphylla C. Koch (Rosaceae) (80.9 ± 1.3%), Nymphaea alba L. (Nymphaeaceae) (66.3 ± 1.2%), Onopordon acanthium L. (Asteraceae) (80.2 ± 2.0%), Quercus infectoria G. Olivier. (Fagaceae) (93.9 ± 2.5%) and Rubus sp. (Rosaceae) (51.3 ± 1.0%). Q. infectoria possessed the highest total phenolic content with 7410 ± 101 mg gallic acid/100 g dry plant. Antioxidant activity of Q. infectoria (IC₅₀ value 1.7 ± 0.03 μg/ml) was more than that of BHT (IC₅₀ value of 10.3 ± 0.15 μg/ml) and Trolox (IC₅₀ value of 3.2 ± 0.06 μg/ml) as the positive controls.

Conclusions

In this study, we introduced six medicinal plants with ACE inhibition activity. Despite the high ACE inhibition and antioxidant activity of Q. infectoria, due to its tannin content (tannins interfere in ACE activity), another plant, O. acanthium, which also had high ACE inhibition and antioxidant activity, but contained no tannin, could be utilized in further studies for isolation of active compounds.     

Renal excretion of an angiotensin I converting enzyme inhibitor (SA-446) in dogs

Summary The renal excretory mechanism of an orally active inhibitor of angiotensin converting enzyme (SA-446) was examined in anesthetized dogs. Parenteral administration of this compound resulted in production of constant levels of about 2 mg/l in the plasma (P_SA) and the urine concentration was 726±200 mg/l, a level significantly higher than that in the plasma. Renal clearance of SA-446 (C_SA) was 2.24±0.34 ml/g·min and was significantly higher than GFR. The clearance ratio (C_SA/GFR) of over 1.0 was indicative of a net tubular secretion. Administration of probenecid resulted in a significant rise in P_SA and in a significant decrease in urinary excretion but with no change in the plasma protein binding ratio. C_SA decreased significantly from 2.24±0.34 to 0.71±0.14 ml/g·min. The inhibotory action of SA-446 (0.02 mg/kg, i.v.) on the pressor response to angiotensin I disappeared at about 50 min, this action being maintained for about 2 h in the probenecid pretreated dog.Since probenecid is a competitive inhibitor of organic anion secretory transport, our results show the net tubular secretion of SA-446, via organic anion transport systems. Prolongation of the action of SA-446, as induced by probenecid may be due to the increase of plasma concentration, by the inhibition of tubular secretion.     

Potentiation of the pro-inflammatory effects of bradykinin by inhibition of angiotensin-converting enzyme and aminopeptidase P in rat paws

The influence of some peptidase inhibitors on oedema and plasma extravasation induced by bradykinin and carrageenan in rat paw was evaluated. Bradykinin-induced oedema in normal rats was increased by o-phenanthroline (3.10^–2 M), by captopril (10^–6 M to 10^–4 M), by lisinopril (10^–6 M to 10^–4 M), or by lisinopril (10^–5 M) in combination with apstatin (8.10^–5 M or 1.4 10^–4 M). It was not modified by phosphoramidon (10^–6 M to 10^–5 M) and by diprotin A (10^–3 M). It was increased by mergepta at high concentrations (2.10^–4 M). Mergepta did not increase the potentiating effect of captopril. Carrageenan-oedema in normal rats was increased by captopril (10^–5 M), lisinopril (10^–5 M) and apstatin (1.4 10 M). It was not modified by mergepta (10^–4 M), phosphoramidon (10^–5 M) and diprotin A (10^–3 M). Des-Argl-bradykinin and Des-Arg⁹-bradykinin have low oedema-promoting effects. Captopril (10^–5 M) increased the effects of bradykinin but not those of carrageenan in kininogen-deficient Brown Norway rats. Angiotensin-converting enzyme and amino-peptidase P appear to be main kinin-inactivating enzymes in rat paws. Carboxypeptidase N, neutral endopeptidase 24.11 and dipeptidyl(amino)peptidase IV do not play a significant role in this inactivation.