Adrenergically Mediated Ventricular Fibrillation in Probucol-Treated Dogs: Roles of Alpha and Beta Adrenergic Receptors

A high incidence of sudden death due to ventricular fibrillation (VF) has been observed in dogs under chronic treatment with probucol, a new hypocholesterolemic agent. The present study describes the cardiac electrophysiologic properties of probucol-treated dogs and characterizes the electrophysiological response of these animals to manipulation of the autonomic nervous system. There was no significant difference in the spontaneous sinus cycle length, the QT interval, refractory period of the atrium, ventricle or A-V junction between normal and probucol-treated dogs. Epinephrine produced VF with few and sometimes no preceding premature ventricular extrasystoles. Electrical stimulation of the stellate ganglion induced VF in 16/19 dogs whereas stimulation of the right stellate ganglion induced VF in 1/19 dogs. Phenylephrine induced VF in 0/19 dogs, isoproterenol in 5/19 dogs, but phenylephrine + isoproterenol induced VF in 9/11 dogs in which isoproterenol did not produce VF. alpha (phentolamine) or beta (propranolol) blockade prevented initiation of VF by epinephrine, phenylephrine + is isoproterenol, and left stellate stimulation but alpha blockade did not prevent induction of VF by isoproterenol when isoproterenol alone produced VF. In this nonischemic model, we conclude that left stellate stimulation is a far more potent initiator of VF than right stellate stimulation and that induction of VF appears to require both alpha and beta adrenergic receptor stimulation.     

Tracer norepinephrine kinetics in coronary circulation of patients with heart failure secondary to chronic pressure and volume overload.

Controversy exists over the nature of the abnormality in cardiac sympathetic nerves in heart failure. In the cardiomyopathy of the Syrian hamster, reduction in tissue stores and increased turnover of norepinephrine is clearly associated with excessive sympathetic stimulation but in animal models and humans with heart failure secondary to mechanical overload there is evidence for depression of neuronal uptake. Because norepinephrine is both released and taken up by sympathetic fibers it is impossible to assess norepinephrine kinetics in an intact heart without separating these two functions. A technique for doing so has recently been developed in normal dogs and we therefore acquired similar data in humans with heart failure secondary to chronic pressure and volume overload. The technique involves the combination of transient norepinephrine tracer coronary sinus outflow in relation to intravascular and interstitial references after simultaneous injection into the left coronary artery and the measurement of endogenous norepinephrine concentrations in artery and coronary sinus. We found a marked reduction in cardiac norepinephrine release and uptake in a group of patients with clinical left ventricular failure secondary to mechanical overload, relative to a group of patients with no failure. Norepinephrine balance and overflow across the heart were not significantly different. We conclude that there is hypofunction of the cardiac sympathetic nerves in heart failure secondary to mechanical overload and that traditional methods are inadequate in assessing cardiac norepinephrine kinetics when there are simultaneous changes in neuronal uptake and release.     

Increased breathing gas density enhances cardiac workload.

The effect of increased breathing gas density on the left ventricular pressure (LVP), cardiac contractility (dP/dt), heart rate (HR), intrapleural pressure (P(ip)) and respiratory frequency (RF) was evaluated in pentobarbital-anaesthetized rats (n = 8) and cats (n = 6). Catheters were placed in the left cardiac ventricle via the right carotid artery to measure the LVP, in the oesophagus for indirect measurements of P(ip) and RF, and into the aorta from the right femoral artery for arterial pressure measurements. The RF fell significantly within the first 30 s and had reached a stable value 2 min after gas shift in both rats and cats. Concomitant with the RF fall, the depth of inspiration and intrapleural pressure differences in both rats and cats increased. The acid-base balance remained at control levels in both animal groups. LVP and dP/dt started to increase during the first half-minute, and reached their maximum values 2-5 min after the introduction of normoxic sulphur hexafluoride. A linear relationship between the enhanced dP/dt and the P(ip) increase was found. The HR remained unchanged in both cats and rats. These findings indicate that the breathing gas density might influence the cardiac contractility found during hyperbaric exposure, and that a gas density of five times that of air at 1 bar does not influence the diffusion of O2 and CO2 in the lung. The O2 consumption of the heart in cats and rats was calculated to rise by 25% and 30% respectively in the dense breathing gas atmosphere.     

Effects of Increasing Heart Rate Induced by Efferent Sympathetic Neuronal Stimulation, Isoproterenol or Cardiac Pacing on Myocardial Function and Oxygen Utilization

The effects of increasing heart rate by six different methods on cardiac /unction were investigated in 17 open-chest anesthetized dogs. Heart rate was increased approximately 30% by (1) right interganglionic nerve stimulation, (2) atrial pacing, (3) ventricular pacing, (4) atriovenfricular sequential pacing, (5) right stellate ganglion stimulntion, and (6) isoproterenoi administration. During heart rate increases induced by atrial pacing left ventricular intramyocardial pressure, coronary Wood flow, oxygen delivery per unit of myocardial oxygen consumption, and myocardial efficiency were unchanged. Ventricular pacing reduced left ventricular cavity and septal intramyocardial pressure, while circumflex coronary flow increased, resulting in reduced oxygen delivery relative to myocardial oxygen consumption. Similarly, atrioventricu-lar sequential pacing increased circumflex coronary artery flow and myocardial oxygen consumption, and decreased septal intramyocardial pressure and oxygen delivery per unit of myocardial oxygen consumption. Right stellate ganglion stimulation and isoproterenol increased left anterior descending and circumflex coronary artery blood flow, intramyocardial pressure, and myocardial oxygen consumption. Estimated myocardial efficiency (left ventricle) was decreased by ventricular pacing and isoproterenol, and was unchanged by atrial pacing and right interganglionic nerve stimulation. Increases in heart rate induced by right interganglionic nerve stimulation did not alter myocardial oxygen consumption, or the index of cardiac efficiency. It is concluded that augmentation of heart rate by either ventricular or atrioventricular pacing impairs myocardial function so that there is a decrease of left ventricular efficiency, and isoproterenol augments chronotropism and myocardial force relative to cardiac external work so there is a reduction in cardiac efficiency. In contrast, atrial pacing or right interganglionic nerve stimulation augments chronotropism such that myocardial oxygen consumption and efficiency are unchanged.     

The effect of sustained stellate ganglion stimulation on left ventricular contractility in the dog

Although a progressive reduction in left ventricular contractility during sustained left stellate ganglion stimulation has been well documented, there have been no reports on the contractile state after nerve stimulation. Left ventricular contractility after cessation of 60 min of electrical (10 V. 10 Hz. 1 msec) left stellate ganglion stimulation has been assessed in open chest dogs. Before and 15 min after stimulation, left ventricular contractility was evaluated by the end-systolic pressure-segment length relationship using ultrasonic crystals during a stepwise aortic constriction to increase left ventricular afterload. Restimulation of the left stellate ganglion was also performed 15 min after cessation of the first stimulation. After sustained left stellate ganglion stimulation, the end-systolic points shifted to the right from the control and the slope of multiple pressure-segment length coordinates significantly decreased (102.5 +/- 16.1 to 76.5 +/- 10.2 mmHg/mm, mean +/- S.E., p less than 0.05, n = 5), indicating a depression of left ventricular contractility. Increased left ventricular dP/dt max and norepinephrine level in the coronary sinus gradually returned to near base line during 60 min of stimulation. These reduced responses lasted for at least 15 min after cessation of stimulation. The myocardial norepinephrine content was reduced to 0.59 +/- 0.08 (mean +/- S.E.) ng/mg wet tissue from 0.90 +/- 0.15 of the control level (p less than 0.05). These data suggested that left ventricular contractility decreased after sustained cardiac sympathetic nerve stimulation, probably due to norepinephrine reduction in the myocardium.     

Tubular Reabsorption of Glucose During Pregnancy

Continuous infusion of isoproterenol or electric stimulation of left stellate ganglion in atropinized dogs changed the cardiac response to high aortic blood pressure. In thoracotomized dogs, cardiac output rose when ventricular systolic blood pressure was increased from 100 to more than 200 mm Hg by constriction of the descending aorta. Myocardial dimensions as measured by ultrasonic distance gauges implanted one cm apart in the left myocardium (myocardial distance) showed only slight changes. In control experiments at normal inotropic levels, or after blocking β-receptors by propranolol, the effect of increasing aortic pressure was maintenance or reduction of cardiac output. Myocardial distances were increased with reductions in amplitude of the beat-to-beat oscillations. In unanesthetized dogs, angiotensin infusion reduced cardiac output and increased myocardial dimensions under control conditions. During infusion of isoproterenol the response to angiotensin at similar increments of blood pressure was an increase in cardiac output and nearly no increase in myocardial dimensions. These studies show that the cardiac response to increased blood pressure is dependent on the level of inotropy.     

Relative contribution of preload and afterload to the reduction in cardiac output caused by nitric oxide synthase inhibition with L-N(G)-methylarginine hydrochloride 546C88

OBJECTIVE: The nitric oxide synthase inhibitor L-N(G)-methylarginine hydrochloride (L-NMMA HC1 546C88) causes reductions in cardiac output (CO), a potential limitation to clinical application. This drop in CO exceeds that from phenylephrine at matched systemic arterial pressure. We tested the hypothesis that the greater fall in CO attributable to L-NMMA primarily reflects a difference in venoconstriction between agents, such that phenylephrine produces larger increases in preload (an independent determinant of CO). DESIGN: Random infusion of phenylephrine or L-NMMA. SETTING: An animal research laboratory. SUBJECTS: Eight healthy, conscious, male dogs. INTERVENTIONS: L-N(G)-methylarginine hydrochloride (20 mg/kg for 1 hr) and phenylephrine (0.5 to 3 microg/kg/min) were administered into eight dogs chronically instrumented to measure left ventricular pressure and dimension. Data were measured at a constant heart rate (140 beats/min) to render CO proportional to stroke dimension. MEASUREMENTS AND MAIN RESULTS: At a matched increase in afterload (effective arterial elastance), L-NMMA increased preload (end-diastolic dimension) to a lesser degree (3.8%+/-1.5%, p < .05) than phenylephrine (9.6%+/-1.6%, p < .05 vs. L-NMMA). Neither L-NMMA nor phenylephrine affected the slope of the end-systolic pressure dimension relationship, although L-NMMA shifted the relationship rightward (1.7+/-0.7 mm, p < .05), consistent with a mild negative inotropic effect. L-NMMA decreased the stroke dimension to a greater extent than phenylephrine (-24.1%+/-6.8% and -10.6%+/-3.4%, respectively, p < .05). CONCLUSIONS: Differential CO responses to phenylephrine and L-NMMA were primarily attributable to changes in preload. Variable venular vs. arteriolar constrictor effects must be considered when evaluating the integrated cardiovascular response to a vasoactive agent.     

Experimental myocardial infarction: VIII. Chronotropic augmentation of cardiac function in left ventricular failure of acute and healing stages in intact conscious dogs

The hemodynamic effects of tachycardia induced by atrial pacing were investigated in left ventricular failure of acute and healing experimental myocardial infarction in 20 intact, conscious dogs. Myocardial infarction was produced by gradual inflation of a balloon cuff device implanted around the left anterior descending coronary artery 10-15 days prior to the study. 1 hr after acute myocardial infarction, atrial pacing at a rate of 180 beats/min decreased left ventricular end-diastolic pressure from 19 to 8 mm Hg and left atrial pressure from 17 to 12 mm Hg, without change in cardiac output. In the healing phase of myocardial infarction 1 wk later, atrial pacing decreased left ventricular end-diastolic pressure from 17 to 9 mm Hg and increased the cardiac output by 37%. This was accompanied by evidence of peripheral vasodilation. In two dogs with healing anterior wall myocardial infarction, left ventricular failure was enhanced by partial occlusion of the circumflex coronary artery. Both the dogs developed pulmonary edema. Pacing improved left ventricular performance and relieved pulmonary edema in both animals. In six animals propranolol was given after acute infarction, and left ventricular function deteriorated further. However the pacing-induced augmentation of cardiac function was unaltered and, hence, is not mediated by sympathetics.The results show that the spontaneous heart rate in left ventricular failure of experimental canine myocardial infarction may be less than optimal and that maximal cardiac function may be achieved at higher heart rates.     

Chronic activation of peroxisome proliferator-activated receptor-alpha with fenofibrate prevents alterations in cardiac metabolic phenotype without changing the onset of decompensation in pacing-induced heart failure

Severe heart failure (HF) is characterized by profound alterations in cardiac metabolic phenotype, with down-regulation of the free fatty acid (FFA) oxidative pathway and marked increase in glucose oxidation. We tested whether fenofibrate, a pharmacological agonist of peroxisome proliferator-activated receptor-alpha, the nuclear receptor that activates the expression of enzymes involved in FFA oxidation, can prevent metabolic alterations and modify the progression of HF. We administered 6.5 mg/kg/day p.o. fenofibrate to eight chronically instrumented dogs over the entire period of high-frequency left ventricular pacing (HF + Feno). Eight additional HF dogs were not treated, and eight normal dogs were used as a control. [3H]Oleate and [14C]Glucose were infused intravenously to measure the rate of substrate oxidation. At 21 days of pacing, left ventricular end-diastolic pressure was significantly lower in HF + Feno (14.1 +/- 1.6 mm Hg) compared with HF (18.7 +/- 1.3 mm Hg), but it increased up to 25 +/- 2 mm Hg, indicating end-stage failure, in both groups after 29 +/- 2 days of pacing. FFA oxidation was reduced by 40%, and glucose oxidation was increased by 150% in HF compared with control, changes that were prevented by fenofibrate. Consistently, the activity of myocardial medium chain acyl-CoA dehydrogenase, a marker enzyme of the FFA beta-oxidation pathway, was reduced in HF versus control (1.46 +/- 0.25 versus 2.42 +/- 0.24 micromol/min/gram wet weight (gww); p < 0.05) but not in HF + Feno (1.85 +/- 0.18 micromol/min/gww; N.S. versus control). Thus, preventing changes in myocardial substrate metabolism in the failing heart causes a modest improvement of cardiac function during the progression of the disease, with no effects on the onset of decompensation.     

Impaired venous return causes circulatory failure in experimental pancreatitic shock in dogs

The haemodynamic effects in the early phase of canine acute experimental pancreatitis (AP) were studied using a cardiac catheterization technique. AP was induced in anaesthetized dogs with an infusion of trypsin-sodium-taurocholate into the pancreatic duct. The initial haemodynamic measurements were performed after the preparation of the animal and 5 min after the induction of AP. Thereafter, pressure and volume parameters were measured at 10 min intervals. AP induced significant increases in heart rate, dP/dt_max and mean arterial pressure, but a decrease in V_max 5 min after the induction of AP. After the initial phase, the heart rate remained significantly increased, while constant and significant decreases of stroke volume, cardiac output, enddiastolic volume and end-diastolic pressure developed. The parameters of the contractility of the left ventricle were not affected to the same extent. It is suggested that the circulatory failure observed in AP, characterised by a prompt reduction of cardiac output, was primarily due to a heavy reduction in preload. This supports the theory that cardiac output is primarily affected by impaired venous return with consequently decreased preload rather than by a loss of ventricular contractility. Hence, the existence of a myocardial depressant factor in the early phase of experimental AP does not gain support from the present results.     

Pathophysiological roles of endogenous endothelin-1 in dogs with chronic heart failure produced by rapid right ventricular pacing.

This study was designed to analyze the pathophysiological role of the endogenous endothelin (ET) system and the therapeutic approach to congestive heart failure (CHF) with ET(A)/ET(B) receptor antagonists in a canine CHF model. After 3 weeks of rapid right ventricular pacing (240 beats/min), concentrations of immunoreactive ET-1 in dogs increased approximately 2-fold in plasma and in the left and right ventricles but not in the lung. There were no meaningful changes in the density and affinity of total ET receptors, or in the ratio of ET(A) to ET(B) receptors. To clarify the functional role of endogenous ET, we examined the effects of acute injection of J-104132 (1 and 3 mg/kg i.v.), an ET(A)/ET(B) receptor antagonist, on cardiovascular and renal function in dogs with CHF. Compared with vehicle, J-104132 at both doses significantly decreased pulmonary artery pressure (PAP), pulmonary capillary wedge pressure (PCWP), and mean arterial pressure (MAP), and increased cardiac output (CO) and renal blood flow. J-104132 had no effects on heart rate and cardiac contractility. In addition, we examined whether J-104132 has an additive effect in the presence of enalaprilat. J-104132 (1 mg/kg i.v.) administered after enalaprilat (0.05 mg/kg i.v.) induced further decreases in MAP, PCWP and PAP, and further increases in CO, resulting in further decreases in total peripheral resistance. These results indicate that the endogenous ET system is exaggerated in CHF and has a detrimental effect on cardiac function. Therefore, J-104132 given alone or as combination therapy may play a beneficial role in the treatment of CHF in humans.     

Influence of Different Atrioventricular and Interventricular Delays on Cardiac Output During Cardiac Resynchronization Therapy

Restoration of the atrioventricular (AVD) and interventricular (VVD) delays increases the hemodynamic benefit conferred by biventricular (BiV) stimulation. This study compared the effects of different AVD and VVD on cardiac output (CO) during three stimulation modes: BiV-LV = left ventricle (LV) preceding right ventricle (RV) by 4 ms; BiV-RV = RV preceding LV by 4 ms; LVP = single-site LV pacing. We studied 19 patients with chronic heart failure due to ischemic or idiopathic dilated cardiomyopathy, QRS ≥ 150 ms, mean LV end-diastolic diameter = 78 ± 7 mm, and mean LV ejection fraction = 21 ± 3%. CO was estimated by Doppler echocardiographic velocity time integral formula with sample volume placed in the LV outflow tract. Sets of sensed-AVDs (S-AVD) 90–160 ms, paced-AVDs (P-AVD) 120–160 ms, and VVDs 4–20 ms were used. BiV-RV resulted in lower CO than BiV-LV. S-AVD 120 ms and P-AVD 140 ms caused the most significant increase in CO for all three pacing modes. LVP produced a similar increase in CO as BiV stimulation; however, AV sequential pacing was associated with a nonsignificantly higher CO during LVP than with BiV stimulation. CO during BiV stimulation was the highest when LV preceded RV, and VVD ranged between 4 and 12 ms. The most negative effect on CO was observed when RV preceded LV by 4 ms. Hemodynamic improvement during BiV stimulation was dependent both on optimized AVD and VVD. LV preceding RV by 4–12 ms was the most optimal. Advancement of the RV was not beneficial in the majority of patients.     

心衰犬单纯左室起搏方式的疗效观察

【目的】评价单纯左室起搏方式治疗心衰的疗效。【方法】建立12只左束支传导阻滞的心衰犬模型,采用自身对照方法随机行右心房一右室心尖部（RVA）、右心房-双心室（Bi—V）、右心房-左室（LV）起搏,起搏频率180次／分钟,每种起搏方式起搏前及起搏稳定15rain后行彩色多普勒超声心动图检查,测定左心／室舒张末期直径（LVEDd）、左室射血分数（LVEF）、室间机械延迟（IVMD）、室间隔与左室后壁运动延迟（SP—wMD）、左心室12个节段达峰时问的标准差（Ts—SD）。【结果】单纯左室起搏时：与起搏前及右室心尖部起搏相比,LVEDd、IVMD、SPWMD、Ts—SD减小,LVEF增大,其差异有显著性（P〈0．05）;与双室起搏相比,上述指标间无显著性差异（P〉0．05）。【结论】单纯左室起搏方式能够改善心室不同步及心功能,可做为心脏再同步化治疗（CRT）心衰的一种选择方式。     

Decreased and abnormal left ventricular filling in acute heart failure: role of pericardial constraint and its mechanism.

Pericardial constraining force is minimal in normal hearts; however, it is considered to be prominent in moderate to severe heart failure. Thus, effects of the pericardium on pulsed Doppler transmitral flow velocity pattern were examined in 17 dogs with acute left ventricular dysfunction. Left ventricular dysfunction with left ventricular end-diastolic pressure > or = 15 mm Hg was produced by injection of microspheres into the left coronary artery. Transmitral flow velocity pattern, left atrial and left ventricular diameters, and high-fidelity left atrial and left ventricular pressures were recorded before and after pericardiectomy. In five of the 17 dogs, mitral regurgitation with giant "v" wave of left atrial pressure occurred with reductions of left ventricular systolic pressure and peak rate of the left ventricular pressure fall (dP/dt) after pericardiectomy. In the other 12 dogs, peak early and late diastolic filling velocities increased with a decrease in left ventricular minimal pressure and increases in left arterial and left ventricular diameters and left atrial and left ventricular compliance after pericardiectomy. In these 12 dogs, left atrial to left ventricular crossover pressure, left ventricular end-diastolic pressure, and references for left ventricular relaxation did not change after pericardiectomy. Thus the release from pericardial constraining force in severe heart failure may increase chamber compliance of the left ventricle and left atrium and, in turn, increase peak early and late diastolic filling velocities through an increment in forward transmitral pressure gradient. Increased pericardial constraining force is a possible cause limiting left ventricular filling and hence cardiac output in heart failure.     

Quantification of cardiac autonomic nervous activities in ambulatory dogs by eliminating cardiac electric activities using cubic smoothing spline

With the development of an implantable radio transmitter system, direct measurement of cardiac autonomic nervous activities (CANAs) became possible for ambulatory animals for a couple of months. However, measured CANAs include not only CANA but also cardiac electric activity (CEA) that can affect the quantification of CANAs. In this study, we propose a novel CEA removal method using moving standard deviation and cubic smoothing spline. This method consisted of two steps of detecting CEA segments and eliminating CEAs in detected segments. Using implanted devices, we recorded stellate ganglion nerve activity (SGNA), vagal nerve activity (VNA) and superior left ganglionated plexi nerve activity (SLGPNA) directly from four ambulatory dogs. The CEA-removal performance of the proposed method was evaluated and compared with commonly used high-pass filtration (HPF) for various heart rates and CANA amplitudes. Results tested with simulated CEA and simulated true CANA revealed stable and excellent performance of the suggested method compared to the HPF method. The averaged relative error percentages of the proposed method were less than 0.67%, 0.65% and 1.76% for SGNA, VNA and SLGPNA, respectively.     

心脏再同步化治疗对心力衰竭犬心脏功能及相关炎性因子的影响

目的探讨心脏再同步化治疗(CRT)对心力衰竭(HF)犬心脏功能及相关炎性因子的影响。方法 10条雌性健康清洁比格犬采用随机数字表法分为2组,实验组与对照组各5只。2组均给予开胸结扎冠脉制作HF动物模型,成模后仅实验组实施为期4周的CRT,对照组不给予CRT。记录与观察所有大鼠在实验期间的活动与进食情况;分别于实验前、HF建模后2周、同步化治疗4周后通过超声心动图检查测定各组大鼠左室舒张末容积(LVEDV)和左室收缩末容积(LVESV);测定所有犬的颈动脉收缩压与舒张压;酶联免疫吸附实验检测各组大鼠血清脑钠肽(BNP)、髓过氧化物酶(MPO)含量。结果所有比格犬均造模成功并完成实验,均无突然死亡或者心律失常发生。与实验前相比,HF后2周及同步化治疗4周后,2组大鼠颈动脉收缩压、舒张压、LVEDV、LVESV、血清BNP与MPO含量均显著升高(P <0.05),而同步化治疗4周后2组以上所有指标水平均显著低于HF后2周,差异均有统计学意义(P <0.05)。同步化治疗4周后,与对照组相比,实验组大鼠颈动脉收缩压、舒张压、LVEDV、LVESV、血清BNP与MPO含量均显著降低,差异均有统计学意义(P <0.05),而实验前及HF后2周,2组大鼠颈动脉收缩压、舒张压、LVEDV、LVESV、血清BNP与MPO含量差异均无统计学意义(P> 0.05)。结论应用CRT治疗HF犬可抑制BNP与MPO等相关炎性因子的表达,从而促进犬心功能与血压恢复正常。     

胸腔阻抗法对乌拉地尔治疗心力衰竭血流动力学变化的观察

目的：观察胸腔阻抗法对乌拉地尔治疗心力衰竭(心衰)的血流动力学变化。方法：16只健康杂种犬麻醉后，制成心衰模型。分为乌拉地尔组和生理盐水对照组，分别于用药前及用药后15、30、60、90和120min用无创血流动力学监测仪测定心率(HR)、每搏量(SV)、心排血量(CO)、射血前时间(PEP)、左室射血时间(LVET)、收缩时间比率(STR，PEP／LVET)、等容舒张时间(IRT)、肺毛细血管楔压(PCWP)、左室舒张末压(LVEI)P)、总外周阻力(TPR)、每搏左室作功(SW)和每分左室作功(CW)。结果：乌拉地尔较对照组明显增加CO和SV，缩短PEP和STR，降低PCWP、LVEDP和TPR，增加SW和CW，而对HR、LVET和IRT无影响。结论：胸腔阻抗法可作为无创、实时和准确的监测方法观察心衰治疗的血流动力学变化；乌拉地尔可以明显降低心脏前后负荷，增加CO和心肌收缩能力，具有改善心功能的作用。     

Compared peripheral vascular responses to intravenous and intra-arterial administrations of positive inotropic agents in conscious dogs

In addition to their direct effects on cardiac contractility, a number of positive inotropic agents also induce, through direct peripheral vasodilation, a reduction in afterload which is of major importance in their beneficial effects in the treatment of congestive heart failure. However, the induced increase in cardiac output can indirectly improve perfusion of peripheral vessels through a flow-mediated mechanism. Thus, the goal of the present study was to compare the direct peripheral vasomotor effects assessed in the iliac vascular bed of four positive inotropic agents: DPI 201-106, ouabain, milrinone and dobutamine, in the presence and absence of simultaneous changes in cardiac function. These drugs were administered either through intravenous or intra-arterial (aorto-iliac catheter) routes in 6 conscious dogs, chronically instrumented for the measurement of heart rate, arterial pressure, left ventricular dP/dt, iliac artery blood flow and iliac artery diameter (sonomicrometry). Intravenous doses were selected as those inducing equipotent positive inotropic responses whereas intra-arterial doses were below those required to induce any significant change in systemic hemodynamics. Ouabain decreased and milrinone increased both iliac blood flow and diameter after either intravenous or intra-arterial administrations. In contrast, iliac blood flow did not change after intra-arterial administration of DPI 201-106 and dobutamine whereas iliac diameter was not modified by DPI 201-106 and even decreased with dobutamine. After intravenous administration, DPI 201-106 but not dobutamine, increased both iliac blood flow and diameter. Thus, this experimental preparation can differentiate inotropic agents with direct vasodilating (milrinone) or constricting (ouabain) properties and those (DPI 201-106 and dobutamine) with indirect vasodilating effects most likely mediated by the improvement in cardiac function.     

Effect of transient vagal cold blockade upon reflex actions of a polar and nonpolar cardiac glycoside.

To determine the role of vagal afferent fibers in expressing the actions of a polar aminosugar digitalis agent [ASI-222 (4-amino-galactose beta-D-digitoxigenin HCl)] and a nonpolar neutral sugar agent (digoxin) on cardiac sympathetic nerve activity (CSNA), we utilized a period of vagal cooling to block traffic in that nerve. Anesthetized dogs were prepared to measure CSNA in efferent fibers from the right stellate ganglion. Both vagi were exposed midcervically and fitted with water-filled glass coils. The vagi were cooled (approximately 4 degrees C) and then either ASI-222 or digoxin was infused i.v. at dose rates which produce cardiac arrhythmias after about 100 min. Saline was infused in a third group. After 50 min of drug infusion, the vagi were rewarmed. During vagal cooling and infusion of saline or ASI-222, CSNA rose by 25 to 30%. Within 10 min after rewarming, CSNA returned to base line values in the saline group but nerve activity in the ASI-222 group promptly fell about 45% below base line and remained depressed. This dose rate of ASI-222 depresses CSNA in neurally intact dogs within 30 min. In contrast, during vagal cooling digoxin caused a slow but progressive fall in CSNA (approximately 20%); with rewarming and higher doses, CSNA began to rise above base-line levels. This profile of changes in CSNA to digoxin is similar to that observed in neurally intact animals. In other dogs given atropine to block the effects of efferent vagal nerve traffic, ASI-222 produced a prompt decline in CSNA like that observed previously in neurally intact dogs.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of cardiac depression and of anesthesia on the myocardial action of a cardiac glycoside

The effects of ouabain (G-strophanthin) 20 mug/kg, on left ventricular (LV) pressure (P), diameter (D), velocity of contraction (dD/dt), and dP/dt were studied in conscious dogs instrumented with ultrasonic diameter gauges and miniature pressure gauges. The effects of ouabain were compared on separate occasions in the same dogs after cardiac depression with propranolol, 3.0 mg/kg, and also after general anesthesia with Na pentobarbital, 30 mg/kg. Maximal pressor effects were observed in the first 10 min, but maximal effects on the contractile state occurred at 30 min after ouabain. At this time, in conscious dogs, ouabain had increased LV isolength systolic pressure by 5%, LV isolength velocity by only 9%, and LV (dP/dt)/P by 21%, while end systolic diameter (ESD) decreased slightly and end diastolic diameter (EDD) and heart rate (HR) were unchanged. After anesthesia, ouabain increased LV systolic pressure by 8%, velocity 32%, (dP/dt)/P by 47%, and ESD decreased by 1.2 mm while EDD rose slightly and HR fell by 26 beats/min. Returning HR to control with atrial pacing decreased EDD 0.9 mm below control. After cardiac depression with propranolol, ouabain caused responses similar to those observed in the anesthetized dogs. Thus, the cardiac glycoside was found to exert only minor inotropic effects on the nonfailing heart of conscious dogs but far more striking inotropic responses in the anesthetized state.