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1.
目的建立了一种高效液相色谱-三重四极杆串联质谱法,对氯沙坦钾原料药中遗传毒性杂质N-亚硝基-N-甲基-4-氨基丁酸(NMBA)进行测定。方法色谱柱为岛津Shim-pack XR-ODSⅡ色谱柱(2.0 mm×150 mm,2.2μm),流动相为0.1%甲酸水溶液(A)和甲醇(B),进行梯度洗脱,流速0.3 mL·min^-1,柱温为40℃,采用ESI离子化-三重四极杆质谱多反应监测(MRM)正离子模式检测,碰撞电压分别为-11,-13和-13 V,碰撞气氩气270 kPa,NMBA的离子对分别为m/z 147.15→117.10,147.15→87.10和147.15→44.10。结果该方法中NMBA在1~100 ng·mL^-1内线性关系良好,日内和日间的保留时间和峰面积的重复性良好(RSD均小于1.10%,n=6和n=18),低、中、高3个浓度的平均回收率在94.40%~98.04%之间。结论本方法简单方便,可快速有效的对氯沙坦钾原料药中NMBA进行限度检查并实现定量分析。 相似文献
2.
Summary— KR31080 (2-butyl-5-methyl-6-(1-oxopyridin-2-yl)-3-[[2'-(1H-tetrazol-5-yl) biphenyl-4-yl]methyl]-3H-imidazo[4,5-b] pyridine) is a potent inhibitor of angiotensin type 1 (AT1 ) receptors in rabbit aorta and human recombinant AT1 receptors. In the isolated rabbit thoracic aorta, KR31080 caused a nonparallel shift to the right of the concentration-response curves to angiotensin II (All) with decreased maximal response (pD'2 = 10.1 ± 0.1), but had no effect on the contractile response induced by norepinephrine. KR31080 inhibited specific [125 I]AII binding to rabbit aortic membranes (AT, receptors) and [125 I][Sar1 , Ile8 ]AII binding to human recombinant AT1 receptors in a concentration-dependent manner with IC50 values of 0.84 ± 0.08 nM and 1.92 ± 0.15 nM, respectively, but did not inhibit specific [125 I)AII binding to bovine cerebellum membranes (ÀT2 receptors). In the Scatchard analysis, KR31080 interacted with rabbit aortic AT1 receptors in a competitive manner, similar to losartan. These results demonstrate that KR31080 is a potent and AT1 selective angiotensin receptor antagonist which exerts a competitive antagonism in the [125 I]AII binding assay and insurmountable AT1 receptor antagonism in the functional study. 相似文献
3.
L. A. Cassis L. P. Dwoskin 《Journal of neural transmission (Vienna, Austria : 1996)》1994,98(2):159-164
Summary To determine if acute or chronic (21 days) losartan (10mg/kg, s.c.) regulates the renin-angiotensin system in interscapular brown adipose tissue, angiotensin II (AII) content and [3H]overflow from slices preloaded with [3H]norepinephrine were examined. Acute or chronic losartan administration had no effect on AII content. AII increased evoked [3H]overflow from slices from control rats. Losartan administration did not alter basal [3H]outflow or evoked [3H]overflow. Acute losartan administration inhibited AII-induced enhancement of evoked [3H]overflow. Tolerance developed to the inhibitory effect of losartan following chronic administration.Supported by a grant from the American Heart Association (Local Kentucky Affiliate) and by a gift from DuPont Merck Pharmaceuticals. Portions of this work have been presented in abstract form [The Pharmacologist 34(3): 157, 1992] 相似文献
4.
EFFECTS OF LOSARTAN ON THE CARDIOVASCULAR SYSTEM, RENAL HAEMODYNAMICS AND FUNCTION AND LUNG LIQUID FLOW IN FETAL SHEEP 总被引:1,自引:0,他引:1
Kathleen M. Stevenson Karen J. Gibson Eugenie R. Lumbers 《Clinical and experimental pharmacology & physiology》1996,23(2):125-133
1. The angiotensin type 1 (AT1) receptor antagonist, losartan (10 mg/kg) was infused intravenously into nine chronically catheterized fetal sheep (125–132 days gestation). Losartan reduced the fetal systolic (P < 0.01) and diastolic (P < 0.01) pressor response to 5 μg angiotensin II (AngII) i.v. from 27.4 ± 1.5 to 7.4 ± 0.9 and from 17.5 ± 1.3 to 5.4 ± 0.6 mmHg, respectively, after 1h and to 6.1 ± 0.5 and 4.4 ± 0.5 mmHg, respectively, after 2h. Maternal pressor responses to 5 μg AngII i.v. were unchanged. Fetal mean arterial pressure decreased (P < 0.05) after losartan administration, but fetal heart rate did not change. 2. Fetal haematocrit increased (P < 0.05), fetal PO2 decreased (P < 0.01), PCO2 did not change and pH decreased (P < 0.01), as did plasma bicarbonate levels (P < 0.01) following administration of losartan. Thus, losartan induced a fetal metabolic acidosis. 3. Fetal placental blood flow did not change following administration of losartan. In the fetal kidney, losartan caused a decrease in vascular resistance (P < 0.01) and an increase in blood flow (P < 0.05). Glomerular filtration rate decreased (P < 0.05); thus, filtration fraction decreased (P < 0.01). There was no change in the fractional reabsorption of sodium and glomerulotubular balance was maintained. Free water clearance decreased (P < 0.01) and became negative. Urine flow decreased (P < 0.01), the excretion rates of sodium, potassium and chloride did not change, but the urinary sodium:potassium ratio decreased (P < 0.05). There was a decrease in lung liquid flow (P < 0.05) following losartan. 4. It is concluded that the fetal renin-angiotensin system (RAS) is important in the maintenance of fetal arterial pressure, the regulation of fetal renal blood flow and is essential in the maintenance of fetal glomerular function. Further, these actions of AngII are mediated via functional AT1 receptors. These effects of losartan on the fetal cardiovascular system, renal blood flow and function are similar to those observed following captopril administration. Thus, the effects of angiotensin converting enzyme (ACE) inhibition in the foetus are due to the blockade of the fetal RAS and are independent of any direct effects on bradykinin or prostaglandin levels. 相似文献
5.
U. EKELUND 《Acta physiologica (Oxford, England)》1996,158(1):29-37
The aim of the present study was to analyse quantitatively, on a cat gastrocnemius muscle preparation in vivo, the effects of local angiotensin-converting enzyme (ACE) inhibition by enalaprilat on total regional vascular resistance (tone) and its distribution to the large-bore arterial resistance vessels (>25 μm), the small arterioles (<25 μm) and the veins. Associated effects on capillary pressure and fluid exchange were also studied. Close-arterial infusion of enalaprilat (0.05–0.20 mg kg muscle tissue min-1) elicited a moderate dilator response in all three consecutive sections of the muscle vascular bed, an increase in capillary pressure and transcapillary fluid filtration. This dilation could be abolished by the selective bradykinin B2-receptor antagonist Hoe 140 (2 mg kg-1 min-1, i.a.), indicating that the dilator mechanism of ACE inhibition was an increased local concentration of bradykinin, and hardly at all a decreased concentration of angiotensin (AT) II. The generalized dilator response to ACE inhibition along the vascular bed suggested a relatively uniform distribution of ACE from artery to vein and this was further supported by the finding that a close-arterial infusion of AT I (0.04–0.32 μg kg-1 min-1), which was vasoactive only after conversion to AT II by local ACE, elicited a generalized constrictor response in all three vascular sections. In contrast, infused AT II (0.01–0.16 μg kg-1 min-1) constricted almost selectively the large-bore arterial vessels. The specific angiotensin AT1-receptor antagonist losartan (2 mg kg-1 min-1, i.a.) abolished the constrictor response to AT II but did not affect vascular tone under control conditions, indicating that AT II is not involved in the initiation of basal vascular tone in muscle. These results, taken together, indicate that under basal conditions vascular ACE contributes to the local control of vascular tone in skeletal muscle by degrading the endogenous dilator bradykinin, and not by converting AT I into vasoconstrictor AT II. 相似文献
6.
采用动态血压监测 (ABPM)法比较 3 0例轻中度高血压病患者经氯沙坦 (5 0mg/d)治疗 4周后 2 4h平均血压、白昼及夜间平均血压、心率、血压负荷、夜间下降率等的变化 ,并与诊室血压 (CBP)相比较。治疗 4周末 ,CBP、2 4h平均血压、白昼及夜间平均血压、血压负荷均有显著降低 ,心率无显著改变。CBP示 4周末总有效率为 70 .0 %。各时点血压均较治疗前下降 ,对夜间血压的影响略小 ,但血压昼夜节律无显著改变。降压疗效谷 /峰比大于 70 %。提示 :氯沙坦能安全有效地降低血压 ,维持正常的血压昼夜节律 ,尤适于夜间血压低的杓型高血压患者。 相似文献
7.
8.
为观察口服氯沙坦(25mg,50mg)对急性心肌梗死患者的血流动力学效应,对10例急性心肌梗死患者放置漂浮导管,测量用药前及用药30min,1,2,3,4,6,9h时,收缩压(SBP)、舒张压(DBP)、平均动脉血压(MAP)、心率(HR)、外周血管阻力(SVR)、耗氧指数、心指数(CI)、肺毛压(PCWP)、左室每搏作功指数(LVSWI)、右房压(RAO)的变化。结果表明。服药后4h作用最明显,SBP、DBP、MAP、SVR、耗氧指数分别较用药前下降12%,11%,13%.14%和15%,25mg较50mg作用明显;CI轻度增加;HR、PCWP、RAP、LVSWI无明显变化。提示急性心机梗死患者口服氯沙坦产生外周阻力及心肌耗氧量下降,心指数增加等有益的血流动力学效应。氯沙坦25mg较50mg效果更明显。下壁心肌梗死早期应用需慎重。 相似文献
9.
洛沙坦抗高血压及左室肥厚的疗效观察 总被引:4,自引:0,他引:4
目的 :观察血管紧张素 受体拮抗剂—洛沙坦的降压效果及对高血压病合并左室肥厚的影响。方法 :4 6例合并左室肥厚的 期高血压病患者服用洛沙坦 5 0 mg/ d,观察其血压的变化及治疗前和 6个月后左室质量 (L VM)。结果 :用洛沙坦后 4 d~ 6d血压开始下降 ,2周血压趋向正常 ,4周血压继续缓慢下降 ,6周时达到最大降压效果。 L VM在 12周时无明显变化。 2 4周表现轻度 L VM减少。结论 :洛沙坦是抗高血压的一个有效治疗药物 ,对左心室肥厚有轻度逆转作用 相似文献
10.
Geoffrey A Head 《Clinical and experimental pharmacology & physiology》1996,23(Z3):93-98
- 1 In a number of species, high concentrations of angiotensin II (AngII) receptors have been found in the rostral ventrolateral medulla (RVLM) in the hindbrain, which is an important region involved in the modulation of sympathetic vasomotor tone. The present review describes studies in which the contribution of angiotensin receptors in the brainstem to cardiovascular regulation, in particular sympathetic vasomotor reflexes, has been examined in conscious and anaesthetized rabbits.
- 2 In conscious rabbits, fourth ventricular infusions of AngII produced dose-dependent pressor responses as doses 400 times less than equipressor intravenous doses. Chronic baroreceptor denervation increased the sensitivity to AngII by 1000-fold. Administration of prazosin i.v. blocked the pressor response, suggesting that the mechanism involved sympathetic vasoconstriction.
- 3 The pattern of haemodynamic changes in response to AngII injected into the fourth ventricle (4V) involved decreased total peripheral conductance and mesenteric conductance, but a rise in hindlimb conductance. Sinoaortic denervation changed the hindlimb fall in conductance to an increase, suggesting that muscle vasomotor pathways were particularly inhibited by baroreceptor feedback mechanisms.
- 4 In anaesthetized rabbits, infusion of AngII into the RVLM increased blood pressure and transiently increased resting renal sympathetic nerve activity. The renal sympathetic baroreflex curves were shifted to the right and the upper plateau of the sympathetic reflex increase was markedly increased.
- 5 The pressor actions of 4V AngII were blocked by administration of a peptide antagonist injected into the RVLM or by the angiotensin AT1 antagonist losartan injected into the 4V. These results suggest that mainly AT1 receptors are involved and that the RVLM is a likely candidate site for the modulation of the renal sympathetic baroreflex.
- 6 Losartan administration into the 4V in conscious rabbits increased resting renal sympathetic tone and enhanced renal sympathetic baroreflex and chemoreflexes.
- 7 Our studies suggest that there are sympathoexcitatory AT1 receptors in the RVLM accessible to AngII from the cerebrospinal fluid. In addition, an AT1 receptor pathway normally inhibits the sympathoexcitation produced by baroreceptor unloading or chemoreceptor activation. The effect of losartan suggests that there is greater tonic activity within the sympathoinhibitory pathways. These two actions suggest that angiotensin receptors in the brainstem modulate sympathetic responses to specific afferent inputs, thus forming part of a potentially important mechanism for the integration of characteristic autonomic response patterns.