4′-甲基-2-腈基联苯的合成

以邻氨基苯甲酸为起始原料, 经重氮化、芳基化、取代和脱水等步骤合成药物中间体4′甲基2 腈基联苯。通过正交实验得到芳基化反应较佳条件为: 10 mol/L氢氧化钠15 mL, 甲苯30 mL, 反应温度5℃, 反应时间5 h, 产物4′甲基2 联苯羧酸的产率为59 4%。考察了脱水剂种类, 脱水反应较佳的实验条件为氯化亚砜15 mL, 4′甲基2 联苯酰胺2 6 g, 反应8 h, 产物4′甲基2 腈基联苯的产率为67 7%。

Effects of combination of irbesartan and perindopril on calcineurin expression and sarcoplasmic reticulum Ca^(2+)-ATPase activity in rat cardiac pressure-overload hypertrophy

Aim： To observe effects of angiotensin （Ang） II receptor antagonist （ATI） irbesartan and angiotensin-converting enzyme （ACE） inhibitor perindopril on rat myocardium calcineurin expression and sarcoplasmic reticulum Ca^2＋-ATPase activity in the model of pressure-overload cardiac hypertrophy. Methods： Forty male adult Sprague Dawley rats were divided into 5 groups One group was treated by sham operation; four groups were myocardium hypertrophy cases caused by banding aortic above renal artery. Drugs were given one week after operation. Group 1： sham group, rats （n=8） were gavaged with normal saline 2 ml/（kg·d） （ig）; Group 2： control group, rats （n=8） were treated with normal saline 2 ml/（kg·d） （ig）; Group 3： rats （n=8） were given perindopril 2 mg/（kg·d） （ig）; Group 4： rats （n=8） were treated with irbesartan 20 mg/（kg·d） （ig）; Group 5： rats （n=8） were given irbesartan 20 mg/（kg·d） plus perindopril 2 mg/（kg·d） （ig）. Morphometric determination, calcineurin expression and sarcoplasmic reticulum Ca^2＋-ATPase activity were done at the end of 6 week of drug intervention. Expression of calcineurin in myocardium was detected by immunohistochemistry. Results： Left ventricular mass index （LVMI）, transverse diameter of myocardial cell （TDM）, calcineurin activity were remarkably decreased after drug intervention and this decrease was most remarkable in the combination drug therapy group. Sarcoplasmic reticulum Ca^2＋-ATPase activity was increased after drug intervention, especially in the combined drug therapy group. Calcineurin expression in myocardium was remarkably decreased after drug intervention. LVMI was positively correlated with TDM and calcineurin, negatively correlated with sarcoplasmic reticulum Ca^2＋-ATPase. Conclusion： These data suggest that irbesartan and perindopril inhibit cardiac hypertrophy through the increased activity of sarcoplasmic reticulum Ca^2＋-ATPase and decreased expression of calcineurin. Their combination had better effects on regressing of ventricular hypertrophy.

EFFECT OF ANGIOTENSIN II RECEPTOR ANTAGONIST AND ENDOTHELIN RECEPTOR ANTAGONIST ON NITROGLYCERIN TOLERANCE IN RATS

Objective. To investigate whether angiotensin II receptor antagonist and endothelin receptor antagonist can improve the nitroglycerin (Nit) tolerance in vivo. Methods. Twenty- four rats were divided into 4 groups (n=6,each): Control group, Nitroglycerin (Nit) group, Nit＋ bosentan group and Nit＋ losartan group. Nitroglycerin tolerance was induced by 2- day treatment of nitroglycerin patch (0.05 mg/h). AngiotensinⅡ receptor antagonist losartan ( 10 mg· kg－ 1· d－ 1 ) and endothelin receptor antagonist bosentan ( 100 mg· kg－ 1· d－ 1 ) were given by gavage for 2 days respectively. Results. The least hypotensive response to sodium nitroprusside (SNP) was observed in Nit group . The effective percentages of hypotensive response to SNP were increased in both Nit＋ losartan group and Nit＋ bosentan group compared with Nit group [(31.95± 4.45 )％ vs (21.00± 3.69 )％ , P< 0.01 and (33.18± 6.16 )％ vs (21.00± 3.69 )％ , P< 0.01 ,respectively]. The maximal vessel relaxation induced by SNP was the same in 4 different groups but the highest EC50 (concentration which produces 50％ of the maximal response to SNP) was found in tolerant group[(34± 10) nmol/ L,P < 0.01 .The ET- 1 amounts in plasma and vascular tissue were markedly increased by 54％ and 60％ in Nit group compared with those in control group(P< 0.01).The ET- 1 amounts in plasma and vascular tissue were decreased by 30％ and 37％ in Nit＋ losartan group compared with those in Nit group (P< 0.01). Conclusion. Endothelin receptor antagonist and angiotensinⅡ receptor antagonist could prevent against the Nit tolerance .

缬沙坦联合黄芪、复方丹参注射液对糖尿病性心脏病患者左心功能的影响

目的观察缬沙坦联合黄芪、复方丹参注射液对糖尿病性心脏病患者左心功能的影响。方法64例糖尿病性心脏病患者随机分为缬沙坦联合黄芪、复方丹参治疗组和对照组各32例，治疗前后分别用彩色多普勒超声心动描记术测定左室射血分数〈LVEF）、每搏量（sv）、心排血量（co）、舒张早期流速峰（E）、舒张晚期流速峰（A），并与健康对照组比较。结果糖尿病性心脏病患者LVEF、每搏量、心排血量、E／A较健康对照组明显降低，应用缬沙坦联合黄芪、复方丹参注射液治疗15d后，患者的LVEF、每搏量、心排血量较治疗前明显增加，有统计学差异（P〈0．05）。结论缬沙坦联合黄芪、复方丹参注射液可以改善糖尿病性心脏病患者的左心舒缩功能，尤其是左心收缩功能，能延缓心室重塑，防止心室扩大的发展，阻断恶性循环，延长寿命。