Benazepril. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy in hypertension and congestive heart failure.

Benazepril is a nonsulfhydryl ACE inhibitor prodrug, which is converted in vivo to its active form, benazeprilat. Data from clinical studies have indicated that benazepril 5 to 80 mg (usually 10 to 20 mg), administered as a single daily dose, effectively decreases blood pressure in patients with mild to moderately severe hypertension. In a small number of comparative studies, the anti-hypertensive efficacy of benazepril appeared to be at least equivalent to that of captopril, enalapril, hydrochlorothiazide, nifedipine, nitrendipine or propranolol at usual therapeutic doses. Combinations of benazepril and hydrochlorothiazide or nifedipine achieved a greater lowering of blood pressure than benazepril alone, and this approach may be suitable for patients with more severe hypertension. Benazepril is reported to have beneficial effects on various indices of cardiac function and to improve clinical symptoms and exercise capacity in patients with congestive heart failure. The tolerability of benazepril in clinical trials has been very good, with an incidence of adverse effects similar to that observed in placebo recipients. Thus, benazepril appears to be an effective alternative to other members of its class for the management of hypertension, and further studies will accurately define its usefulness in congestive heart failure.     

Protection of Renal Function with ACE Inhibitors: Experience with Benazepril

Research into progressive renal scarring has been closely linked over the last two decades with angiotensin II (AII). This has led to a better understanding of the mechanisms underlying the development of glomerulosclerosis and tubulointerstitial scarring. AII appears to play an important role in the pathogenesis of both; this may be because of either a direct proliferative and fibrogenic effect of AII or an indirect effect mediated by growth factors such as platelet-derived growth factor (PDGF) and transforming growth factor (TGF(beta1)). These findings have led to significant therapeutic advances as ACE inhibition prevents the progression of experimental renal scarring and attenuates the progression of chronic renal failure in humans. Benazepril, through its metabolite benazeprilat, is a non-sulfhydryl orally active ACE inhibitor. The kinetics of benazeprilat are substantially affected by severe renal impairment; for patients with a creatinine clearance of <30 ml/min the initial recommended daily dose is 5mg. The angiotensin converting enzyme inhibition in a progressive renal insufficiency (AIPRI) study confirmed that benazepril provides protection against the progression of renal insufficiency in patients with various renal diseases and that this treatment is well tolerated.     

Antihypertensive action of the novel angiotensin converting enzyme inhibitor benazepril hydrochloride in hypertensive rat models

Single or repeated administration of benazepril hydrochloride (CGS 14824 A, CAS 86541-74-4), a novel angiotensin I converting enzyme inhibitor, (0.3-10 mg/kg p.o.) caused significant antihypertensive effects in renal and spontaneously hypertensive rats (SHR). The antihypertensive effects of benazepril hydrochloride was about 3 times as potent as that of captopril in these models. Single administration (0.3-3 mg/kg p.o.) of benazepril hydrochloride and enalapril maleate showed an equipotent antihypertensive effect in SHR. Benazepril hydrochloride (3-30 mg/kg p.o.), however, showed no clear effect on the blood pressure and heart rate in normotensive or DOCA/salt hypertensive rats.     

Pharmacological studies on (4S)-1-methyl-3-[(2S)-2-[N-((1S)-1-ethoxycarbonyl-3-phenylpropyl)amino] propionyl]-2-oxo-imidazolidine-4-carboxylic acid hydrochloride (TA-6366), a new ACE inhibitor: I. ACE inhibitory and anti-hypertensive activities

TA-6366 and its active metabolite 6366A inhibited swine renal angiotensin converting enzyme (ACE) activity with IC50s of 9900 and 2.6 nM, respectively. TA-6366 (0.05-0.5 mg/kg, p.o.) inhibited the angiotensin I (AT-I)-induced pressor response in rats. 6366A augmented bradykinin (BK)-induced contraction of guinea pig ileum more potently than captopril. However, when the augmentation on BK-induced hypotension in rats was used as an indicator, TA-6366 was less active than captopril. TA-6366 increased plasma renin activity and plasma AT-I concentration. Oral administration of TA-6366 lowered the blood pressure in two-kidney one-clip renal hypertensive rats at 0.5 to 2 mg/kg and in spontaneously hypertensive rats (SHRs) at 2 to 10 mg/kg. The antihypertensive effect of TA-6366 was approximately 5 times more potent than that of captopril and almost as potent as that of enalapril. In SHRs, the antihypertensive action of TA-6366 was intensified in potency when administered repeatedly. The duration of action was longer than those of captopril and enalapril. However, TA-6366 had no substantial effect on the blood pressure in DOCA/saline hypertensive rats. These results indicate that TA-6366 is a potent and long lasting antihypertensive agent and that its antihypertensive action is attributable to the inhibition of ACE.     

Involvement of p44/42 mitogen-activated protein kinases in regulating angiotensin II- and endothelin-1-induced contraction of rat thoracic aorta

In order to elucidate the signal transduction pathway of vascular smooth muscle contraction induced by the activation of receptors for angiotensin II and endothelin-1, we examined whether tyrosine kinases and mitogen-activated protein (MAP) kinases are involved in the development of force of contraction in the rat aorta. Isolated aortic smooth muscles without endothelium were incubated in a modified Krebs-Henseleit solution and stimulated with angiotensin II (100 nM) or endothelin-1 (10 nM). A tyrosine kinase inhibitor genistein (10 microM) reduced the angiotensin II- and endothelin-1-induced aortic contraction, while 10 microM of daidzein (an inactive analogue of genistein) did not. The K(+) depolarization-induced contraction was not attenuated by 10 microM of genistein. Selective inhibitors of MAP kinase/extracellular signal-regulated kinase (Erk) kinase (MEK) such as PD98059 [2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one] and U0126 [1,4-diamino-2,3-dicyano-1,4-bis(2-aminophenylthio)butadiene] inhibited the angiotensin II- and endothelin-1-induced vasocontraction. The p44/42 MAP kinases were phosphorylated in cultured aortic smooth muscle cells and in physiologically contracted aortic vessels stimulated with angiotensin II and endothelin-1 for 5 min. The angiotensin II- and endothelin-1-induced phosphorylations of p44/42 MAP kinases were inhibited by PD98059 as well as U0126 in the intact aorta. These results suggest that the activation of genistein-sensitive tyrosine kinases and p44/42 MAP kinases is involved in the angiotensin II- and endothelin-1-induced rat aortic contraction.     

Pharmacokinetics of the angiotensin-convertingenzym e inhibitor,benazepril, and its active metabolite,benazeprilat, in dog

1. The pharmacokinetics of the angiotensin-converting-enzyme (ACE) inhibitor benazepril were evaluated in eight healthy Beagle dogs. Benazepril was administered orally at a dosage of 7·5?mg (about 0·5?mg/kg) both as a single dose and then once daily for 14 consecutive days. The prodrug, benazepril, and its active metabolite, benazeprilat, were measured in plasma using a gas chromatography mass-spectrometry method with massselective detection. 2. Benazepril appeared quickly in the plasma (t_max 0·5?h) and was rapidly eliminated by max metabolism to benazeprilat. Peak benazeprilat concentrations were attained later (t_max 1·25?h) and declined biphasically with a rapid elimination phase (t_½λ₁ 1·1 and 1·7?h after single and the last repeated dose respectively) followed by a terminal elimination phase (t_½λ_Z 11·7 and 19·0?h after single and repeated dose respectively). The mean residence time for benazeprilat was 15·2?h after the single dose and 17·4?h after the 14th dose. 3. Repeated administration of benazepril produced moderate bioaccumulation of benazeprilat; the ratio of AUC_{[0→24 h]}'s after the 14th dose as compared with the single dose was 1·47, equivalent to a half-life for accumulation (t_½acc) of 14·6?h. Steady-state benazeprilat concentrations at peak (C_max) and trough (C_min) were reached within three doses. 4. The pharmacodynamics of benazepril were assessed by measurement of plasma ACE activity. After both single doses and at steady-state, benazepril produced inhibition of ACE activity in all dogs that was maximal at peak effect (E_max = 100%) and long-lasting max (> 85% inhibition was present at 24?h). The long duration of action of benazepril on plasma ACE is due to the presence of the terminal elimination phase of benazeprilat, even though most of the metabolite is rapidly eliminated from the plasma.     

Disposition of [14C]-benazepril hydrochloride in rat, dog and baboon. Absorption, distribution, kinetics, biotransformation and excretion

The compound 3-[(1-ethoxycarbonyl-3-phenyl-(1S)-propyl)-amino]-2,3,4,5- tetrahydro-2-oxo-1-(3S)-benzazepine-1-acetic acid hydrochloride (benazepril.HCl, CGS 14 824 A) is an ethyl ester prodrug of the angiotensin converting enzyme (ACE) inhibitor benazeprilat (CGS 14 831). The disposition of both compounds was studied in rat, dog and baboon after peroral and intravenous dosing of 14C-labelled preparations (2.5-3 mg/kg). Perorally dosed benazeprilat was poorly absorbed in rats, whereas benazepril.HCl was well absorbed in all species. Onset of absorption of benazepril.HCl was fast. Plasma concentrations of radioactivity indicated a prolonged absorption process. Upon intravenous benazepril.HCl, plasma levels declined rapidly in all species but showed a slow terminal elimination phase. Distribution to all organs and tissues occurred rapidly and was typical for an acid compound. Passage of the blood-brain barrier and of the placenta occurred to a minimal extent. No accumulation was observed after repeated dose. Radioactivity was rapidly and completely eliminated; biliary excretion was important. In the rat, benazepril was completely hydrolysed by first pass metabolism to the pharmacologically active benazeprilat. In dog and baboon hydrolysis was incomplete and additional hydrophilic metabolites were formed also.     

Pharmacokinetics of the angiotensin converting enzyme inhibitor benazepril.HCl (CGS 14 824 A) in healthy volunteers after single and repeated administration

The pharmacokinetics of the new angiotensin converting enzyme (ACE) inhibitor benazepril.HCl were evaluated in healthy male volunteers. The single dose kinetics were established from data of 62 subjects receiving an oral 10 mg dose of the drug. The steady state kinetics were investigated in 15 subjects after once-daily oral doses of 5, 10 or 20 mg. The compound is a prodrug which, on absorption, is hydrolysed to the pharmacologically active metabolite benazeprilat. Thus, plasma concentrations and urinary excretion of parent compound and active metabolite were determined. Benazepril.HCl was rapidly absorbed (tmax = 0.5 h) and rapidly eliminated from plasma (t1/2 = 0.6 h). Only trace amounts were excreted unchanged in urine. The drug was rapidly metabolized to benazeprilat (tmax = 1.5 h). The elimination of the metabolite from plasma was biphasic. About 80 per cent of benazeprilat formed was eliminated within 24 h (t 1/2 = 2.7 h), whereas the terminal phase (t1/2 = 22.3 h) controlled a minor amount of elimination. About 17 per cent of dose was excreted in the 24-h urine as benazeprilat. The drug disposition did not change during repeated oral dosing and only small accumulation of the metabolite occurred. The accumulation ratio was 1.20 for AUC and 1.24 for urinary excretion. The effective half-life for accumulation was estimated at about 10-11 h. The comparison with other ACE inhibitors showed similarities but also marked differences with respect to the drug kinetics and excretion.     

Preclinical pharmacology of zofenopril, an inhibitor of angiotensin I converting enzyme

Zofenopril calcium (one-half calcium salt) is a prodrug ester analog of captopril whose biological effects are manifested by its active component, SQ 26,333. Because of the relative insolubilities of both zofenopril calcium and SQ 26,333, zofenopril potassium salt and SQ 26,703, the arginine salt of the active ACE (angiotensin I converting enzyme) inhibitory moiety of zofenopril, were employed in many of the following studies. The in vitro and in vivo pharmacological effects of zofenopril have been evaluated and comparisons have been made to captopril. In vitro, SQ 26,703 was more potent than captopril as an inhibitor of rabbit lung ACE (IC50 = 8 vs. 23 nM). SQ 26,703 was also a potent inhibitor of angiotensin I (AI)-induced contractions (EC50 = 3 nM) and a potentiator of bradykinin-induced contractions (EC50 = 1 nM) of isolated guinea pig ileum, while it had no effect on the inotropic effects of angiotensin II, BaCl2, PGE1, histamine, serotonin, or acetycholine in the same tissue, signifying that zofenopril is a specific inhibitor of ACE. In vivo, the potency of SQ 26,703 was equal to or greater than that of captopril as an inhibitor of an AI pressor response when given intravenously to rats, dogs, and monkeys. After oral administration of equimolar doses, zofenopril was the more effective and longer lasting ACE inhibitor in all three species. In SHR, doses of 6.6 and 22.0 mg/kg, p.o. lowered pressure by 20 and 33 mm Hg, respectively, while 30 mg/kg of captopril lowered pressure by 25 mm Hg.(ABSTRACT TRUNCATED AT 250 WORDS)     

Steady-State Pharmacokinetics and Pharmacodynamics of Benazeprilat in Spontaneously Hypertensive Rats (SHR) and Wistar–Kyoto (WKY) Rats

The effects of the simultaneous steady-state intravenous infusion of benazeprilat, the active metabolite of benazepril HC1, and angiotensin I (AI) on mean arterial blood pressure were investigated in the conscious, unrestrained spontaneously hypertensive rat (SHR) and its normotensive parent strain, the Wistar–Kyoto (WKY) rat. A competitive inhibition model is applied and the limits of its validity are discussed. Deviations from the model are apparent at high drug infusion rates and may relate to the effect of benazeprilat on the clearance of AI. The strains differ in the amounts of angiotensin converting enzyme (ACE) or responsiveness to angiotensin II (AII), the drug clearances, and either the pharmacology or the distribution of the drug. Since the latter two differences are drug dependent, prediction between strains is rendered difficult. This steady-state approach relates the hypertension in the SHR to the amount of ACE or responsiveness to AII and renal function.     

Pharmacokinetics and pharmacodynamics of benazepril hydrochloride in patients with major proteinuria

Summary We have investigated whether the pharmacokinetics and pharmacodynamics of the ACE inhibitor benazepril hydrochloride are altered with proteinuria by studying 8 patients with major proteinuria of different causes who were given a single dose of 10 mg p.o.The maximum plasma concentration of benazepril was found between 0.5 and 2 h after dosing (median 1 h). Its elimination was almost complete within 6 h. Peak plasma levels of benazeprilat, the active metabolite of benazepril, were observed between 1 and 6 h (median 2.5 h). The elimination of benazeprilat from plasma was biphasic, with mean initial and terminal half-lives of 3.0 and 17.3 h, respectively. On average, the pharmacokinetic parameters of benazepril and benazeprilat in the patients did not differ from those in a historical control group of healthy volunteers, but intersubject variability in the AUC and half-lives of benazeprilat was greater in the patients.Plasma ACE was completely inhibited from 1.5 to 6 h after dosing, and at 48 h the mean inhibition was still 42 %. Plasma renin showed substantial intersubject variation. Mean supine blood pressure (systolic/diastolic) was reduced from baseline by a maximum of 18/13 mm Hg at 6 h. Proteinuria was diminished after benazepril in 7 patients.In conclusion, the results of this study suggest that proteinuria in the nephrotic range does not require a change in benazepril dosage.     

Inhibition of thromboxane A2-induced vasocontraction by KF4939, a new anti-platelet agent, in rabbit mesenteric and dog coronary arteries

The effect of a new anti-platelet agent, KF4939, on thromboxane A2 (TXA2)-induced vasocontraction was studied in superfused rabbit mesenteric and dog coronary arteries, in comparison with the effects on the contractions evoked by KCl, noradrenaline, serotonin, angiotensin II and histamine. The calcium sources involved in the TXA2-induced vasocontraction were also examined. The TXA2-induced contraction of the rabbit mesenteric artery was partly attenuated after exposure to the calcium-free medium, but was not attenuated by nifedipine. The TXA2-induced contraction of the dog coronary artery was markedly attenuated by nifedipine. These results indicate that TXA2 utilizes both intracellularly stored calcium and an extracellular source of calcium for its vasocontraction, and the voltage-dependent calcium channel plays an important role in the dog coronary artery, but in the rabbit mesenteric artery. KF4939 inhibited the TXA2-induced contraction in both arteries. In the rabbit mesenteric artery, three times and more higher concentration than that to inhibit TXA2-induced one were required to inhibit other agonist induced contractions, KF4939 caused no alteration in the KCl-induced contraction of both arteries. Thus, KF4939 seems to be a selective inhibitor of TXA2-induced vasocontraction, and the receptor-linked mechanism may be a possible site of the TXA2 antagonistic action of KF4939.     

Clinical pharmacokinetics of the newer ACE inhibitors. A review

The orally active angiotensin-converting inhibitors (ACE inhibitors) such as captopril and enalapril represent a significant therapeutic advance in the treatment of hypertension and congestive heart failure. Enalapril differs from captopril in several respects. It is a prodrug converted by hepatic esterolysis to the active (but more poorly absorbed) diacid, enalaprilat. Enalaprilat is more potent than captopril, more slowly eliminated and does not possess a sulfhydryl (SH) group. Enalapril was rapidly followed by a number of newer ACE inhibitors, the majority of which are similar to enalapril in that they are prodrugs, converted by hepatic esterolysis to a major active but poorly absorbed diacid metabolite. In one case (delapril) there are 2 active metabolites; in another (alacepril) the prodrug is converted in vivo to captopril. Lisinopril is an exception in that it is an enalaprilat-like diacid but with acceptable oral bioavailability, so that the prodrug route is not employed. The newer ACE inhibitors are at widely different stages of development, and it is not yet clear how many will reach regular clinical use. Of these newer drugs, lisinopril is the longest established and is the subject of the widest published literature. For a number there is as yet little published pharmacokinetic information. A variety of assay methods have been employed to characterise the pharmacokinetics of the ACE inhibitors, including enzymatic techniques, radioimmunoassay and chromatography. The peak plasma concentrations of the prodrugs are generally observed at around 1 hour and those of the diacid metabolites at about 2 to 4 hours. However, there is considerable variation within and between drugs, with benazepril and benazeprilat reaching peak concentrations early and enalapril and enalaprilat typical of later times to peak. Absorption of the active diacids is generally poor, and moderate (typically 30 to 70%) for the prodrugs. The bioavailability of lisinopril is about 25%. It is difficult to talk meaningfully about half-lives of the active drugs. The declines in their plasma concentrations are polyphasic and, if analytical sensitivity allows, active drug may be found at 48 hours or more following administration. This may reflect binding to ACE in plasma. Half-lives of accumulation are of the order of 12 hours; protein binding varies from little (lisinopril) to 90% (benazeprilat). Elimination is mostly renal but there may be biliary elimination for some, such as benazeprilat and fosinopril. The half-lives of the prodrugs are short. Impaired renal function decreases the elimination rate of the diacids.(ABSTRACT TRUNCATED AT 400 WORDS)     

Hemodynamic effects of benazeprilat in the anesthetized dog with acute left ventricular failure

To examine the hemodynamic effects of benazepril, an angiotensin converting enzyme inhibitor, in left ventricular failure, its active metabolite benazeprilat was administered during acute ischemic left ventricular failure in anesthetized open chest dog induced by repeated injections of plastic microspheres into the left coronary artery. The coronary embolization with microspheres resulted in a moderate and stable left ventricular pump failure characterized by increased left ventricular end-diastolic pressure (LVEDP) and decreased cardiac output (CO). Benazeprilat (30 micrograms/kg) administered intravenously after a stabilization period lowered LVEDP and maintained CO. The total peripheral resistance was reduced with benazeprilat. The oxygen consumption and the coronary blood flow were reduced with benazeprilat because of a decrease in wall tension and afterload. These results suggest that benazeprilat (benazepril) has beneficial effects for the treatment of acute left ventricular failure.     

Role of ACE and NEP in bradykinin-induced relaxation and contraction response of isolated porcine basilar artery

The aim of the present study was to clarify the role of angiotensin converting enzyme (ACE) and neutral endopeptidase (NEP) in bradykinin (BK)-induced relaxation and contraction of isolated porcine basilar artery by measuring isometric tension, ACE and NEP activities and their localization. BK induced endothelium-dependent relaxation followed by contraction; however, in the presence of indomethacin BK induced relaxation but not contraction, in contrast, in the presence of L-nitro-arginine BK induced contraction but not relaxation. Captopril and thiorphan increased the p D(2) value for BK-induced relaxation from 8.11 to 9.55 and the p A(2) value for [Thi(5,8), D-Phe(7)]-BK (a B(2)-receptor antagonist) from 6.95 to 7.59. The same treatment increased the p D(2) value for BK-induced contraction from 7.93 to 8.97 and the p A(2) value for [Thi(5,8), D-Phe(7)]-BK from 6.86 to 7.50. Captopril inhibited ACE activity with an IC(50) of 38.0 nM, and thiorphan inhibited NEP and ACE activities with an IC(50) of 1.4 nM and 295.0 nM, respectively. Endothelial denudation decreased the ACE and NEP activities by 76.7% and 15.9%, respectively, and ACE mRNA level by 59.4%, but had no significant effect on NEP mRNA level. These results suggest that BK-induced relaxation and contraction in the porcine basilar artery are enhanced by captopril and thiorphan which predominantly inhibit ACE activity localized on endothelial cells.     

Pharmacological properties of the new non-sulfhydryl angiotensin converting enzyme inhibitor N-[8-amino-1(S)-carboxyoctyl]-L-alanyl-L-proline

AB-47 (N-[8-amino-1(S)-carboxyoctyl]-L-alanyl-L-proline) is a non-sulfhydryl angiotensin converting enzyme (ACE) inhibitor with omega-aminoalkyl group. AB-47 was slightly more potent than enalaprilat in inhibiting rabbit lung ACE. The ACE inhibition and bradykinin (BK) potentiation by AB-47 in guinea-pig ileal longitudinal muscle were as potent as with enalaprilat. In conscious rat, AB-47 (i.v.) inhibited angiotensin I (A-I)-induced pressor response and augmented BK-induced depressor response more potently and in a long-lasting manner than enalaprilat. Furthermore, AB-47 exhibited higher selectivity for ACE inhibition than for BK inactivation and higher selectivity than enalaprilat and captopril. The inhibition of A-I-induced pressor response by AB-47 (p.o.) was as potent as that of enalapril. These results suggest that AB-47 is a highly potent, long-lasting and relatively A-I-selective ACE inhibitor.     

贝那普利与卡托普利治疗原发性高血压的比较

目的 :比较贝那普利与卡托普利对原发性高血压的降压效应与安全性。方法 :原发性高血压病人 6 0例随机分为 2组。贝那普利组 30例给贝那普利 10mg ,po ,qm (8:0 0 )× 4wk ;卡托普利组 30例给卡托普利 12 .5mg ,po ,tid (8:0 0 ,12 :0 0 ,2 0 :0 0 )× 4wk ;2组均于用药 1wk后血压控制未达到正常水平则剂量加倍 ,每组 2 0例行动态血压监测。结果 :贝那普利组与卡托普利组偶测血压的降压总有效率分别为 90 %与 87% (P >0 .0 5) ;动态血压监测夜间舒张压卡托普利组下降不显著 ,与贝那普利组比较差别有非常显著意义 (P <0 .0 1)。结论 :贝那普利治疗原发性高血压疗效好而安全 ,降低夜间血压优于卡托普利。     

盐酸贝那普利的合成及精制

盐酸贝那普利是世界卫生组织推荐的一线抗高血压药物,是一种强效的血管紧张素转化酶抑制剂。本文介绍了盐酸贝那普利的合成及精制的工艺过程,所得产品经核磁共振、红外光谱确证结构。     

苯那普利与厄贝沙坦对心衰大鼠心室重构过程中AngⅡ受体及ACE2的影响

目的探讨苯那普利、厄贝沙坦及两者联合用药对心衰大鼠心室重构过程中心肌血管紧张素Ⅱ1型受体(AT1R)、2型受体(AT2R)及ACE2蛋白表达的影响。方法采用大鼠腹主动脉缩窄法造成压力负荷性心肌肥厚致心力衰竭模型。苯那普利或(和)厄贝沙坦连续给药8wk,检测血流动力学参数、心脏指数、心肌和血浆AngⅡ含量、心肌中AT1R、AT2R和ACE2蛋白的表达情况。结果模型组心脏指数、LVEDP、血浆和心肌AngⅡ的含量及心肌AT1R、AT2R和ACE2蛋白的表达明显升高;各治疗组心脏指数、LVEDP明显下降;苯那普利组血浆和心肌AngⅡ的含量降低,厄贝沙坦组心肌AT1R蛋白的表达明显下降而AT2R和ACE2蛋白的表达明显升高,联合应用具有协同作用。结论联合应用苯那普利和厄贝沙坦对改善心衰大鼠心室重构具有协同作用,可能与AngⅡ和AT1R的下调而AT2R和ACE2的上调有关。     

Endothelin receptor antagonist activity of (R)-(-)-2-(benzo[1,3]dioxol-5-yl)-N-(4-isopropylphenylsulfonyl)-2-(6-methyl- 2-propylpyridin-3-yloxy)acetamide hydrochloride (PABSA) in rat aortic smooth muscle cells and isolated rat thoracic aorta

Antagonist activities of (R)-(-)-2-(benzo[1,3]dioxol-5-yl)-N-(4-isopropylphenylsulfonyl)-2-(6-methyl- 2-propylpyridin-3-yloxy) acetamide hydrochloride (CAS 188710-94-3, PABSA), a novel endothelin (ET) receptor antagonist, for ETA and ETB receptors were evaluated using rat aortic smooth muscle A7r5 cells and isolated rat thoracic aorta. PABSA concentration-dependently inhibited the ET-1-induced increase in intracellular calcium concentration ([Ca2+]i) mediated via ETA receptors in A7r5 cells with an IC50 of 0.17 nmol/l. PABSA antagonized the ETA receptor-mediated contraction induced by ET-1 in endothelium-denuded rat aorta with a Kb of 0.74 nmol/l. The potency of PABSA in inhibiting ETA receptor-mediated vasocontraction was approximately 40- and 100-fold greater than those of BQ-123, a selective ETA antagonist, and bosentan, a mixed ETA/ETB receptor antagonist, respectively. ETB receptor-mediated endothelium-dependent vasorelaxation induced by ET-3 in the aorta was also antagonized by PABSA, with a Kb of 9.8 nmol/l. In contrast, PABSA affected neither the vasocontraction induced by KCl or norepinephrine nor the vasorelaxation induced by acetylcholine or prostaglandin I2 in the aorta. These results suggest that PABSA is a highly potent and selective ETA receptor antagonist.