Hemodynamic and neurohumoral responses to intravenous nicorandil in congestive heart failure in humans.

Nicorandil is a vasodilator drug that combines potassium channel opening properties with nitrate effects. The resulting potent and unique vasodilating properties suggest a potential therapeutic role in congestive heart failure. We therefore studied the acute hemodynamic and neurohumoral responses to nicorandil, given as single intravenous bolus doses of 158, 251, 398, or 630 micrograms/kg, to 22 patients with chronic congestive heart failure (ejection fraction less than 40%). Hemodynamic responses occurred within 5 min of dosing and terminated within 240 min. The heart rate was significantly increased only at 5 min after the 158 micrograms/kg dose, and was unchanged after all other doses. The mean arterial pressure was reduced only by the 398 and 630 micrograms/kg doses. The pulmonary capillary wedge pressure and right atrial pressure were significantly reduced by all doses within the initial 30 min; this reduction in pulmonary capillary wedge pressure was better sustained over time by the two larger doses, whereas the reduction in right atrial pressure was sustained only by the 158 micrograms/kg dose. The cardiac index was reduced by the 158 micrograms/kg dose, but increased after 251, 398, and 630 micrograms/kg of nicorandil. Plasma nicorandil concentrations were positively correlated with changes in cardiac index, systemic arterial pressure, pulmonary capillary wedge pressure, heart rate, and systemic vascular resistance. When measured 1 h after dosing, plasma immunoreactive ANF decreased, norepinephrine concentrations did not change, and plasma renin activity increased, but only at the 630 micrograms/kg dose level.(ABSTRACT TRUNCATED AT 250 WORDS)     

Vasodilating effects of nicorandil and nitroglycerin in anaesthetized open-chest dogs

Vasodilating effects of intravenous administrations of nicorandil (SG-75) and nitroglycerin were analyzed in anaesthetized open-chest dogs by measuring simultaneously, and continuously, coronary (CBF), vertebral (VBF), renal (RBF) and aortic blood flow (AoF). Nicorandil 10-300 micrograms/kg i.v. and nitroglycerin 1-30 micrograms/kg i.v. decreased aortic blood pressure and increased CBF in a dose-dependent fashion. The doses of nicorandil and nitroglycerin which reduced coronary vascular resistance to about 60% of the predrug value were 100 micrograms/kg and 10 micrograms/kg, respectively. Nicorandil 100 micrograms/kg i.v. significantly increased AoF and heart rate, significantly decreased left ventricular end-diastolic pressure and did not significantly change VBF, RBF and left ventricular dP/dt. Nitroglycerin 10 micrograms/kg i.v. significantly increased VBF and heart rate, significantly decreased left ventricular end-diastolic pressure and produced an initial increase followed by a decrease in AoF and RBF. When compared with these doses of both drugs, the ratio of percent decrease in coronary vascular resistance to that in total peripheral resistance was over 1.0 in both drugs and the value of this ratio in nicorandil was significantly larger than that in nitroglycerin. The duration of increase in CBF produced by nicorandil 10-300 micrograms/kg i.v. was dose-dependent, but was not changed by nitroglycerin 1-30 micrograms/kg i.v. The results indicate that nicorandil and nitroglycerin dilate coronary vasculature more markedly than other vascular beds and that the potency of selective coronary vasodilatation and the duration of action are more significant in nicorandil than in nitroglycerin.     

The dopamine congener, ibopamine, in congestive heart failure

The hemodynamic effects of the dopamine congener, ibopamine, were investigated in nine patients with chronic congestive heart failure. A placebo-controlled design was utilized. Placebo and ibopamine in doses of 100, 200, and 300 mg were given orally as a single dose to each patient on 4 successive days. Dopamine at 1, 2, 4, and 6 micrograms/kg/min intravenously, was used as an internal standard. Ibopamine did not significantly change heart rate, systemic and pulmonary arterial pressures, pulmonary capillary wedge pressure, or mean right atrial pressure. Significant decreases of systemic arterial resistance (19%) and total pulmonary arterial resistance (21%), and significant increases of cardiac index (20%) and stroke volume index (16%) were elicited by ibopamine at doses of 200 and 300 mg. Peak effects occurred at 1 to 2 h with a duration of action of less than 4 h. The 2 changes were comparable with those obtained by dopamine 2-4 micrograms/kg/min. Except for mild changes at 30 min postdosing, the inotropic indices of the systolic time intervals were not altered significantly by ibopamine. Ibopamine elicits significant hemodynamic effects in patients with chronic congestive heart failure; in large part, these effects appear to be mediated through vasodilatory properties rather than direct positive inotropy.     

Effect of prostaglandin E1 on pulmonary hypertension after protamine injection during cardiac surgery

Background: The effects of prostaglandin E₁ on pulmonary hypertension were assessed after protamine injection at the end of cardiopulmonary bypass during cardiac surgery. Methods: Ten patients scheduled for cardiac surgery presented with pulmonary hypertension (mean pulmonary artery pressure greater than 30 mmHg) after protamine injection and were treated by infusion of 0.02 μg · kg⁻¹ · min⁻¹ prostaglandin E₁. Hemodynamic measurements were made on occasions after cardiopulmonary bypass. Prostaglandin E₁ decreased pulmonary artery pressure, pulmonary vascular resistance, right ventricular stroke work index and pulmonary vascular resistance/systemic vascular resistance ratio, but did not change blood pressure, systemic vascular resistance, left ventricular stroke work index or cardiac output. Conclusion: Prostaglandin E₁ normalized pulmonary hypertension after protamine injection, but did not change arterial blood pressure and cardiac output. Received: 22 August 1997 / Accepted in revised form: 30 October 1997     

Pulmonary vascular remodelling in hypoxic rats: effects of amlodipine, alone and with perindopril

This study investigated whether pulmonary vascular remodelling in hypoxic pulmonary hypertensive rats (10% oxygen; 4 weeks) could be prevented by treatment, during hypoxia, with amlodipine (10 mg/kg/day, p.o.), either alone or in combination with the angiotensin converting enzyme inhibitor, perindopril (30 mg/kg/day, p.o.). Medial thickening of pulmonary arteries (30-500 microm o.d.) was attenuated by amlodipine whereas it was totally prevented by the combination treatment (amlodipine plus perindopril); neomuscularisation of small alveolar arteries (assessed from critical closing pressure in isolated perfused lungs) was not affected. Pulmonary vascular resistance (isolated perfused lungs) was reduced by both treatment regimes but only combination treatment reduced right ventricular hypertrophy. Thus, amlodipine has anti-remodelling properties in pulmonary hypertensive rats. The finding that combining amlodipine with another anti-remodelling drug produced effects on vascular structure that were additive raises the question of whether combination therapy with two different anti-remodelling drugs may be of value in the treatment of patients with hypoxic (and possibly other forms of) pulmonary hypertension.     

Effect of the thromboxane A2-receptor antagonists, SQ 29,548 and SQ 28,668, on the pulmonary hypertensive response to endotoxemia in swine

The effects of two selective thromboxane (Tx) A2 antagonists (SQ 29,548 and SQ 28,668) on endotoxin-induced pulmonary hypertension were determined in anesthetized pigs. SQ 29,548 (10 micrograms/kg/min, i.v., n = 6) or vehicle (n = 7) was infused from 15 min before until 60 min after an intravenous infusion of Salmonella enteritidis endotoxin (1.0 microgram/kg). Within 20 min, vehicle-treated animals developed an acute 350 +/- 25% increase in pulmonary vascular resistance (PVR) with a 43% survival rate. In the presence of SQ 29,548 this initial pulmonary vasoconstriction was absent and all animals survived. However, a delayed increase in PVR of 58 +/- 20% was detected. The primary manifestation of the increase in PVR was an increase in pulmonary arterial pressure. In a similar preparation, septicemia was produced by Escherichia coli endotoxin (0.5 microgram/kg, i.v.) and SQ 28,668 (3, 10, 30 or 100 micrograms/kg/min, i.v., n = 5-6 per dose level) and vehicle (n = 6) treatments were compared. SQ 28,668 doses of 30 and 100 micrograms/kg/min mitigated the early, but not late, increases in PVR. These data demonstrate that endotoxemia in pigs produces an initial TxA2-receptor-dependent vasoconstriction and also a more slowly developing pulmonary hypertension which is probably due to other mediators.     

超声检测腺苷对先天性心脏病肺动脉高压血流动力学效应

目的　观察外周静脉注射腺苷对先天性心脏病肺动脉高压的血流动力学影响。方法　选取先天性心脏病肺动脉高压患者 30例 ,肘静脉注射腺苷 75 μg/ kg,应用彩色多普勒超声心动图检测心率、平均动脉压、肺动脉收缩压、肺循环阻力、体循环阻力、肺动脉 /主动脉收缩压比值、肺循环 /体循环血流量比值及心室射血分数的变化 ,并与用药前的各项指标相比较。结果　静脉注射腺苷后 ,肺动脉收缩压、肺循环阻力及肺动脉 /主动脉收缩压比值与用药前比较明显下降 (P<0 .0 5 ) ,而肺循环 /体循环血流量比值及右室射血分数增加 (P<0 .0 5 )。心率、平均动脉压、体循环阻力、左室射血分数用药前后无明显变化 (P>0 .0 5 )。结论　腺苷选择性地作用于肺血管 ,降低肺动脉压力及肺循环阻力 ,并改善右心功能 ,可作为判定肺动脉高压是否可逆的理想指标     

Lack of synergistic effect of molsidomine and sildenafil on development of pulmonary hypertension in chronic hypoxic rats

The present study addressed whether combined treatment with a phosphodiesterase type 5 inhibitor, sildenafil, and a nitric oxide donor, molsidomine, prevents development of pulmonary hypertension in chronic hypoxic rats. Two weeks of hypoxia increased right ventricular systolic pressure, and right ventricular and lung weight. Treatment with either sildenafil (10 mg/kg/day) or molsidomine (15 mg/kg/day) in drinking water reduced right ventricular systolic pressure and weight, while lung weight was unchanged. Combining sildenafil and molsidomine did not have additional effects compared to molsidomine alone. The number of muscularized pulmonary arteries with diameters below 50 microm was increased in vehicle and sildenafil-treated, but not in molsidomine-treated hypoxic rats. Acetylcholine relaxation was blunted in arteries from vehicle and molsidomine-treated, but not in sildenafil-treated rats. In conclusion, both sildenafil and molsidomine blunts pulmonary hypertension and right ventricular hypertrophy in chronic hypoxic rats, but no synergistic effects were observed.     

The pulmonary and systemic circulatory response to dopamine infusion

1. The pulmonary and systemic circulatory responses to dopamine infused at 8, 15, 25 and 30 mug/kg per min were studied in eight mongrel dogs.2. Mean pulmonary artery pressure, mean left atrial pressure, mean aortic pressure, mean aortic flow and the electrocardiogram were monitored in openchest preparations. Pulmonary vascular resistance, systemic vascular resistance and stroke volume were calculated.3. Significant increases in mean pulmonary and aortic pressures were noted at dopamine infusions of 25 and 30 mug/kg per min. The left atrial pressure fell significantly at 15 mug/kg per min and rose significantly at 30 mug/kg per min. Mean aortic flow increased at all four doses, while heart rate showed no change. Pulmonary vascular resistance did not change significantly at any dose level, but systemic vascular resistance fell slightly at 8 and 15 mug/kg per min and rose significantly at 30 mug/kg per min. Stroke volume was significantly elevated at infusions of 25 and 30 mug/kg per min.4. The systemic circulatory response to dopamine is similar to that described by previous investigators.5. The increased pulmonary pressures without change in resistance suggest a dopamine-induced increase in smooth muscle tension in the pulmonary vasculature.     

Combination therapy with inhaled nitric oxide and intravenous dobutamine during pulmonary hypertension in the rabbit

Combination therapy with an intravenous inovasodilator and inhaled nitric oxide (NO) may be appropriate in patients with pulmonary hypertension and associated right ventricular failure. We examined whether dobutamine and inhaled NO would have additive pulmonary vasodilator effects in experimental pulmonary hypertension. Pulmonary hypertension was produced in anesthetized, mechanically ventilated rabbits by infusion of U46619, a thromboxane analogue. Dobutamine was administered in increasing doses (2.5-20 microg/kg/min) with and without inhaled NO (40 ppm). Dobutamine produced dose-dependent decreases in pulmonary vascular resistance (PVR) and mean arterial pressure (MAP) and increases in cardiac output (CO). Inhaled NO alone decreased pulmonary artery pressure (PAP) and PVR with no effect on MAP or CO. The effects of dobutamine and inhaled NO were additive, so that at each dose of dobutamine, inhaled NO decreased PAP and PVR with no effect on systemic hemodynamics. This study suggests that the combination of dobutamine and inhaled NO should produce additive pulmonary vasodilation in patients with pulmonary hypertension and associated right ventricular dysfunction.     

Acute hemodynamic and neuroendocrine effects of dopexamine, a new vasodilator for the treatment of heart failure: comparison with dobutamine, captopril, and nitrate

Dopexamine (FPL 60278) is a new vasodilator possessing both postjunctional dopaminergic and beta 2-adrenoceptor agonist actions. Its acute haemodynamic effects were compared in a cross-over study with those of dobutamine, captopril, and glyceryl trinitrate (GTN) in eight adult patients with chronic heart failure. Dopexamine, 1 microgram/kg/min intravenously (i.v.) for 10 min, increased cardiac index, systolic blood pressure, and heart rate while reducing systemic vascular resistance. Pulmonary artery end-diastolic pressure was unchanged. Plasma norepinephrine (NE) increased during dopexamine infusion. No arrhythmias occurred. Dobutamine, 5 micrograms/kg/min i.v. for 10 min, increased cardiac index and systolic blood pressure similarly but did not increase heart rate or reduce vascular resistance. Captopril, 25 mg orally, did not alter cardiac index at 1 h, but reduced heart rate, blood pressure, pulmonary diastolic pressure, and vascular resistance. GTN, 100 micrograms sublingually, reduced pulmonary diastolic pressure but did not affect other variables at 5 min. Dopexamine, because it combines some of the properties of dopamine and salbutamol, may have a role in the management of severe low output cardiac failure.     

Hemodynamic and myocardial metabolic effects of the beta-agonist prenalterol in ischemic left ventricular dysfunction

Hemodynamic and myocardial metabolic parameters in ischemic left ventricular (LV) dysfunction were evaluated in response to the beta-agonist prenalterol. Twenty micrograms/kg intravenous prenalterol increased resting heart rate and cardiac output and decreased LV filling pressure, systemic vascular resistance, and pulmonary artery pressure. Resting coronary blood flow and myocardial oxygen consumption increased but net myocardial lactate and oxygen extraction did not change significantly. During pacing induced tachycardia (121 +/- 4 beats/min), prenalterol improved cardiac index and stroke work index; whereas, LV filling pressure, systemic vascular resistance, and pulmonary artery pressure decreased. Coronary blood flow and myocardial oxygen extraction did not change significantly. Net myocardial lactate extraction during pacing decreased insignificantly; one patient developed overt lactate production. Thus, prenalterol improves cardiovascular function at rest and during pacing-induced tachycardia in ischemic LV failure, but at the cost of higher resting myocardial oxygen consumption. The majority of subjects had no adverse metabolic response.     

Dose-response relationship in intoxication by the pyrrolizidine alkaloid monocrotaline

Rats develop pulmonary hypertension over a 2-wk period of continuous ingestion of monocrotaline dissolved in drinking water (20 mg/l). The relationship between monocrotaline concentration and duration of exposure was investigated by giving male rats (initial body weight 100 g) monocrotaline in drinking water (5, 10, 20, 40, or 60 mg/l) for 0, 1, 2, 4, 6, 10, or 20 d. Rats were killed 20 d after initiating treatment, and increased lung and right ventricular to body weight ratios were measured as indices of pulmonary hypertension. The accumulative dose of monocrotaline delivered over a 10-d period using a drinking water concentration of 10 mg/l (18 mg/kg) produced the same degree of right ventricular hypertrophy and lung weight increases as the doses ingested over a 4-d period by rats consuming 20 or 40 mg/l monocrotaline water (14 and 29 mg/kg). Phenobarbital pretreatment did not substantially alter the time course of toxicity induced with 20 mg/l monocrotaline water. Ingestion of 60 mg/l monocrotaline water for 1 d (11 mg/kg) resulted in right ventricular hypertrophy at 20 d. Since accumulative doses of less than 11 mg/kg did not produce toxicity and all doses greater than 14 mg/kg did, this range may be considered a threshold for inducing toxicity. However, organ weight increases following threshold exposures reversed over a 4-wk period. Increases in the wall thickness of pulmonary arteries correlated with the development of right ventricular hypertrophy. Pulmonary inflammation was not an early response to monocrotaline administration, since there was no change in the proportion of cell types recovered in lung lavage fluid during the first 6 d of monocrotaline treatment.     

INFLUENCE OF NICORANDIL, AN ANTIANGINAL AGENT, ON THE THERAPEUTIC AND TOXIC CARDIOVASCULAR ACTIONS OF OUABAIN IN THE ANAESTHETIZED DOG

The effects of nicorandil were investigated on ouabain-induced cardiovascular actions in pentobarbitone-anaesthetized dogs. Nicorandil (500 micrograms/kg per h) and ouabain (100 micrograms/kg per h), alone and in combination, were infused intravenously to three groups of dogs. Nicorandil gradually decreased systemic blood pressure, pressure-rate product, left ventricular systolic pressure, and coronary vascular resistance, but did not significantly affect heart rate, left ventricular dP/dt max, coronary blood flow, plasma electrolyte concentrations and ECG patterns. The lethal dose of ouabain was 122 micrograms/kg (s.e.m. = 3, n = 6) and the dose required to elicit ventricular premature beats was 63 micrograms/kg (s.e.m. = 3, n = 6). When nicorandil and ouabain were simultaneously infused intravenously, nicorandil did not affect either the lethal dose of ouabain or the dose required to produce ventricular premature beats, but it significantly inhibited the marked increases in coronary vascular resistance and systemic blood pressure induced by ouabain alone. Even in combination with nicorandil, ouabain maintained its own positive inotropic effect. The results indicate that the combination of ouabain with nicorandil may be beneficial in some conditions of angina pectoris.     

Effects of KB-2796, a new diphenylpiperazine calcium antagonist, on renal hemodynamics and urine formation in anesthetized dogs.

The effects of KB-2796, a new calcium antagonist with a diphenylpiperazine moiety, on renal hemodynamics and urine formation were investigated in anesthetized dogs. Intravenous infusion of KB-2796 (10, 30, and 100 micrograms/kg/min) decreased mean blood pressure (MBP) and renal vascular resistance (RVR) in a dose-dependent manner, but did not change renal blood flow (RBF). At the highest dose, glomerular filtration rate (GFR) and urine flow (UF) tended to decrease. Nicardipine (0.1, 0.3, and 1 microgram/kg/min) also dose-dependently decreased MBP, RVR, GFR, and UF. When KB-2796 was infused into the renal artery at lower doses of 3 and 10 micrograms/kg/min, UF and urinary excretion of electrolytes increased without a significant change in RBF and GFR. Intrarenal infusion of KB-2796 at 30 micrograms/kg/min and nicardipine at 0.3 microgram/kg/min produced a significant increase in GFR, RBF, UF, urinary excretion of electrolytes, and renin secretion rate. These results suggest that KB-2796 administered intrarenally exerts a diuretic action via tubular effects and the alteration of renal hemodynamics. However, its diuretic action might be masked by diminished urine formation via a reflex activation of the sympathetic nerves and/or via a reduction of renal perfusion pressure when it is administered systemically.     

Hemodynamic and electrophysiologic effects of combined infusion of lidocaine and propafenone in humans

The hemodynamic and electrophysiologic effect of a combined intravenous infusion of lidocaine (100 mg bolus followed by 2 mg/min infusion) and propafenone (1 or 2 mg/kg) in patients with a history of ventricular arrhythmia was studied. Lidocaine infusion alone significantly increased the mean pulmonary artery (+28%) and pulmonary capillary wedge (+17%) pressure, with no effect on cardiac index. Lidocaine alone produced no consistent change in any measured electrophysiologic parameter, except slight QTc shortening (-2%, P less than .05). Propafenone alone, particularly at the higher dose (2 mg/kg), produced significant increases in mean blood pressure (+14%), right atrial pressure (+78%), pulmonary artery pressure (+50%), pulmonary capillary wedge pressure (+65%), systemic vascular resistance (+29%), and pulmonary vascular resistance (+61%) and a decrease in cardiac index (-12%). Significant prolongation of PR (+9%), AH (+29%), and HV (+23%) intervals, atrial functional refractory period (+12%), ventricular effective (+7%) and functional (+6%) refractory period, and Wenckebach cycle length (+13%) also occurred after the administration of propafenone alone. Only the effects on atrioventricular (AV) node were observed at the lower dose of propafenone (1 mg/kg). Combined infusion of lidocaine with propafenone produced a mild, statistically insignificant additional negative inotropic effect but reversed the prolongation in atrial and ventricular refractoriness produced by propafenone alone. Thus, the data show that lidocaine attenuates certain electrophysiologic effects of propafenone, which might alter its antiarrhythmic efficacy, while producing mild additive negative inotropic effects that may be of hemodynamic significance.     

野百合碱诱导大鼠肺动脉高压动物模型的制备

目的采用注射野百合碱(MCT)制备大鼠肺动脉高压模型,并对肺动脉压测定方法进行优化。方法通过ip MCT诱导建立大鼠肺动脉高压模型,通过测定大鼠肺血管阻力的方法来对大鼠右心室压进行测定,采用阳性药对照、血流动力学测定和组织学观察确定模型是否建立成功。结果 ip 50 mg/kg MCT 4周后大鼠右心室平均压、右心肥大指数对比对照组明显增高,观察病理组织切片,可见明显的内皮细胞损伤,分布不均,动脉管壁明显增厚,肺组织有大量的炎性细胞浸润,出现肺血管的重构,证实肺动脉高压动物模型造模成功。结论采用ip MCT可以建立稳定的大鼠肺动脉高压模型,且具有较高的存活率,同时建议采用改良的心导管测定方法测定大鼠右心室压力。     

Effect of epinine on systemic hemodynamics and regional blood flow in conscious pigs.

Intravenous (i.v.) infusions (1, 2.5, 5, and 10 micrograms/kg/min for 10 min) were used to evaluate the cardiovascular effects of epinine (N-methyl-dopamine) in 8 conscious pigs. Epinine is a nonselective and nonspecific dopamine (DA) agonist, that also stimulates alpha- and beta-adrenoceptors. Epinine (1-5 microgram/kg/min) increased cardiac output (CO) by up to 15 +/- 5% (p less than 0.05), owing to an increase in heart rate (HR, 24 +/- 6%), but an increase in stroke volume (SV, 16 +/- 4%) caused the further increase in CO at 10 micrograms/kg/min. Mean arterial blood pressure decreased gradually from 100 +/- 5 mm Hg to 84 +/- 4 mm Hg during infusions up to 5 microgram/kg/min, but increased to 89 +/- 4 mm Hg during infusion of 10 micrograms/kg/min (p less than 0.05). Systemic vascular resistance had decreased from 36.5 +/- 2.8 to 27.5 +/- 3.0 mm Hg/L/min after infusion of 5 micrograms/kg/min but did not change further during infusion of 10 micrograms/kg/min. LV dP/dtmax increased only at 10 micrograms/kg/min. Myocardial blood flow did not change at any dose, owing to metabolically regulated coronary vasodilatation (myocardial work did not change). Flow to the adrenals (up to 110 +/- 37%) and the spleen (up to 95 +/- 13%) increased dose dependently. Cerebral blood flow increased only at the highest dose (15 +/- 5%, p less than 0.05); flow to the kidneys, liver, small intestine, and skeletal muscle did not change. Flow decreased to the stomach (21 +/- 5%) and skin (for doses less than 2.5 micrograms/kg/min).(ABSTRACT TRUNCATED AT 250 WORDS)     

Inhaled nitric oxide potentiates actions of adenosine but not of sodium nitroprusside in experimental pulmonary hypertension

Inhaled nitric oxide (NO), a selective pulmonary vasodilator, increases intracellular cyclic guanosine monophosphate. In contrast, adenosine, another selective pulmonary vasodilator, increases intracellular cyclic adenosine monophosphate. There has been only limited study on effects of inhaled NO combined with other pulmonary vasodilators. The current study examined the hypothesis that inhaled NO would potentiate in vivo pulmonary vasodilator effects of adenosine, but not those of sodium nitroprusside (SNP). Like inhaled NO, SNP acts via cyclic guanosine monophosphate. Rabbits were anesthetized and mechanically ventilated. The NO synthesis inhibitor NG-nitro-L-arginine methyl ester was administered. U46619, a thromboxane A2 mimetic, was infused to produce pulmonary hypertension. Rabbits then received either SNP at doses of 0.5, 1, 2, 4, 8, 16, and 32 microg/kg/min or adenosine at doses of 12.5, 25, 50, 100, 150, and 300 microg/kg/min. Hemodynamic measurements were obtained with or without inhaled NO (40 ppm) at each dose of SNP or adenosine. During U46619-induced pulmonary hypertension, inhaled NO decreased pulmonary artery pressure and pulmonary vascular resistance. Adenosine and SNP produced dose-related decreases in pulmonary artery pressure and pulmonary vascular resistance and increases in cardiac output. Inhaled NO decreased pulmonary artery pressure and pulmonary vascular resistance at all doses of adenosine, but had no significant pulmonary vasodilator effects at doses of SNP >0.5 microg/kg/min. We conclude that inhaled NO does not produce additional pulmonary vasodilation over that achieved at higher doses of SNP, but does produce additional vasodilation when combined with a vasodilator having different mechanisms of action. Since both inhaled NO and adenosine produce selective pulmonary vasodilation, such combination therapy may be effective in patients with pulmonary hypertension.     

Effects of MCI-154, a novel cardiotonic agent, on mean circulatory filling pressure in anesthetized dogs

The effects of MCI-154, a novel cardiotonic agent, on mean circulatory filling pressure (an index of total body venous tone), total peripheral resistance and the heart were examined in anesthetized dogs. The bolus injection of MCI-154 (10-100 micrograms/kg i.v.) caused a dose-dependent decrease in mean circulatory filling pressure and resistance to venous return. MCI-154 also decreased the mean blood pressure and total peripheral resistance, and increased cardiac output and heart rate. Right atrial pressure was reduced only by the lowest dose (10 micrograms/kg i.v.) of MCI-154. These hemodynamic effects of MCI-154, except those on mean circulatory pressure and resistance to venous return, reached a maximum with 30 micrograms/kg of the drug. Nitroglycerin (50 micrograms/kg i.v.), a venodilator, decreased mean circulatory filling pressure, resistance to venous return, mean blood pressure and total peripheral resistance, and increased heart rate. However, unlike MCI-154, nitroglycerin did not alter cardiac output and right atrial pressure. These results suggest that the venodilator effect of MCI-154, as well as the positive inotropic and vasodilator effects, could potentially benefit patients with congestive heart failure.