In vivo evaluation of left ventricular function in aged SHR by volume loading and the positive inotropic effect of denopamine

The positive inotropic effect of denopamine on the hypertrophied heart was studied in 12-months spontaneously hypertensive rats (12-month-SHR) with and without volume loading. Firstly, the influence of volume loading on cardiac function was studied in 12-month-SHR compared with the age-matched normotensive Wistar-Kyoto rats (WKY) and younger WKY (4-month-WKY) as well. Left ventricular end-diastolic pressure (LVEDP) and maximum rate of rise of left ventricular pressure (LV dp/dtmax) were significantly higher in SHR than in WKY and 4-month-WKY. Volume loading (saline, 2 ml/kg/min, i.v., for 10 min) caused a marked increase in LVEDP both in SHR and WKY, but a higher elevation of LVEDP was observed in SHR. LV dp/dtmax, however, was increased in WKY and more markedly in 4-month-WKY, while it was not increased in SHR. Administration of denopamine to SHR at a rate of 1 microgram/kg/min, i.v., for 10 min before and during 10 min of volume loading produced a marked increase in LV dp/dtmax and a significant decrease in LVEDP. Under denopamine infusion, volume loading caused an increase in LV dp/dtmax and produced a LVEDP elevation to a similar level to that of WKY. Denopamine at this dose caused no significant effects on heart rate and mean arterial blood pressure, indicating a selective inotropic action. The present study suggests that functional cardiac reserve is reduced in the aged SHR and that denopamine increases the functional reserve of the hypertrophied heart.     

Effects of nitroglycerin on regional myocardial function in the underperfused canine heart

Effects of nitroglycerin (3 micrograms/kg/min i.v.) on regional myocardial contractility during acute coronary stenosis were studied in open-chest dogs using a strain-gauge arch. Stenosis-induced stepwise decreases in coronary perfusion pressure (CPP) at less than 40 mm Hg correspondingly reduced contractility in the underperfused area and increased the left ventricular end-diastolic pressure (LVEDP). Nitroglycerin caused significant increases in contractility, along with decreases in arterial and left ventricular pressures; at stenosis-induced CPP less than 30 mm Hg, contractility in the underperfused are fell precipitously below the control, while LVEDP increased. When nitroglycerin infusion under coronary stenosis (CPP of 40 mm Hg) decreased CPP to less than 30 mm Hg, contractility fell. When CPP greater than 30 mm Hg was maintained, contractility increased and LVEDP decreased. In conclusion, at least in the absence of well-developed collateral circulation, the critical level of CPP was 40 mm Hg for contractility and LVEDP without nitroglycerin, which shifted to 30 mm Hg with the addition of nitroglycerin. Nitroglycerin resulted in a significant increase in plasma catecholamines, and the increase in contractility diminished with propranolol, indicating participation of beta-adrenoceptor in the positive inotropic effect of nitroglycerin. However, catecholamines at high concentrations probably further aggravated the impaired cardiac function at CPP less than 30 mm Hg.     

苓桂术甘汤对犬急性心肌缺血的影响

目的研究苓桂术甘汤对犬急性心肌缺血、心脏血流动力学及心肌耗氧量的影响。方法采用结扎麻醉犬冠状动脉左前降支中段的方式 ,造成实验性急性心肌缺血病理模型 ,观察药物对心肌缺血、血流动力学及心肌耗氧量各指标的变化 (冠脉流量CBF、心输出量CO、心率HR、左室内压LVP、左室舒张末期压LVEDP、左室内压最大变化速率dp/dtmax等 )。结果苓桂术甘汤 8g/kg显著减少由NBT染色的心肌梗死面积 ,增加CBF ,降低冠脉阻力CVR、LVP、LVEDP、dp/dtmax、HR、氧利用率、耗氧指数、心肌耗氧量 ,与空白对照组及药前值比较差异有显著意义 (P <0 0 5～ 0 0 1 )。同时对血清磷酸激酶 (CPK)、乳酸脱氢酶 (LDH)、谷草转氨酶 (GST)没有明显影响。结论苓桂术甘汤能增加心肌的供血供氧 ,改善心肌缺血状况。     

Arterial and venous vasodilator actions of RS-1893, a novel cardiotonic agent, in the hindlimb preparation of the dog

RS-1893, an orally active cardiotonic agent, has been suggested to dilate venous blood vessels, because it markedly decreases central venous pressure in anesthetized dogs. In order to evaluate venous vasodilator action of the agent, we measured hindlimb volume (HLV) in anesthetized dogs using a plethysmographic technique. RS-1893 (1-10 micrograms/kg, i.v.) produced dose-dependent increases in HLV, femoral blood flow, and left ventricular (LV)dP/dt, and a decrease in central venous pressure (CVP). In another series of experiments, we autoperfused the hindlimb with a constant flow and injected the drugs intraarterially (i.a.) to separately evaluate arterial and venous vasodilator actions. In this preparation, a decrease in perfusion pressure and an increase in HLV were considered to reflect arterial vasodilatation and venous vasodilatation, respectively. RS-1893 (0.3-3 micrograms i.a.) produced a dose-dependent increase in HLV and a decrease in perfusion pressure. Comparison of doses which increased HLV by 0.3 ml revealed that RS-1893 was about 20 times more potent than milrinone. The arterial vasodilator action of RS-1893 was about 15 times more potent than that of milrinone. We conclude that RS-1893 is a potent venous and arterial vasodilator with cardiotonic activity.     

阻断内皮素受体和抑制血管紧张素转化酶在慢性心衰大鼠中的相加作用

目的:评价一种新的内皮素受体拮抗剂tezosentan对慢性心衰大鼠血流动力学的急性作用,并进一步研究该药与血管紧张素转化酶(ACE)抑制剂依那普利合用是否有相加作用。方法:在结扎左侧冠状动脉所致的慢性心衰大鼠中测量血流动力学的指标。结果:心肌梗死3-5周后,大鼠产生慢性心衰,与假手术大鼠相比,慢性心衰大鼠左心室舒张末期压(LVEDP)显著升高,其均值为23-26mmHg,心肌收缩力(左心室dp/dt_(max))降低30％-40％,平均动脉压(MAP)降低大于10％。在慢性心衰大鼠中,静脉注射tezosentan(10mg·kg~(-1))或依那普利(1mg·kg~(-1))显著降低其MAP和LVEDP,并对其心率或dp/dt_(max)无影响。与tezosentan或依那普利单用组相 比,两者合用对慢性心衰大鼠的MAP和LVEDP具有相加作用,对其心率或dp/dt_(max)无显著性作用。结论:急性静脉注射tezosentan改善慢性心衰大鼠心脏血流动力学,降低其LVEDP和后负荷(MAP),其心率和心肌收缩性(dp/dt_(max))并不受影响。Tezosentan的这些有利作用与依那普利相似。而且在抑制ACE作用的基础上,Tezosentan的这些有益作用也是很明显的。因此,tezosentan有望成为急性治疗心衰的有效新药。     

Effects of isosorbide 5-mononitrate on cardiovascular function. (I). Effects on the left ventricular system

Effects of isosorbide 5-mononitrate (5-ISMN) on cardiovascular function were compared with those of isosorbide dinitrate (ISDN), verapamil and propranolol. In anesthetized open-chest dogs, intravenous injection of 5-ISMN (1 mg/kg, 3 mg/kg) scarcely decreased cardiac contractile force (CCF) and heart rate (HR). The systolic blood pressure (SBP) fell in a dose-dependent manner, and the degree of the change was greater than that in diastolic blood pressure (DBP). Especially, left ventricular pressure (LVP) and left ventricular dp/dt (LVdp/dt) were significantly decreased, and a considerable reduction in left ventricular end-diastolic pressure (LVEDP) was also observed. Intravenous injection of verapamil (0.3 mg/kg) considerably lowered DBP. While HR, CCF, LVP and LVdp/dt were markedly decreased, LVEDP showed a moderate increase. Propranolol (0.5 mg/kg, i.v.) greatly decreased LVdp/dt together with HR and CCF. Conversely, LVEDP showed a slight increase. There was no change in SBP, DBP and LVP. The vasodilating potency of 5-ISMN was 150 times smaller than that of ISDN on the contractile response in isolated rabbit thoracic aorta. On the other hand, in terms of decrease in pulse pressure, the potency exhibited by 5-ISMN was about 4 times (intravenous administration in anesthetized dogs) or 1.5 times (oral administration in conscious dogs) smaller than that of ISDN. The present results suggest that 5-ISMN shows a high bioavailability and a potency comparable to ISDN, especially in the case of peroral administration. Taking these results together with the fact that transient left ventricular failure occurs during myocardial ischemia into consideration, it is thought that peroral 5-ISMN preparation may be useful in the therapy of angina pectoris.     

Effects of nipradilol, a new beta-adrenoceptor blocking agent with vasodilating properties, on transmural energy metabolism in the underperfused canine heart

Effects of nipradilol on hemodynamics and transmural energy metabolism of underperfused (ischemic) canine hearts were investigated. The ischemic heart was prepared by constricting a tube connecting the circumflex coronary artery with the carotid artery for 10 min so that the perfusion pressure (CPP) was reduced to 30 mmHg. The reduction in CPP resulted in decreases in coronary blood flow (CBF) by 70%, regional myocardial contractile force (MCF) by 30%, myocardial ATP contents by 32% (inner layer)-22% (outer) and creatine phosphate by 75% (inner)-60% (outer). Increases in the left ventricular end diastolic pressure (LVEDP) by 4.8 mmHg, myocardial inorganic phosphate contents by 1.9 times (inner)-1.3 (outer) and lactate by 4.3 times (inner)-2.4 (outer) were also observed. In dogs with normal hearts, an infusion of nipradilol (10 micrograms/kg/min, i.v., for 15 min) decreased CPP by 25%, CBF by 40%, cardiac effort index by 45% and MCF by 30 to 40%, and it slightly increased LVEDP without affecting myocardial high-energy phosphate and lactate levels. In ischemic hearts, nipradilol infusion starting 5 min before ischemia attenuated the ischemia-induced elevation of LVEDP to 1.8 mmHg, and the ischemia-induced changes in high-energy phosphate contents to 1/2 (inner)-1/3 (outer) and changes in lactate to 1/6 (inner)-1/10 (outer). These results indicate that nipradilol improves the ischemic derangement of both transmural energy metabolism and hemodynamics.     

Effects of R 56,865, a preventer of cellular calcium overload, on left ventricular diastolic properties during pacing-induced ischemia in dogs.

The effects of R 56,865, a compound with unusual calcium antagonistic properties, on altered left ventricular (LV) diastolic properties were studied during pacing-induced ischemia in dogs with coronary stenosis. Severe coronary artery stenosis was produced on both the left anterior descending (LAD) and circumflex (Cx) coronary arteries in anesthetized beta-blocked dogs. The right atrium was paced at 200 beats/min for 3 min. In the post-pacing period and before drug intervention, the most characteristic observation was a significant increase in LV end-diastolic pressure (LVEDP) and in the time constant of (tau) LV pressure decrease; after return of LV hemodynamics to baseline values (15 min), R 56,865 (0.16 mg.kg-1) or solvent (control) was injected and four subsequent pacing runs were performed at 30-min intervals. In the postpacing period of these four subsequent runs, there was a steep increase in LVEDP and tau-values while HR returned more slowly to baseline values. After R 56,865 infusion, the increase in LVEDP and tau-values was significantly lower than in the pretreatment run and all LVEDP values were significantly lower than in the control group. We conclude that R 56,865 effectively attenuates ischemia-induced changes in LV diastolic stiffness.     

Participation of the vasodilating property of nipradilol in improving ischemic derangement of myocardial energy metabolism

The effects of equipotent doses in negative inotropic and chronotropic properties of nipradilol [10 micrograms/kg/min intravenously (i.v.)] and propranolol (20 micrograms/kg/min i.v.) on hemodynamics and transmural energy metabolites in ischemic hearts were examined in anesthetized dogs. After 5-min infusion of these agents, coronary perfusion pressure of 30 mm Hg was induced by acute coronary stenosis for 10 min. Coronary blood inflow and myocardial contractile force (MCF) in the control ischemic area decreased to about one-third and two-thirds of the respective starting levels. In the nipradilol group, similar changes were observed, but in the propranolol group the MCF tended to decrease further. Cardiac effort index decreased to about two-thirds in both groups. The left ventricular end-diastolic pressure (LVEDP) increased by 4.3 mm Hg with saline, by 8.8 mm Hg with propranolol, and by 1.3 mm Hg with nipradilol. ATP depletion in the ischemic myocardium (by 29 and 22% in inner and outer layers, respectively) was restored to normal level by either agent. A decrease in creatine phosphate and an accumulation of lactate were significantly alleviated by nipradilol (by 74 and 59----by 39 and 21%, and by 4.9 and 2.3----by 0.7 and 0.2 times, respectively), but not by propranolol. The results indicate that in addition to a decrease in myocardial oxygen consumption caused by the beta-adrenoceptor blocking effects of nipradilol, reductions in preload and afterload caused by the vasodilating property significantly contribute to nipradilol-induced improvement in the ischemic derangement of transmural energy metabolism.     

Comparative hemodynamic effects of MK-422, a converting enzyme inhibitor, and a renin inhibitor in dogs with acute left ventricular failure

The angiotensin-converting enzyme (ACE) inhibitor MK-422 (enalaprilat) was compared with the potent renin inhibitor SCRIP for its ability to improve left ventricular function in closed-chest dogs. Acute left ventricular failure (ALVF) was induced by repeated embolization (EMB) of the left coronary arterial vasculature with 50-micron plastic microspheres. Baseline stability data were obtained in 30 dogs in which the evolution of ALVF was monitored over time. Guided by a progressive rise in left ventricular end-diastolic pressure (LVEDP), a stepwise perturbation of the coronary circulation with microspheres over 30 min caused reductions in left ventricular dP/dt and cardiac output, averaging 47 and 40%, respectively. EMB reduced heart rate (20 beats/min) and mean arterial pressure by approximately 20 mm Hg which, along with other hemodynamic variables remained stable after induction of heart failure. MK-422 (100 micrograms/kg i.v.) given 45 min after ALVF was induced, decreased mean arterial pressure by 20 mm Hg (p less than 0.05) and reduced total peripheral resistance (TPR) from 5,453 to 4,150 dyne X s X cm-5 (p less than 0.05). The decline in LVEDP (from 14 +/- 1 to 11 +/- 1 mm Hg) and TPR suggests that MK-422 dilates resistance and, conceivably, capacitance vessels. In dogs with sham EMB (vehicle injections into coronary circulation), MK-422 reduced arterial pressure but had no important effects on the other hemodynamic indices.(ABSTRACT TRUNCATED AT 250 WORDS)     

吗丙嗪逆转多药抗药性作用及其分子机制的探讨

目的：探讨吗丙嗪逆转肿瘤多药抗药性（ＭＤＲ）的作用及其机制。方法：以ＭＴＴ与Ｆｕｒａ－２－ＡＭ法进行吗丙嗪逆转ＭＤＲ活性测定；以ＤＰＨ荧光测定法探讨吗丙嗪对膜脂流动性的影响；以荧光分光光度计法测定吗丙嗪与高钙或低钙对细胞内阿霉素（Ｄｏｘ）积累的影响及Ｆｕｒａ－２－ＡＭ法测定吗丙嗪对细胞内游离钙离子浓度的影响。结果：在浓度２．５μｍｏｌ·Ｌ－１时，吗丙嗪能显著增加ＭＣＦ－７／ＡＤＲ细胞内Ｆｕｒａ－２的积累和降低ＭＣＦ－７／ＡＤＲ对Ｄｏｘ的ＩＣ５０而对敏感株ＭＣＦ－７无明显影响，表明吗丙嗪具有逆转ＭＤＲ的作用。吗丙嗪能显著增加ＭＤＲ细胞内Ｄｏｘ积累和降低ＭＤＲ细胞的膜脂流动性。高钙或低钙对ＭＤＲ细胞内Ｄｏｘ积累无影响，吗丙嗪也不能改变１９９７－０４－１１收稿１中山医科大学中心实验室，广州５１００８９作者简介：符立梧，男，３２岁，博士，讲师，主要从事逆转多药抗药性的研究；潘启超，男，６７岁，教授，博士生导师，主要从事肿瘤药理与化疗方面的研究ＭＤＲ细胞内游离钙离子浓度。结论：吗丙嗪有逆转ＭＤＲ作用。其逆转机制与降低膜脂流动性增加细胞内ＤＯＸ积累有关，与钙离子浓度无关     

EFFECT OF EXERCISE ON PLASMA ADRENOMEDULLIN AND NATRIURETIC PEPTIDE LEVELS IN MYOCARDIAL INFARCTION

1. We investigated the effect of exercise on plasma adreno-medullin, atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) concentrations and studied the relationship between these peptides and haemodynamic parameters in nine patients with old myocardial infarction (MI) and in eight normal subjects. 2. The exercise protocol consisted of two fixed work loads (40 and 80 W) for 4 min each and venous blood samples were taken at rest, during each exercise stage and after exercise while monitoring the mean arterial pressure (MAP) and heart rate (HR). In MI, pulmonary arterial pressure (PAP), pulmonary capillary wedge pressure (PCWP), left ventricular end-diastolic pressure (LVEDP) and cardiac output (CO) were measured throughout exercise. 3. Adrenomedullin levels did not significantly increase with exercise. Adrenomedullin levels correlated with PAP and PCWP at rest (P < 0.05). Atrial natriuretic peptide levels correlated with PAP, PCWP and LVEDP throughout exercise (P < 0.05) but, on multiple regression analysis, PCWP correlated only with ANP (P < 0.01). Brain natriuretic peptide levels correlated with LVEDP throughout exercise (P < 0.01) and its increment correlated closely with basal BNP levels at rest (P < 0.01). 4. These results suggest that adrenomedullin does not respond to the acute haemodynamic changes of exercise, whereas ANP responds to it and PCWP is the major stimulus factor. Brain natriuretic peptide responds to exercise in proportion to the basal synthesis of BNP in patients with left ventricular dysfunction and LVEDP may play a role in increasing BNP during exercise.     

Cardiovascular effects of the new calcium antagonist isradipine and of diltiazem in anesthetized open-chest dogs

Cardiovascular effects of the new calcium antagonist, isradipine (PN 200-110), were compared with those of diltiazem in anesthetized open-chest dogs. Isradipine 5 micrograms/kg i.v. produced significant decreases in systolic, diastolic and mean aortic blood pressure (AoP) concomitant with a decrease in mean renal blood flow (RBF) and increases in mean vertebral blood flow (VBF), mean coronary blood flow (CBF) and left ventricular dP/dt (LVdP/dt), but almost unchanged heart rate (HR) and left ventricular enddiastolic pressure (LVEDP). Diltiazem 300 micrograms/kg i.v. also produced decreases in AoP and RBF and increases in AoF, VBF and CBF. LVdP/dt and LVEDP were not significantly changed, but HR was decreased by this drug. Duration of increase in AoF, VBF and CBF was significantly longer in isradipine than in diltiazem. The decrease of coronary vascular resistance relative to total peripheral resistance was significantly greater than 1.0 for diltiazem, but not for isradipine. Results indicate that isradipine produces effects on AoP, AoF, VBF, CBF, RBF and LVEDP similar to diltiazem and the drug increases LVdP/dt without a decrease in HR in contrast to diltiazem, and that the effects of isradipine were long sustained when compared with those of diltiazem.     

Vasodilator properties of prostacyclin after coronary artery bypass surgery

The vasodilatory properties of prostacyclin were studied in 12 intubated patients who underwent coronary artery bypass surgery. When infused in doses of 2.5, 5, 10, and 20 ng/kg/min, prostacyclin produced a dose-dependent decrease in systemic vascular resistance from 2,702 +/- 143 to 1,654 +/- 106 dynes/cm5/m2 (p less than 0.05). Heart rate, right atrial pressure, and pulmonary arterial and capillary wedge pressures did not change. Cardiac function was improved, since stroke volume index increased from 29.5 +/- 1.4 to 35.5 +/- 2.0 ml/min/m2 (p less than 0.05) and the rate pressure product decreased from 13.3 +/- 1.3 to 10.9 +/- 0.9 X 10(3) mm Hg/beats/min (p less than 0.05), while stroke work index remained unchanged. These hemodynamic changes were associated with a dose-dependent decrease in arterial oxygen tension which occurred from 278 +/- 25 to 133 +/- 22 mm Hg; however, oxygen transport increased as a result of the prostacyclin-induced increase in cardiac index. This study demonstrates that prostacyclin is a potent arterial vasodilator that may be of interest in the treatment of postoperative vasoconstriction occurring after coronary artery bypass surgery.     

氯沙坦对心力衰竭大鼠心肌细胞缝隙连接的作用机制研究

目的观察氯沙坦对心力衰竭(心衰)大鼠心功能的影响并探讨其对心肌细胞缝隙连接的作用机制。方法 SD大鼠60只随机分为假手术组、模型组、氯沙坦高、中、低剂量组,灌胃给药7 d后,采用冠脉结扎复制大鼠心衰模型。测定心功能:左心室压峰值(LVP)、左心室舒张末期压(LVEDP)、左心室内压最大上升速率(+LVdp/dtmax)、左心室内压最大下降速率(-LVdp/dtmax)。采用Western Blot方法测定心肌缝隙连接蛋白43(Cx43)和Cx45的表达。结果氯沙坦能显著改善心衰大鼠心功能,与模型组比较,氯沙坦低、中剂组LVP明显上升(P<0.01),LVEDP明显下降(P<0.05或<0.01),高剂组LVP、+LVdp/dtmax明显上升,LVEDP明显下降(P<0.01);显著提高Cx43表达,降低Cx45表达(P<0.05或<0.01)。结论氯沙坦对心室的间隙连接通道有保护作用,可以提高心室传导速度,从而降低心律失常的发生。     

苦碟子注射液对犬心脏功能和血流动力学的影响

目的考察苦碟子注射液对麻醉开胸犬心脏功能和血流动力学的影响。方法采用麻醉开胸犬模型,测量其心率、心输出量、冠脉流量、心肌耗氧量以及血流动力学各参数。结果苦碟子注射液以2.0、4.0 g.kg-1静脉注射给药可显著增加戊巴比妥钠麻醉犬的心输出量和冠脉流量,降低平均动脉压、左心室内压和左心室舒张末期压力,减少左室内压力变化速度和心肌耗氧量(P<0.05,P<0.01)。结论苦碟子注射液能显著改善麻醉开胸犬血流动力学。     

Effects of arachidonic acid in the rabbit pulmonary and systemic vascular beds in vivo

We studied the effects of arachidonic acid (AA) in the pulmonary and systemic circulations of rabbit under constant blood flow conditions in vivo, using a total heart bypass model. AA (100-150 micrograms/kg) injected into the pulmonary artery produced a dose-dependent increase in pulmonary arterial pressure (Ppa), without altering systemic arterial pressure (Psa). Conversely, injection of AA into the aorta reduced Psa in a dose-dependent fashion, but did not significantly alter Ppa. FPL55712, a leukotriene receptor antagonist, did not affect any of these responses to AA. Indomethacin, a cyclo-oxygenase inhibitor, totally prevented the pulmonary pressor response to intravenously administered AA and reduced the systemic depressor response to intra-arterially administered AA. The thromboxane A2 synthetase inhibitor, 7-(1-imidazolyl)heptanoic acid, totally abolished the increase in Ppa in response to intravenously administered AA, but did not alter the dose-dependent decrease in Psa in response to intra-arterially administered AA. These results suggest that in rabbits (1) AA produces pulmonary vasoconstriction and systemic vasodilation, (2) blood metabolites of AA mediate these effects and are then rapidly deactivated, and (3) AA-induced pulmonary vasoconstriction appears to be largely dependent on thromboxane A2.     

Selective adenosine-2 agonist produces both direct and reflex tachycardia in normotensive rats.

Hemodynamic responses to intravenous (i.v.) injection of DPMA [N6-[2-(3,5-dimethoxyphenyl)-2-(2-methylphenyl)ethyl] adenosine); PD 125,944], a potent adenosine agonist with a 32-fold selectivity for the adenosine-2 (A2) receptor subtype, were characterized in conscious and anesthetized rats. In conscious rats instrumented with miniaturized pulsed-Doppler flow probes, i.v. injection of increasing doses of DPMA (3-30 micrograms/kg) had little effect on mean arterial pressure (MAP, maximal decrease -8 +/- 4 mm Hg) or renal and mesenteric resistance (maximal change 8 +/- 14 and 0 +/- 15%, respectively). In contrast, DPMA markedly reduced MAP (maximal decrease -61 +/- 8 mm Hg) in a dose-dependent (1-30 micrograms/kg) fashion in pentobarbital-anesthetized rats. The A2 agonist also caused a sustained, dose-dependent increase in heart rate (HR, maximal increase 75 +/- 12 beats/min) in conscious rats. The tachycardia and decrease in arterial pressure were completely reversed by i.v. administration of CGS 15943 (250 micrograms/kg), a selective adenosine receptor antagonist. Pretreatment with propranolol or hexamethonium significantly reduced but did not abolish the tachycardia, suggesting that the increase in HR was mediated only partially through reflex increases in sympathetic tone. These data indicate that (a) anesthesia potentiates the depressor actions of DPMA and (b) stimulation of A2 receptors increases HR through both direct and indirect mechanisms of action.     

Effects of Theo-Esberiven on the coronary circulation and myocardial metabolisms in dogs (author's transl)

In isolated dog heart, Theo-Esberiven 0.1 mg, which contains 12 mg proxyphylline, 2.5 mg rutin and 5 mg Melilotus extract, and proxyphylline (12 mg) increased coronary blood flow (CBF) and was associated with increased heart rate (HR) and myocardial contractile force (MCF). The effect of Theo-Esberiven on CBF was about 1.7 times higher than that of proxyphylline. Theo-Esberiven did not significantly affect myocardial oxygen consumption (QO2) and redox potential (deltaEh), while proxyphylline aggravated myocardial metabolisms, as determined from these parameters. Esberiven 0.1 ml, which contains 2.5 mg rutin and 5 mg Melilotus extract, slightly but signficantly increased CBF and decreased QO2 and deltaEh without changing HR and MCF. In situ, intra-coronary injection of either Theo-Esberiven or proxyphylline resulted in a dose-dependent increase in left circumflex coronary flow (LCCF). The effect of Esberiven on LCCF was much less and was slight at the higher doses. Intravenous injection of Theo-Esberiven (0.1 ml/kg) increased LCCF. Besides this change, marked fall in blood pressure and tachycardia were induced by both Theo-Esberiven and proxyphylline without the change in dP/dtmax. Esberiven by the same route led to the decrease in blood pressure associated with HR and dP/dtmax. These results indicate that Theo-Esberiven may be appropriately prescribed for ischemic heart diseases.     

Antiadrenergic and hemodynamic effects of ranolazine in conscious dogs

Effects of ranolazine alone and in the presence of phenylephrine (PE) or isoproterenol (ISO) on hemodynamics, coronary blood flow and heart rate (HR) in the absence and presence of hexamethonium (a ganglionic blocker) were studied in conscious dogs. Ranolazine (0.4, 1.2, 3.6, and 6 mg/kg, intravenous) alone caused transient (<1 minute) and reversible hemodynamic changes. PE (0.3-10 μg/kg) caused a dose-dependent increase in blood pressure and decrease in HR. ISO (0.01-0.3 μg/kg) caused a dose-dependent decrease in blood pressure and an increase in HR. Ranolazine at high (11-13 mM), but not at moderate (4-5 mM) concentrations partially attenuated changes in mean arterial blood pressure and HR caused by either PE or ISO in normal conscious dogs. However, in dogs treated with hexamethonium (20 mg/kg) to cause autonomic blockade, ranolazine (both 4-5 and 11-13 μM) significantly attenuated both the PE- and ISO-induced changes in mean arterial blood pressure. The results suggest that a potential antiadrenergic effect of ranolazine was masked by autonomic control mechanisms in conscious dogs but could be observed when these mechanisms were inhibited (eg, in the hexamethonium-treated dog). Ranolazine, at plasma concentrations <10 μM and in conscious dogs with intact autonomic regulation, had minimal antiadrenergic (α and β) effects.