Laser Doppler flowmetry for assessment of myocardial microperfusion in the beating rat heart

Although laser Doppler flowmetry (LDF) is widely used for measuring microperfusion, it is rarely used to measure coronary microcirculation. The present in vivo study investigated the use of LDF to measure myocardial microperfusion in beating rat hearts. Ascending aortic flow and other hemodynamic parameters were simultaneously recorded. A needle probe with a holder was adhered to the epicardium of the left ventricular myocardium close to the left anterior descending coronary artery in an anaesthetized open-chest rat. Myocardial microperfusion was measured in response to bolus intravenous administration of both two representative vasodilators (captopril and nifedipine) and a vasoconstrictor (pituitrin). Myocardial microperfusion was found to be predominately diastolic, and in an opposing phase to the ascending aortic flow. Captopril (5 or 10 mg/kg) increased the initial myocardial microperfusion phase. Nifedipine at 75 microg/kg caused a sustained myocardial microperfusion elevation with a peak increase of 7.1+/-1.1%, but this was not observed using 150 microg/kg nifedipine. Both drugs caused an increase in the cardiac index. In contrast, myocardial microperfusion decreased (28.7+/-0.1% maximum decrease) in response to 1 IU/kg pituitrin. In conclusion, LDF provided a means of assessing myocardial microperfusion in beating rat hearts, and can be applied to evaluate the coronary microcirculation response to drugs.     

Pharmacokinetics, tissue distribution, metabolism, and excretion of depside salts from Salvia miltiorrhiza in rats.

Salviae miltiorrhiza, a traditional Chinese medical herb known as "Danshen," has been widely used in clinics to improve blood circulation, relieve blood stasis, and treat coronary heart disease. Depside salts from S. miltiorrhiza are a novel drug in which magnesium lithospermate B and its analogs are the active components. The pharmacokinetics, tissue distribution, metabolism, and excretion of three of the major components, lithospermic acid B, rosmarinic acid (RA), and lithospermic acid (LA), were studied by liquid chromatography-tandem mass spectrometry following intravenous administration in Sprague-Dawley rats. The elimination half-lives for LSB, RA, and LA were 1.04, 0.75, and 2.0 h, respectively, when 60 mg/kg S. miltiorrhiza depside salts were administrated. The areas under the curve for LSB, RA, and LA were 51.6, 6.6, and 25.2 mg . h/l, respectively, and the values decreased in the individual tissues in the following order: kidney > lung > liver > heart > spleen > brain for LSB; kidney > lung > heart > liver > spleen > brain for RA; and heart > lung > kidney > liver > spleen > brain for LA. After intravenous administration of 60 mg/kg S. miltiorrhiza depside salts, 86% of the LSB was excreted in the bile within 6 h. The main metabolites M1 and M2 were found in the serum. Overall, the results show that depside salts from S. miltiorrhiza are rapidly and widely distributed to tissues after intravenous administration in rats but that they are also rapidly cleared and excreted.     

对贵刊刊登的“利多卡因合用复方丹参注射液治疗眩晕”一文的验证

目的 :通过经颅多普勒 (TCD)的检查验证利多卡因合用复方丹参注射液治疗眩晕的疗效。方法 :眩晕病人 35例 (男性 18例 ,女性 17例 )给予利多卡因 2 0 0mg ,复方丹参 16mL加入 5 %葡萄糖注射液 5 0 0mL中静脉滴注 ,qd ,连用 3～ 7d。利用TCD检测治疗前后脑动脉平均血流速度的变化。结果 :治疗前后脑动脉 (大脑中动脉、大脑前动脉、大脑后动脉、椎动脉、基底动脉 )平均血流速度加快分别为 (2 3± 10 )cm·s- 1,(19± 8)cm·s- 1,(16± 10 )cm·s- 1,(11± 4 )cm·s- 1,(10± 6 )cm·s- 1,差异有非常显著意义 (p <0 .0 1)。结论 :利多卡因合用复方丹参注射液治疗眩晕有较好疗效     

丹参多酚酸盐对持续性高正加速度造成大鼠颞颌关节损伤的保护作用

目的：观察丹参多酚酸盐对在持续性高正加速度（＋Gz）引起颞颌关节病的作用。方法：40只雄性SD大鼠随机分为5组：第1组的大鼠只在实验装置上固定5min作为阴性对照组；第2组在＋10GZ条件下处置5min，每日重复5次，每周4次，连续3周作为阳性对照组；第3～5组处置方法同第2组，每日离心前30min肌肉注射丹参多酚酸盐（给药剂量分别为1、3、10mg／kg），阴性对照组给予等容积的生理盐水。用电子显微镜观察形态学变化，用RT-PCR技术检测颞肌c—fos mRNA基因表达。结果：丹参多酚酸盐能有效地保护持续性高正加速度对于颞颌关节造成损伤，电子显微镜的影像学显示该作用具有剂量依赖性。丹参多酚酸盐对于持续性高正加速度引起的颞肌c—fos mRNA表达有抑制作用。结论：丹参多酚酸盐对于持续性高正加速度引起的大宣灏铴关节桶伤有保护作用。     

COMPARATIVE HAEMODYNAMIC EFFECTS OF VERAPAMIL, FLECAINIDE, AMIODARONE AND SOTALOL IN THE CONSCIOUS RABBIT

1. The effect of intravenous boluses of verapamil (0.15 mg/kg), flecainide (2 mg/kg), amiodarone (5 mg/kg), and sotalol (l.5 mg/kg) on mean arterial pressure, heart rate (HR), cardiac output (CO), total peripheral resistance (TPR), and peak rate of change of left ventricular pressure (LV dP/dt) were assessed in the conscious rabbit. 2. All four drugs had negative inotropic effects: verapamil reduced peak LV dP/dt by 19±4% (mean±s.e.m.; P<0.01), flecainide by 27 ± 9% (P<0.001), amiodarone by 11 ± 2% (P<0.01) and sotalol by 13 ± 3% (P<0.01). 3. The drugs had different effects on CO as a result of differences in their actions on peripheral blood vessels: verapamil and amiodarone produced, respectively, a 12 ± 4% (P<0.03) and 16 ± 6% (P<0.01) increase in CO associated with a substantial vasodilatory effect (TPR reduced 15 ± 7%[P<0.05] and 20 ± 5% [P<0.01], respectively). Flecainide caused only a small (6 ± 1%; P<0.01) increase in CO and sotalol had no effect on either CO or TPR. 4. Bolus intravenous injections of verapamil, flecainide and amiodarone produced an increase in HR, while sotalol reduced HR by 10 ± 2% (P<0.01). The increase in HR and cardiac output seen with verapamil, flecainide and amiodarone was in part secondary to reflex increase in sympathetic tone and these changes were abolished after total cardiac autonomic blockade. 5. The modest reduction in cardiac performance associated with sotalol was abolished by cardiac autonomic blockade, suggesting that the predominant effect of sotalol on contractility was mediated through its β-adrenoceptor blocking effect.     

地奥心血康防治白血病心脏损害

目的：为了防治白血病多种因素的心脏损害，我们观察了地奥心血康（简称ＤＡＸＸＫ）的心脏保护作用。方法：治疗组１０８例（男性６６例，女性４２例，年龄３１±ｓ１４ａ），用ＤＡＸＸＫ２００ｍｇ，ｐｏ，ｔｉｄ，疗程４－６ｗｋ；对照组１０４例（男性４６例，女性５８例，年龄３３±１１ａ），用安慰剂（淀粉片）２００ｍｇ，ｐｏ，ｔｉｄ，共４－６ｗｋ，其他治疗条件与治疗组一致。观察指标以常规心电图，彩色多普勒超声心动图，高频心电图、心肌酶学改变为判断指标。结果：治疗组用药前心肌损害发生率２０．４％，用药后发生率４．６％（Ｐ＜０．０１）；对照组用药前发生率２３．１％，用药后发生率２９．８％（Ｐ＜０．０５）。组间比较差异非常显著（Ｐ＜０．０１）。结论：ＤＡＸＸＫ能减少白血病多因素心脏损害，对心脏有保护作用，未发现明显不良反应。     

Short-term effects of celiprolol on blood pressure and left ventricular performance in hypertensive cardiomyopathy.

Celiprolol (C) is a new selective beta 1-blocker with partial beta 2-agonistic activity. The purpose of this study was to explore its antihypertensive efficacy and its short-term effect on systemic vascular resistances (SVR), cardiac output (CO), left ventricular ejection fraction (LVEF), and left ventricular diastolic performance (LVDP). The Doppler technique was used. In an open-label study, 20 hypertensive patients (15 males, 5 females, age range of 29-68 years) with left ventricular hypertrophy detected by echography were daily treated with 400 mg of C in a single dose, for a period of 4 weeks. C reduced significantly the systolic blood pressure (SBP) and the diastolic blood pressure (DBP) (158 +/- 12 vs. 142 +/- 11 mm Hg, p < 0.05 and 101 +/- 6 vs. 87 +/- 4 mm Hg, p < 0.001, respectively) with a decrease in heart rate (74 +/- 12 vs. 67 +/- 8 beats/min, p = NS). The SVR decreased significantly (2,050 +/- 22 vs. 1,495 +/- 23 dyn/s/cm5, p < 0.001) with a slight but not significant increase in the CO (4.5 +/- 0.69 vs. 5.11 +/- 0.82 L/min). The LVEF did not decrease significantly (58 +/- 5 vs. 56.9 +/- 6%, p = NS) while the LVDP was modified favorably, significantly reducing the early diastolic deceleration time (EDDT) (199 +/- 61 vs. 132 +/- 80 ms, p < 0.01) and reducing the isovolumetric relaxation time (IVRT) (167 +/- 16 vs. 117 +/- 23 ms, p < 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)     

In vitro and in vivo pharmacology of a structurally novel Na+-H+ exchange inhibitor, T-162559

1. We investigated the inhibitory effects of a non-acylguanidine Na(+)-H(+) exchange (NHE) inhibitor, T-162559 ((5E,7S)-[7-(5-fluoro-2-methylphenyl)-4-methyl-7,8-dihydro-5(6H)-quinolinylideneamino] guanidine dimethanesulphonate), on NHE-1, and its cardioprotective effect against ischaemia and reperfusion injury in rats and rabbits. 2. T-162559 inhibited human platelet NHE-1 in a concentration-dependent manner, with an IC(50) value of 13+/-3 nmol l(-1), making it 16 and three times more potent than cariporide IC(50): 209+/-75 nmol l(-1), P<0.01) and eniporide (IC(50): 40+/-11 nmol l(-1), P=0.066), respectively. T-162559 also inhibited rat NHE-1 with an IC(50) value of 14+/-2 nmol l(-1), which was five and three times lower than that of cariporide (IC(50): 75+/-7 nmol l(-1), P<0.01) and eniporide (IC(50): 44+/-2 nmol l(-1), P<0.01), respectively. 3. T-162559 inhibited, in a concentration-dependent manner, the reduction in cardiac contractility, progression of cardiac contracture, and increase in lactate dehydrogenase release after global ischaemia and reperfusion in perfused rat hearts. The inhibitory effects of T-162559 were observed at a lower concentration range (10 - 100 nmol l(-1)) than with cariporide and eniporide. T-162559 did not alter basal cardiac contractility or coronary flow after reperfusion, suggesting that it exerts direct cardioprotective effects on the heart. 4. Intravenous administration of T-162559 (0.03 and 0.1 mg kg(-1)) significantly inhibited the progression of myocardial infarction induced by left coronary artery occlusion and reperfusion in rabbits; the infarct size normalized by area at risk was 74+/-6% in the vehicle group, and 47+/-5% and 51+/-7% in the T-162559-0.03 mg kg(-1) and T-162559-0.1 mg kg(-1) groups (both P<0.05), respectively. 5. These results indicate that the new structural NHE-1 inhibitor T-162559 is more potent than cariporide and eniporide and possesses a cardioprotective effect against ischaemia and reperfusion injury in rat and rabbit models.     

Magnesium lithospermate B ameliorates renal cortical microperfusion in rats

AIM: To investigate the effects of magnesium lithospermate B (MLB) isolated from Salviae miltiorrhizae on renal microcirculation, and renal and systemic hemodynamics in Sprague-Dawley rats. METHODS: MLB (10, 30, and 60 mg/kg) was injected intravenously and renal blood flow (RBF), renal cortical microperfusion (RCM), and systemic hemodynamic function parameters including heart rate (HR), mean arterial pressure (MAP), left ventricular systolic pressure (LVSP), left ventricular end-diastolic pressure (LVEDP), and maximal velocity of pressure increase (dp/dt(max)) were measured for 45 min after administration. RESULTS: Intravenous MLB at doses of 10, 30, and 60 mg/kg increased RCM significantly, but had no obvious effects on RBF or systemic hemodynamics. The effect of MLB on RCM reached its peak 15 min after injection and returned to baseline after 45 min. Up to 60 mg/kg MLB increased RCM by 62.4%+/-20.2% (changes from baseline, P<0.01), whereas RBF (3.7%+/-9.7% vs baseline) and renal vascular resistance (-1.4%+/-9.1% vs baseline) did not obviously change. CONCLUSION: These results indicate that MLB ameliorates renal microcirculation in a dose-dependent manner, which may be related to the renoprotective effects of MLB.     

Analysis of cardioprotective effects using purified Salvia miltiorrhiza extract on isolated rat hearts

The purpose of the current study is to evaluate the cardioprotective effects of purified Salvia miltiorrhiza extract (PSME) on myocardial ischemia/reperfusion injury in isolated rat hearts. Hearts were excised and perfused at constant flow (7 - 9 ml.min(-1)) via the aorta. Non-recirculating perfusion with Krebs-Henseleit (KH) solution was maintained at 37 degrees C and continuously gassed with 95% O2 and 5% CO2. KH solution with or without PSME (100 mg per liter solution) was used after 30-min zero-flow ischemia for the PSME and control group, respectively. Left ventricular (LV) developed pressure; its derivatives, diastolic pressure, and so on were continuously recorded via a pressure transducer attached to a polyvinylchloride balloon that was placed in the left ventricle through an incision in the left atrium. PSME treated hearts showed significant postischemic contractile function recovery (developed pressure recovered to 44.2 +/- 4.9% versus 17.1 +/- 5.7%, P<0.05; maximum contraction recovered to 57.2 +/- 5.9% versus 15.1 +/- 6.3%, P<0.001; maximum relaxation restored to 69.3 +/- 7.3% versus 15.4 +/- 6.3%, P<0.001 in the PSME and control group, respectively). Significant elevation in end-diastolic pressure, which indicated LV stiffening in PSME hearts might have resulted from the excess high dose of PSME used. Further study will be conducted on the potential therapeutic value with lower dose of PSME on prevention of ischemic heart disease.     

Sensory nitrergic meningeal vasodilatation and non-nitrergic plasma extravasation in anaesthesized rats

The aim of the present study was to evaluate the role of nitric oxide (NO) of sensory neural origin in neurogenic inflammatory response in the trigeminovascular system. Antidromic vasodilatation and plasma extravasation in response to electrical stimulation (15 V, 5 Hz, 0.5 ms, 100 impulses) of the trigeminal ganglion were investigated in the dura mater and nasal mucosa/upper eyelid by laser Doppler flowmetry and [(125)I]-labelled bovine serum albumin, respectively. Electrical stimulation of the trigeminal ganglion of rats elicited a reproducible ipsilateral enhancement of both meningeal and nasal mucosal blood flow. N(omega)-nitro-L-arginine (L-NNA; 4, 8, and 16 mg/kg, i.v.), a nonselective inhibitor of nitric oxide synthase (NOS), inhibited antidromic vasodilatation both in the dura mater (15.86+/-2.05%, 22.82+/-2.51%, and 36.28+/-4.37%) and nasal mucosa (35.46+/-8.57%, 58.72+/-9.2%, and 89.99+/-8.94%) in a dose-dependent manner. Specific inhibitors of neuronal NOS, 7-nitroindazole (7-NI; 20 mg/kg, i.v.) and 3-bromo-7-nitroindazole (3Br-7NI; 10 mg/kg, i.v.) were administered to assess the possible role of NO released from the trigeminal sensory fibres. The meningeal vasodilatation was inhibited by both 3Br-7NI and 7-NI (63.36+/-7.7% and 49+/-6.5%, respectively). The nasal hyperaemic response was also reduced by 3Br-7NI (78.26+/-8.7%). Plasma extravasation in the dura mater and upper eyelid evoked by electrical stimulation of the trigeminal ganglion (25 V, 5 Hz, 0,5 ms, 5 min), expressed as extravasation ratios (ERs) of the stimulated vs. nonstimulated sides, was 1.80+/-0.8 and 4.63+/-1.24, respectively. This neurogenic oedema formation was not inhibited by neither L-NNA nor 3Br-7NI. It is concluded that neural nitrergic mechanisms are involved in the meningeal vasodilatation evoked by electrical stimulation of the trigeminal ganglion.     

Influence of atropine on the dose requirements of propofol in humans

OBJECTIVE: The purpose of this study was to evaluate the effect of atropine on the dose requirement of propofol for induction of anesthesia and propofol concentrations during continuous infusion. METHODS: Study 1: Forty patients were randomly allocated to the control or atropine groups. Induction of anesthesia commenced 3 min following the administration of 0.9% saline or atropine (0.01 mg kg(-1)), using a Diprifuser set to achieve propofol concentration of 6.0 microg mL(-1). The primary end point was the propofol dose per kg at the moment of loss of response to a command. Study 2: Fifteen patients undergoing elective surgery were enrolled. Propofol was administered to all subjects via target-controlled infusion to achieve a propofol concentration at 2.0 microg mL(-1) after intubation. Before and after administration of atropine (0.01 mg kg(-1)), cardiac output (CO) was measured using indocyanine green as an indicator and blood propofol concentration was determined using high-performance liquid chromatography. RESULTS: Study 1: The propofol dose for each group was 2.22+/-0.21 mg kg(-1) for control group and 2.45+/-0.28 mg kg(-1) for atropine, respectively (p=0.014). Study 2: After the administration of atropine, CO was significantly increased from 4.28+/-0.83 to 5.76+/-1.55 l min(-1) (p<0.0001). Propofol concentration was significantly decreased from 2.12+/-0.28 to 1.69+/-0.27 microg mL(-1) (p<0.0001). CONCLUSIONS: Following the administration of atropine, the propofol requirements for the induction of anesthesia were increased and propofol concentrations were decreased during continuous infusion by the administration of atropine.     

Levosimendan enhances cardiac performance after cardiopulmonary bypass: a prospective, randomized placebo-controlled trial.

Levosimendan is a new myofilament calcium (Ca2+) sensitizer that increases myocardial contractility by stabilizing the Ca2+-bound conformation of troponin C. We tested the hypothesis that levosimendan enhances cardiac performance after cardiopulmonary bypass (CPB). Anesthesia was induced and maintained with midazolam, sufentanil, and vecuronium in 18 patients randomly assigned to receive levosimendan (18 or 36 microg/kg loading dose and 0.2 or 0.3 microg/kg/min infusion, respectively) or placebo 15 min before and continued for 6 h after CPB. Significant (p < 0.05) increases in heart rate (HR) and decreases in systemic vascular resistance (SVR) occurred 15 min after CPB in patients receiving placebo. Later increases in mean arterial pressure (MAP) and cardiac output (CO) and decreases in stroke volume (SV) and pulmonary vascular resistance also were observed. HR was greater in patients receiving high- but not low-dose levosimendan versus placebo immediately after CPB. MAP also was lower in patients treated with either dose of levosimendan compared with placebo after CPB. Levosimendan increased CO and decreased SVR (4.2 +/- 0.4 to 7.9 +/- 0.4 L/min and 1,150 +/- 99 to 512 +/- 42 dyn/s/cm5, respectively, 15 min after CPB; mean +/- SEM). CO and SV were higher and SVR was lower in patients receiving levosimendan versus placebo after CPB. No differences in arterial oxygenation and perioperative arrhythmias (Holter analysis) were observed between groups. The results indicate that levosimendan enhances cardiac performance after CPB in humans.     

Hemodynamic and renal effects of the protein kinase inhibitor staurosporine in conscious rats.

To evaluate the pattern of hemodynamic responses produced by an inhibitor of protein kinase C (PKC), staurosporine 0.03-0.55 mg/kg was administered intravenously (i.v.) to conscious, normotensive rats chronically instrumented with vascular catheters for direct measurement of blood pressure (BP) and i.v. administration of drugs and either an aortic flow probe for measurement of cardiac output (CO) or miniaturized pulsed Doppler flow probes for measurement of hindquarter, renal, and mesenteric vascular resistances. Staurosporine decreased mean arterial pressure (MAP) and total peripheral resistance (TPR) and increased heart rate (HR) in a dose-dependent manner. Because staurosporine decreased resistance in all three vascular beds monitored (hindquarter, renal, and mesenteric), staurosporine is probably a nonselective vasodilator that decreases MAP by decreasing resistance in a number of peripheral vascular beds. Staurosporine produced biphasic effects on CO, dF/dtmax and peak aortic blood flow; these parameters were significantly increased at doses less than 0.3 mg/kg and decreased to levels equal to or significantly less than control values at doses greater than 0.3 mg/kg. In comparison, the calcium channel blocker nitrendipine decreased MAP and TPR and increased HR, CO, dF/dtmax, and peak aortic flow in a dose-dependent manner over the entire dose range (0.01-1 mg/kg i.v.). Staurosporine (0.3 mg/kg) and nitrendipine (1 mg/kg) produced similar changes in MAP (-44 +/- 3 and -33 +/- 2 mm Hg, respectively), yet staurosporine affected dF/dtmax to a lesser extent than nitrendipine (-5 +/- 36 and 390 +/- 46 ml/s/s, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)     

Dosing time-dependent effect of trandolapril on the prevention of cardiac hypertrophy in rats with aortic banding.

Trandolapril was given to male Wistar rats with aortic banding at 10 AM or 10 PM for 6 weeks to examine the influence of dosing time on the development of left ventricular mass (LVM). Aortic banding increased the LVM compared with the sham-operated animals (P<0.01). Trandolapril (1 mg/kg) at 10 AM reduced LVM (1.74+/-0.04 [S.E.M.] mg/g) more than the dosing at 10 PM (1.92+/-0.04 mg/g, P<0.05), suggesting that trandolapril has a dosing time-dependent effect in the prevention of cardiac hypertrophy in rats with aortic banding.     

地尔硫静脉滴注治疗冠心病优于丹参注射液

目的：比较地尔硫与丹参注射液静脉滴注（静滴）治疗冠心病的疗效。方法：冠心病８６例分为２组，地尔硫组４６例（男性２９例，女性１７例；年龄６２ａ±ｓ９ａ）用地尔硫注射液５０ｍｇ加入５％葡萄糖注射液２５０ｍＬ中静滴，ｑｄ×１０ｄ；丹参组４０例（男性２７例，女性１３例；年龄５８ａ±８ａ）用丹参注射液１６ｍＬ加入５％葡萄糖注射液２５０ｍＬ中静脉滴注，ｑｄ×１０ｄ。结果：地尔硫组与丹参组症状总有效率分别为６１％与３８％（Ｐ＜０．０１）；心电图总有效率分别为６１％与２８％（Ｐ＜０．０１）。地尔硫组对表示心肌缺血范围和程度的ＮＳＴ，ΣＳＴ及左室功能的ＳＶ，ＣＯ，ＥＦ改善均有显著意义（Ｐ＜０．０５），丹参组则无。结论：地尔硫治疗冠心病优于丹参。     

Simvastatin preserves cardiac function in genetically determined cardiomyopathy

Endothelial dysfunction characterizes heart failure (HF). Simvastatin (Sim) increases endothelial nitric oxide (NO) independent of lipid-lowering. We evaluated the effect of Sim on cardiac function, apoptosis, and NO availability in HF. Five-month-old cardiomyopathic (CM) hamsters were divided into 2 groups: Sim (20 mg/kg, 6 weeks, n = 6) and Untreated (n = 6). Age-matched normal hamsters served as controls (n = 6). Serial echocardiograms were performed to measure LV function. Myocardial apoptosis, eNOS, and capillary density were measured at 6 weeks. Cardiomyopathic hamsters had lower LV shortening fraction (SF) compared with controls (17 +/- 3% vs 59 +/- 2%), higher LV end-diastolic volume (30 +/- 3 vs 6 +/- 2 mL/m2), and lower LV mass/volume ratio (0.5 +/- 0.04 vs 0.72 +/- 0.02 mg/ml, P < 0.001). During follow-up, SF decreased (9 +/- 2%) and LV volume increased (38 +/- 1 mL/m2) in untreated hamsters (P < 0.05 from baseline) but did not change significantly in the Sim group (P < 0.05 vs untreated). Myocardial caspase-3 activity was higher and apoptotic nuclear density was lower in Sim compared with untreated CM hamsters (0.072 +/- 0.02% vs 0.107 +/- 0.03%, P < 0.01). Myocardial capillary density was highest in the Sim group (P < 0.05). eNOS expression was not different between groups. Sim retards the progression of HF in CM hamsters. This may be related to an increase in coronary microvasculature, increase in NO availability, and decreased apoptosis.     

Cardiovascular and renal effects of milrinone in beta-adrenoreceptor blocked and non-blocked anaesthetized dogs.

The cardiovascular effects of the low Km cAMP phosphodiesterase inhibitor milrinone (0.01-0.3 mg/kg, i.v.) were characterized in anaesthetized dogs with or without beta-adrenoreceptor blockade (nadolol, 1 mg/kg, i.v.). Heart rate was increased by milrinone at greater than or equal to 0.1 mg/kg in non-blocked dogs (61 +/- 5 beats/min [mean +/- SEM, max. change] or 40.5 +/- 6.0%) and at greater than or equal to 0.03 mg/kg in beta-blocked dogs (33 +/- 5 beats/min or 26 +/- 4%). Mean arterial pressure was decreased at greater than or equal to 0.03 mg/kg in non-blocked dogs (-34 +/- 6mmHg or -27 +/- 5%) and at greater than or equal to 0.1 mg/kg in beta-blocked dogs (-17 +/- 4 mmHg or -15 +/- 3%). These changes were or tended to be greater in non-blocked than beta-blocked dogs. The maximum rate of rise in left ventricular pressure was increased at all doses in non-blocked (3747 +/- 388 mmHg/sec or 131 +/- 14%) and beta-blocked dogs (2517 +/- 445 mmHg/sec or 131 +/- 25%), with the absolute but not percent increase being greater in non-blocked than beta-blocked dogs. Left ventricular end diastolic pressure (LVEDP) was or tended to be reduced at greater than or equal to 0.03 mg/kg in beta-blocked dogs (-3 +/- 1 mmHg or -64 +/- 20%) and at 0.01-0.1 mg/kg in non-blocked dogs (-1.4 +/- 0.9 mmHg or -50 +/- 29%). The absolute, but not percent, decrease in LVEDP at 0.03 mg/kg was greater in beta-blocked than non-blocked dogs (-2.2 +/- 0.8 mmHg or 32 +/- 10% vs. 0.0 +/- 0.7 mmHg or 0 +/- 8%). Cardiac output (CO) was or tended to be similarly increased at 0.01-0.03 mg/kg in beta-blocked (0.2 +/- 0.1/min or 15 +/- 5%) and non-blocked dogs (1.2 +/- 0.7 1/min or 40 +/- 16%). In conclusion, beta-blockade attenuated the hypotensive and chronotropic effects, but did not eliminate the positive inotropism, the reduction in cardiac preload or the increase in CO induced by milrinone in anaesthetized dogs.     

Chronic exposure to carbon monoxide and nicotine: endothelin ET(A) receptor antagonism attenuates carbon monoxide-induced myocardial hypertrophy in rat.

The aims of the present study were to determine the effects of endothelin ET(A) receptor antagonism on carbon monoxide (CO)-induced cardiac hypertrophy and endothelin-1 (ET-1) expression and to compare myocardial effects of chronic nicotine with CO exposure. Female Sprague-Dawley rats (n = 84) were randomized to three groups exposed 20 h/day to CO (200 ppm), nicotine (500 microg/m3), or air for 14 consecutive days. In each exposure group, animals were randomized to ET(A) receptor antagonist LU 135252 in drinking water (0.5 mg/ml) or placebo. Myocardial ET-1 and atrial natriuretic peptide (ANP) expression was measured by competitive RT-PCR and plasma ET-1 by immunoassay. Carboxyhemoglobin was 22.1 +/- 0.3% in CO-exposed animals and 2.8 +/- 0.3% in controls. Plasma nicotine was 57 +/- 7 ng/ml and plasma cotinine was 590 +/- 23 ng/ml in nicotine-exposed animals and below detection levels in controls. CO exposure induced a 21% increase in right ventricular hypertrophy (p < 0.01), a 7% increase in left ventricular hypertrophy (p < 0.01), a 25% increase in right ventricular ET-1 expression (p < 0.05), and an eightfold increase in ANP expression (p = 0.08). ET(A) receptor antagonism reduced right ventricular hypertrophy by 60% (p < 0.05) with no significant effect on left ventricular hypertrophy or myocardial ET-1 expression. Chronic nicotine exposure did not significantly affect cardiac weights or ANP and ET-1 expression. We conclude that ET(A) receptor antagonism reduces right ventricular hypertrophy induced by chronic CO exposure, whereas CO-induced myocardial ET-1 expression remains unchanged.     

In vivo neuroprotective effects of the novel imidazolyl nitrone free-radical scavenger (Z)-alpha-[2-thiazol-2-yl)imidazol-4-yl]-N-tert-butylnitrone (S34176)

Herein, we report an extensive investigation of the neuroprotective effects of the compound (Z)-alpha-[2-thiazol-2-yl)imidazol-4-yl]-N-tert-butylnitrone (S34176) and the prototypic nitrone alpha-phenyl-N-tert-butylnitrone (PBN), in different in vivo paradigms of neuronal degeneration. Administration of S34176 (75 mg/kg i.p.) 30 min before transient (10 min) global ischaemia in Wistar rats significantly prevented delayed neuronal cell death in the hippocampal CA1 area 7 days post-ischaemia (24% vs. 73% in ischaemia control; P<0.05) whereas PBN was inactive under similar conditions. Furthermore, oral administration of S34176 (30 mg/kg) 60 min before and during (1 x 30 mg/kg p.o.) 6 days post-ischaemia, in combination with an acute post-ischaemia sub-protective dose (3 x 10 mg/kg i.p.) of the glutamate receptor antagonist, 1,2,3,4-tetrahydro-6-nitro-2,3-dioxo-benzo[f]quinoxaline-7-sulfonamide (NBQX), resulted in an increased neuroprotective action (29% cell loss in drug-treated vs. 84% in ischaemia control P<0.001) compared to either compound alone. S34176 (20 mg/kg i.p.) also partially prevented kainic acid-induced neuronal cell death at 7 days post-exposure in the CA1 (41% in drug-treated vs. 74% for kainate-treated controls; P<0.01) and CA3 hippocampal region (22% vs. 53%; P<0.01). Under similar conditions, S34176 administered orally (40 mg/kg) produced a more marked protection against kainate-induced neuronal cell loss in the CA1 (13% in drug-treated vs. 82%; P<0.001) and CA3 areas (10% vs. 52%; P<0.001). Sub-chronic oral administration of S34176 (10 mg/kg) also partially reduced kainate-induced hippocampal cell death in the CA1 (53% vs. 77%; P<0.01) and CA3 (23% vs. 53%; P<0.01) areas. Dopamine depletion in the striatum of C57BL/6 mice induced by systemic D-methamphetamine injection was significantly reduced by S34176 (40+/-5% vs. 11.5+/-8%; P<0.001) (150 mg/kg i.p.) whereas PBN was inactive under similar conditions. S34176 represents a new centrally acting nitrone-based radical scavenger with neuroprotective properties in in vivo models of delayed neuronal cell death, and supports the therapeutic potential of this class of compound for the treatment of cerebral pathologies implicating chronic neurodegeneration.