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.     

Metabolism of bradykinin and angiotensin I by human basilar artery and rabbit aorta

Summary 1. The role of angiotensin converting enzyme in the metabolism of bradykinin and angiotensin I by in vitro human basilar artery and rabbit aorta was studied. 2. On both human basilar artery and rabbit aorta concentration-effects curves to angiotensin I were significantly attenuated by captopril at a concentration which had no effect on bradykinin responses on both tissues. 3. The metabolism of bradykinin and angiotensin I was studied using high performance liquid chromatography. Both peptides were broken down by human basilar artery and rabbit aorta in a similar fashion. The breakdown of angiotensin I but not bradykinin was significantly attenuated by captopril. 1,10-phenanthroline did attenuate breakdown of bradykinin but this was found not to be significant compared with controls. 4. The results confirm that angiotensin converting enzyme is present in both these tissues and is important for the conversion of angiotensin I to angiotensin II. It appears that other peptidases are important in the breakdown of kinins by these tissues and should be taken into account when investigating the mechanism of action of such peptides on these vascular preparations.     

Differential modulation by basilar and mesenteric endothelium of angiotensin-induced contraction in canine arteries

The contraction of ring segments of canine mesenteric and basilar arteries in response to angiotensins II and III was investigated. Removal of the mesenteric endothelium resulted in markedly intensified contraction in response to angiotensin II but did not affect the contractile response to angiotensin III. This angiotensin II-induced contraction was augmented by indomethacin (10⁻⁵ M) and by methylene blue (5 × 10⁻⁶ M) in the intact rings. These findings suggest that mesenteric endothelium modulates the vasoconstriction induced by angiotensin II but not that induced by angiotensin III. They also indicate that the mesenteric endothelium may contain relaxing factors such as prostacyclin or endothelium-derived relaxing factor as mediators. In contrast with mesenteric endothelium, removal of the basilar endothelium produced a much reduced contraction in response to either angiotensin. Acetylcholine, which caused a dose-dependent contraction in the basilar artery, elicited only a low-grade response if the functional endothelium was absent. These results suggest that basilar endothelium may release a contracting factor. It is possible that the main modulator of the peripheral arteries is a relaxing factor but that of the cerebral arteries is a contracting factor.     

Analysis of the receptors mediating vascular actions of bradykinin

Summary A range of bradykinin (BK) analogues was assessed for their ability to antagonise the action of BK on rabbit jugular vein, a B₂-receptor containing tissue, and compared with their action against BK-induced increases in skin vascular permeability in the rabbit and rat. The results demonstrate that modification of the BK (nonapeptide) structure by the insertion of certain d-amino acids in positions 5, 7 and 8 in addition to elongation of the amino terminal resulted in compounds with potent antagonistic action against BK on rabbit jugular vein and rabbit skin vascular permeability. The same BK analogues did not antagonise the action of BK on rat skin vascular permeability. It is concluded that the kinin receptor mediating an increase in vascular permeability in the rabbit is the same as that mediating contraction of the rabbit jugular vein in vitro, that is the B₂-type. The kinin receptor mediating an increase in skin vascular permeability in the rat is difficult to classify but does not appear to be of the B₂ type. Send offprint requests to E. T. Whalley     

Potentiating mechanism of bradykinin action on smooth muscle by sulfhydryl compounds.

(4R)-3-[(2S)-3-Mercapto-2-methylpropanoyl]-4-thiazolidinecarboxylic acid (YS-980), a potent angiotensin I (AI) converting enzyme inhibitor, inhibited the contractile response of isolated guinea-pig ileum to AI but not to AII, while it potentiated the response to bradykinin. Other sulfhydryl compuonds also produced inhibition of AI action, and the effects were closely correlated with their potentiating activities against bradykinin action. These results suggest that it is mainly inhibition of the enzyme in the tissue which participates in the mechanism of potentiation of kinin action by YS-980.     

基底动脉尖综合征21例临床分析

目的 探讨基底动脉尖综合征的临床和影像学特征,提高基底动脉尖综合征诊疗水平.方法 对21例基底动脉尖综合征的临床资料进行回顾性分析.结果 多急性或亚急性起病,首发症状以眩晕最常见,意识障碍发生率较高,眼球运动障碍和瞳孔异常为核心症状.影像学改变病灶以中脑和丘脑为主,并且多个病灶同时存在.结论 基底动脉尖综合征的临床和影像学改变复杂多样,只有掌握其特征,提高对基底动脉尖综合征的认识,才能早期诊断,规范治疗,改善预后.     

Hypotension induced by inhibition of angiotensin-converting enzyme in pentobarbital-anesthetized dogs.

The mechanism of the hypotensive response produced by inhibition of the angiotensin converting enzyme was studied in pentobarbital anesthetized dogs. A recently developed potent inhibitor of the converting enzyme, SQ 14,225 (D-3-mercapto-2-methyl propanoyl-L-proline), administered i.v. to intact dogs resulted in a rapid marked decrease in blood pressure. In nephrectomized dogs, SQ 14,225 retained significant hypotensive activity, although the absolute magnitude of the decreases in blood pressure were less than had been observed in dogs with intact kidneys. SQ 14,225 also lowered blood pressure when administered to intact dogs in which angiotensin II receptors had been blocked with the receptor antagonist Sar1,Ala8-angiotensin II. This apparent ability of SQ 14,225 to decrease blood pressure in the absence of a functional renin angiotensin system was shared by a structurally dissimilar, nonapeptide, angiotensin converting enzyme inhibitor, SQ 20,881 (Glu-Trp-Pro-Arg-Pro-Gln-Ile-Pro-Pro). SQ 20,881 also produced significant decreases in blood pressure in nephrectomized dogs. These findings indicate that the angiotensin converting enzyme inhibitors, SQ 14,225 and SQ 20,881 may lower blood pressure in anesthetized normotensive dogs via a mechanism unrelated to either the renin angiotensin system or the renal kinin system.     

染料木素对狗基底动脉环舒张作用及其机制的离体研究

目的：探讨血管张力变化对染料木素的脑血管保护作用及相关机制的比较。方法：（1）制备狗基底动脉血管环固定于恒温肌槽内,待平衡后,加入各种药物观察血管张力的变化。结果：（1）200μmol／L GST可浓度依赖性地压低氯化钾（KCl）量效曲线,使其明显右移,最大收缩反应和肌条对KCl的敏感性明显降低。（2）无Ca^2＋K—H液中。染料术素对去甲肾上腺素（NA）诱发产生第一时相收缩和CaCl2产生第二时相收缩均具有明显的抑制作用。（3）染料木素可使60mmol／L KCl预收缩基底动脉血管环产生明显的舒张作用,除内皮细胞或加入一氧化氮合酶抑制剂Nω—L-硝基精氨酸1×10^-4mol／L．甲烯兰1×10^-5mol／L．1×10^-5mol／L吲哚美辛或格列本脲1×10^-5mol／L温育后,染料木素对60mmol／L KCl预收缩动脉血管环产生的量效舒张作用无明显改变（P〉0．05）。结论：（1）染料木素对基底动脉血管舒张可能是直接作用于平滑肌而引起的,即抑制电压依赖性的钙通道。无Ca^2＋K—H液中,抑制NA从细胞内释放贮存的Ca^2＋。（2）染料木素对基底动脉血管的舒张作用与内皮细胞及其释放的一氧化氮无关。前列腺素类物质的合成和KATP通道亦无关。     

眩痛停方对离体犬基底动脉收缩反应的影响

目的观察眩痛停方对犬离体基底动脉收缩反应的影响。方法分离犬基底动脉并置于血管环灌流装置中,基底动脉预先给予含药血清,记录去氧肾上腺素或高钾离子作用于犬基底动脉后的血管收缩反应。结果眩痛停方对血管平滑肌的张力性收缩具有较好的拮抗作用（与生理盐水组比,P〈0．05）,且随剂量的增加呈现出一定的量效关系;眩痛停方对血管平滑肌的相位性收缩没有抑制作用。结论眩痛停方降低麻醉犬脑血管阻力,增加脑血流量的机制可能与其抑制细胞外钙内流,抑制基底动脉血管收缩有关。     

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     

Met-Lys-bradykinin-Ser-Ser, a peptide produced by the neutrophil from kininogen, is metabolically activated by angiotensin converting enzyme in vascular tissue

Bradykinin (BK) is a vasoactive nonapeptide cleaved from circulating kininogens and that is degraded by angiotensin converting enzyme (ACE). It has been reported that the PR3 protease from human neutrophil releases an alternate peptide of 13 amino acids, Met-Lys-BK-Ser-Ser, from high molecular weight kininogen. We have studied vascular actions of this kinin. Its affinity for recombinant B₁ and B₂ receptors is very low, as assessed by the binding competition of [³H]Lys-des-Arg⁹-BK and [³H]BK, respectively, but Met-Lys-BK-Ser-Ser effectively displaced a fraction of [³H]enalaprilat binding to recombinant ACE. Mutant recombinant ACE constructions revealed that affinity gap between BK and Met-Lys-BK-Ser-Ser is larger for the N-terminal catalytic site than for the C-terminal one, based on competition for the substrate Abz-Phe-Arg-Lys(Dnp)-Pro-OH in an enzymatic assay. Met-Lys-BK-Ser-Ser is a low potency stimulant of the rabbit aorta (bioassay for B₁ receptors), but the human isolated umbilical vein, a contractile bioassay for the B₂ receptors, responded to Met-Lys-BK-Ser-Ser more than expected from the radioligand binding assay, this agonist being ∼30-fold less potent than BK in the vein. Venous tissue treatment with the ACE inhibitor enalaprilat reduced the apparent potency of Met-Lys-BK-Ser-Ser by 15-fold, while not affecting that of BK. In the rabbit isolated jugular vein, Met-Lys-BK-Ser-Ser is nearly as potent as BK as a contractile stimulant of endogenous B₂ receptors (EC₅₀ values of 16.3 and 10.5 nM, respectively), but enalaprilat reduced the potency of Met-Lys-BK-Ser-Ser 13-fold while increasing that of BK 5.3-fold. In vascular tissue, ACE assumes a paradoxical activating role for Met-Lys-BK-Ser-Ser.     

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.     

超选择动脉溶栓救治基底动脉尖综合征12例体会

目的：观察基底动脉尖综合征急诊动脉溶栓的安全性和疗效。方法对基底动脉尖综合征脑血行管造影显示基底动脉主干及其较大主要分支闭塞12例。符合动脉溶栓条件,予r-TPA超选择接触性动脉溶栓的病人12例。结果12例病人溶栓后血管成功再通8例（66.7%）,血管部分再通3例（25%）。溶栓后栓塞复发l例,颅内出血1例,死亡1例,病死率8.3%。结论超选择动脉溶栓是有效治疗基底动脉尖综合征的方法,可增加血管再通率,改善病人的预后。     

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.     

血管紧张肽转换酶抑制药在冠心病治疗中的应用

血管紧张肽转换酶抑制药可通过改善心肌供氧耗氧平衡、改善血管内皮功能、抑制交感神经兴奋性、抑制血管平滑肌迁移和增殖、抑制血小板聚集和促进纤维蛋白溶解、抑制低密度脂蛋白氧化修饰、抑制心肌肥厚、延迟心脏重构等机制在动脉粥样硬化和冠心病的治疗中发挥重要作用     

Mechanisms underlying diabetes enhancement of endothelin-1-induced contraction in rabbit basilar artery

The influence of alloxan-induced diabetes on the reactivity of rabbit basilar artery to endothelin-1 was examined. Endothelin-1 induced concentration-dependent contraction of basilar arteries that was higher in diabetic than in control rabbits. Endothelium removal produced a higher enhancement of the endothelin-1-induced contraction in control than in diabetic rabbits. N(G)-nitro-L-arginine (L-NOArg) enhanced the maximal contraction induced by endothelin-1 in control rabbits and potentiated this response in diabetic rabbits. Endothelin ETA receptor antagonist, cyclo(D-Asp-Pro-D-Val-Leu-D-Trp) (BQ-123), inhibited endothelin-1-induced contraction in both rabbit groups. Endothelin ETB receptor antagonist, 2,6-Dimethylpiperidinecarbonyl-gamma-Methyl-Leu-Nin-(Methoxycarbonyl)-D-Trp-D-Nle (BQ-788), enhanced endothelin-1-induced contraction in control rabbits and decreased the potency of endothelin-1 in diabetic rabbits. Sodium nitroprusside-induced relaxation of basilar arteries was lower in diabetic than in control rabbits. These results suggest that mechanisms underlying rabbit basilar artery hyperreactivity to endothelin-1 include decreased endothelial modulation of endothelin-1-induced contraction, with impaired endothelial endothelin ETB receptor activity; decreased sensitivity to nitric oxide (NO) in vascular smooth muscle; and enhanced participation of muscular endothelin ETA and ETB receptors.     

Effect of hydroxocobalamin on vasodilatations to nitrergic transmitter, nitric oxide and endothelium-derived relaxing factor in guinea-pig basilar artery

In endothelium-denuded guinea-pig isolated basilar artery preparations, hydroxocobalamin (30, 100 and 300 μM) concentration-dependently inhibited the vasodilator responses to exogenous nitric oxide (NO), whereas the vasodilator responses to nitrergic nerve stimulation were slightly reduced by high (100 and 300 μM) but not by the low (30 μM) concentration of hydroxocobalamin. Vasodilatation in response to sodium nitroprusside (10–100 nM) was totally abolished by 300 μM hydroxocobalamin. In endothelium-intact preparations, vasodilator responses to acetylcholine (0.3–3 μM) were significantly reduced or abolished by hydroxocobalamin (30–300 μM). The mean reduction by hydroxocobalamin of relaxations to acetylcholine was significantly greater than that of the equivalent response evoked by nitrergic nerve stimulation. The findings suggest that the nitrergic transmitter in the guinea-pig basilar artery may be quantitatively less susceptible than the endothelium-derived relaxing factor to the NO scavenger hydroxocobalamin.     

埃他卡林对人肺动脉内皮细胞内皮素系统的作用

目的研究新型ATP敏感性钾通道(KATP)开放剂埃他卡林(iptakalim,IPT)对人肺动脉内皮细胞内皮素(ET)系统的作用。方法原代培养人肺动脉内皮细胞(HPAECs),分别加入不同浓度埃他卡林,共同孵育24h后;应用放射免疫法测定各组细胞上清内皮素-1(ET-1)浓度的变化,同时用逆转录多聚酶链反应(RT-PCR)方法检测各组细胞ET-1及内皮素转换酶(ECE)mRNA表达的变化。结果在IPT浓度为10-6mol·L-1及以上时,能够剂量依赖性地抑制HPAECs合成分泌ET-1,同时也降低ET-1mRNA的表达量;在IPT浓度为10-7mol·L-1及以上时,能够剂量依赖性地降低ECEmRNA的表达量。结论IPT通过抑制人肺动脉内皮细胞ET-1和ECEmRNA的表达量,继而抑制内皮细胞合成分泌ET-1,可能成为较有前途的治疗肺动脉高压的有效药物。