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.     

Hemodynamic actions of nicorandil, a new antianginal agent, in the conscious dog

We studied the hemodynamic effects of nicorandil (SG-75) and nitroglycerin in conscious dogs before and after beta-adrenergic receptor blockade. Nicorandil (25-300 micrograms/kg/min) and nitroglycerin (5-60 micrograms/kg/min) produced increases in heart rate and decreases in aortic and left ventricular pressures. In the doses studied, nicorandil caused greater decreases in aortic and left ventricular systolic pressure than nitroglycerin; however, nitroglycerin reduced left ventricular end-diastolic pressure to a greater degree. Nicorandil but not nitroglycerin produced an increase in cardiac output secondary to an increase in heart rate. Global contractility (peak positive dP/dt) was increased in a dose-related manner during nicorandil infusion before beta-blockade. In spite of marked hypotensive responses to higher doses, mean coronary blood flow and coronary conductance were increased by nicorandil. In contrast, both parameters were reduced during nitroglycerin infusion. The effects of nicorandil on coronary blood flow were unaltered by beta-adrenergic blockade, suggesting that metabolic autoregulation is not an important mediator of the response. Nicorandil (75-300 micrograms/kg/min) produced a dose-related increase in transmural myocardial blood flow with the greatest increases in perfusion occurring in the subepicardium and midmyocardium. The results of the present study demonstrate that despite structural similarities, nicorandil and nitroglycerin have varying hemodynamic spectra.     

Acute haemodynamic effects of felodipine in congestive heart failure

Summary The haemodynamic effects of felodipine 0.1 mg/kg p.o., a new arteriolar dilator, were studied in 7 patients with severe congestive heart failure of NYHA Class IV (Group A) and in 3 patients in Class II–III (Group B). In Group A, measurements were made before and 1 and 4 h after felodipine administration. There was a substantial fall in systemic arterial pressure, which was not associated with a compensatory tachycardia. In fact, there was a fall in heart rate from 92 to 82 beats/min 1 h after drug administration. The pulmonary capillary wedge pressure was reduced from 22 to 14 mm Hg and the cardiac index and stroke volume index rose significantly. Consequently, there was a marked reduction in systemic vascular resistance. In Group B measurements were performed at rest and during exercise before and 1 h after felodipine. The pulmonary wedge capillary pressure during exercise was lower than in the control situation. Coronary sinus flow was increased and there was a pronounced fall in coronary vascular resistance. The results would suggest that felodipine, by virtue of its ventricular unloading potency, might be a valuable drug in the treatment of congestive heart failure.     

Evaluation of intravenous amrinone: the first of a new class of positive inotropic agents with vasodilator properties

Amrinone is the first noncatecholamine inotropic agent with substantial vasodilating properties to be approved by the Food and Drug Administration. Its use in acute congestive heart failure (CHF) is associated with significant increases in cardiac index, reductions in pulmonary capillary wedge pressure and systemic vascular resistance and little or no change in mean arterial pressure. Pharmacokinetic studies of amrinone report an elimination half-life of 2.6-8.3 hours, with slower elimination more likely in patients with compromised renal or hepatic function. Intravenous bolus doses of 0.75-3.5 mg/kg followed by infusions of 5-20 micrograms/kg/min produce hemodynamic improvements similar to those with dobutamine. Side effects with amrinone therapy are usually mild, but thrombocytopenia occurs in 2.4% of patients. Amrinone appears equally as efficacious as dobutamine in the management of acute CHF, but its role in therapy depends on efficacy and side effect data in greater numbers of patients.     

Infusion of atrial natriuretic peptide to patients with congestive heart failure

Atrial natriuretic peptides (ANP) exert vasodilating and natriuretic actions. The present study was undertaken to test the effect of low dose infusions of synthetic ANP on hemodynamic and humoral variables of patients with severe heart failure. Eight patients, aged 26 to 71 years, with severe congestive heart failure due to ischemic heart disease or idiopathic dilated cardiomyopathy were included in the study. Synthetic human (3-28) ANP was infused at doses ranging from 0.5 to 2 micrograms/min for up to 3 h. Pulmonary capillary wedge pressure fell from 24 +/- 1 to 16 +/- 2 mm Hg (mean +/- SEM) (p less than 0.01) and cardiac index tended to rise from 2 +/- 0.2 to 2.3 +/- 0.2 L/min/m2 (NS), while blood pressure and heart rate did not change. One patient experienced a marked drop in pulmonary capillary wedge and arterial blood pressure that necessitated the administration of saline. ANP infusion did not alter plasma renin activity or plasma aldosterone, norepinephrine, or vasopressin levels. It decreased plasma epinephrine levels from 0.472 +/- 0.077 to 0.267 +/- 0.024 nmol/L (p less than 0.05). Plasma ANP levels were markedly elevated in all patients before initiating the infusion. They had no predictive value for the hemodynamic response to exogenous ANP. No correlation was observed between the hemodynamic effects of ANP and those induced by the subsequently administered converting enzyme inhibitor captopril, which seemed to improve cardiac function more consistently.(ABSTRACT TRUNCATED AT 250 WORDS)     

Intravenous captopril in congestive heart failure

Hemodynamic and neurohumoral effects of intravenous captopril were studied in ten patients with severe chronic congestive heart failure (NYHA Functional Class III and IV). Incremental bolus doses of captopril, titrated to a maximum cumulative dose of 15 mg, were given at 10-minute intervals. Systemic arterial pressure, mean pulmonary capillary wedge pressure, systemic vascular resistance, mean pulmonary artery pressure, and heart rate decreased (P less than .05). Cardiac index and stroke volume index increased (P less than .05). Maximum hemodynamic effects occurred after cumulative doses of 7 mg and were seen within 30 minutes after initiation of therapy; responses persisted for 30-90 minutes after the last dose. Plasma renin activity increased, and plasma atrial natriuretic factor concentration decreased. No adverse effects were observed with the use of intravenous captopril. Thus, intravenous captopril produces rapid and favorable hemodynamic improvement in advanced heart failure patients.     

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.     

Use of intermittent dobutamine infusion in congestive heart failure

Dobutamine is a cardiac inotrope useful in the acute treatment of congestive heart failure. Dobutamine improves cardiac output, decreases pulmonary wedge pressure, and decreases total systemic vascular resistance with little effect on heart rate or systemic arterial pressure. Clinical benefit has been observed to continue for weeks to months following the discontinuation of dobutamine. In addition, tolerance to dobutamine has been observed when infusions last 72 hours or longer. This has led investigators to study the effectiveness of chronic intermittent infusions of dobutamine. Studies utilizing dobutamine doses ranging from 1.5 to 15 micrograms/kg/min for 4-48 h/wk have shown sustained clinical and hemodynamic improvement in patients suffering from congestive heart failure. The mechanism by which dobutamine creates this effect is not entirely known; however, studies suggest dobutamine exerts a physical conditioning effect similar to exercise. Dobutamine infusions have also been associated with morphological and metabolic changes in myocardial tissue consistent with improved myocardial structure and function. The intermittent use of dobutamine may be beneficial in the chronic treatment of congestive heart failure in patients who fail to respond to conventional therapy.     

Intermittent dobutamine hydrochloride infusions in outpatients with chronic congestive heart failure

Patients with severe chronic congestive heart failure were treated with intermittent dobutamine hydrochloride infusions administered on an outpatient basis with a portable infusion device. Eleven patients (eight women and three men), ages 28-71 years, were given initial dobutamine hydrochloride infusions at a rate of 1-2 micrograms/kg/min, and the dose was gradually increased to a maximum dose of 15 micrograms/kg/min. Patients were considered dobutamine responders if their cardiac output increased by at least 30% and pulmonary-capillary wedge pressure did not rise. After a sustained hemodynamic response was demonstrated, the infusion was discontinued to assess the patients' symptoms during drug-free intervals. The patients were instructed and trained in proper catheter care after a venous-access catheter was surgically implanted. Patients were also shown how to use the ambulatory infusion pump. The patients were treated with long-term intermittent dobutamine hydrochloride infusions for 3-24 months. All patients adjusted easily to the routine of catheter and pump care and drug administration. The mean dose of dobutamine hydrochloride resulting in the maximum improvement in cardiac index was 9.4 micrograms/kg/min. All patients observed an improvement in their symptoms of congestive heart failure during the drug infusions and the intervals between the infusions. There was a mean reduction of 1.2 in New York Heart Association functional class. There were 18 congestive heart failure-related hospital readmissions among the 11 patients during 108 cumulative months of long-term dobutamine therapy. The intermittent administration of dobutamine hydrochloride via a portable infusion system appears to have improved the functional capacity of the 11 patients studied. This may be a viable treatment alternative for selected ambulatory patients with severe heart failure who demonstrate hemodynamic improvement with dobutamine.     

Hemodynamic effects of a constant intravenous infusion of piroximone in patients with severe congestive heart failure

The hemodynamic effects and serum levels of piroximone (MDL 19,205), a new inotropic agent with vasodilating properties, were measured in 10 patients with chronic severe congestive failure during a constant 48-h infusion. The initial five patients (group A) received piroximone at 10 micrograms/kg/min; however, because a sustained increase in heart rate greater than or equal to 25% from baseline developed in two patients and an episode of paroxysmal supraventricular tachycardia developed in another, the last 5 patients (group B) received an 8 micrograms/kg/min infusion. Because the steady-state hemodynamic alterations of group A prior to the onset of tachyarrhythmias were similar to those of group B, these results were combined. A significant increase in cardiac output from 3.65 +/- 0.31 (SE) to 5.20 +/- 0.49 L/min and decrease in pulmonary capillary wedge pressure (27 +/- 2 to 20 +/- 2 mm Hg), right atrial pressure (18 +/- 2 to 11 +/- 2 mm Hg), and systemic vascular resistance (1811 +/- 172 to 1293 +/- 80 dynes.s.cm-5) occurred (all p less than 0.05) without a significant change in mean arterial pressure. The peak plasma piroximone level was lower in the eight patients who did not develop a sustained increase in heart rate greater than or equal to 25% above baseline (2.1 +/- 0.5 micrograms/ml; range 1.6-2.9 micrograms/ml) than in the two who did (5.0 and 5.8 micrograms/ml). The latter two patients had the highest serum creatinine levels in the study population.(ABSTRACT TRUNCATED AT 250 WORDS)     

乌拉地尔对风心病肺动脉高压的急性降压效应

目的 :观察乌拉地尔对合并有肺动脉高压的风心病患者右心血流动力学的影响。方法 :以风心病继发肺动脉高压的34例患者为研究对象 ,观察静脉注射0 4mg/kg乌拉地尔后10、40、60min右心血流动力学参数及体循环血压的变化。结果 :乌拉地尔能显著降低风心病患者的肺动脉压、肺循环阻力、肺毛细血管楔嵌压及体循环血压 ,但对肺循环的影响要明显强于体循环 ,且几乎不引起心率及心输出量的改变。未见严重不良反应发生。结论 :乌拉地尔治疗术前风心病肺动脉高压可能有很好的临床效应     

Study on the effectiveness of toborinone (OPC-18790) in the treatment of heart failure in patients following cardiac surgery.

Toborinone ((+/-)-6-[3-(3,4-dimethoxybenzylamino)-2-hydroxypropoxy]-2(1H)-qui nolinone, CAS 128667-95-8, OPC-18790), a novel cardiotonic agent with an inhibitory action on phosphodiesterase, is known to have a potent positive inotropic action with no positive chronotropic effect. The effectiveness of this drug in the treatment of heart failure occurring immediately after extracorporeal circulation (ECC) in cardiac surgery was investigated. The study was conducted in 12 patients with valvular heart disease showing a cardiac index (CI) of below 2.8 l/min/m2 and/or pulmonary capillary wedge pressure (PCWP) or pulmonary arterial diastolic pressure (PAD) of above 8 mmHg immediately after extracorporeal circulation. In group A (n = 6), toborinone was infused at a rate of 40 micrograms/kg/min for the first 5 min and then at 10 micrograms/kg/min for 85 min. In group B (n = 6), the drug was infused at a rate of 10 micrograms/kg/min for the entire 90 min. CI, mean systemic arterial pressure (mSAP), mean pulmonary artery pressure (mPAP), CVP, PCWP, and heart rate were measured at 5, 15, 30, 60, and 90 min after the start of infusion. The infusion volume required to maintain a constant PCWP was also estimated. In group A, CI increased rapidly and significantly from the baseline of 2.48 +/- 0.23 l/min/m2 to 3.57 +/- 1.07 l/min/m2 at 5 min after the start of infusion, and at that time mSAP was slightly decreased. In group B, CI increased gradually from the baseline of 2.53 +/- 0.18 l/min/m2 to 3.08 +/- 0.34 l/min/m2 at 15 min after the start of infusion, but almost no change was seen in mSAP. During the first 30 min, group A required a significantly larger infusion volume (983 +/- 395 ml) than group B (475 +/- 184 ml). From 30 to 90 min after the start of infusion, CI remained increased to similar levels in both groups and mSAP levels were also similar. There were no significant differences between the two groups in any other parameter. Continuous infusion of toborinone appears to be effective for treating heart failure occurring immediately after ECC in cardiac surgery. Initial loading at a rate of 40 micrograms/kg/min rapidly increased CI but was accompanied by mild hypotension. Constant infusion at 10 micrograms/kg/min brought about a more gradual effect that was similar to that of loading at 40 micrograms/kg/min, but without inducing hypotension. Thus, infusion at 10 micrograms/kg/min is considered preferable in order to avoid a larger-than-necessary infusion volume.     

Hemodynamic Responses to Indoramin at Rest and During Exercise in Congestive Heart Failure

Twenty patients with congestive heart failure underwent hemodynamic studies before and over 10 hours after the administration of 25, 50, and 75 mg of indoramin, an alpha₁-adrenergic antagonist. Hemodynamic studies were repeated during exercise after the administration of the optimal dose of indoramin. The drug reduced resting and exercise pulmonary capillary wedge pressure, right atrial pressure, systemic blood pressure and vascular resistance, and pulmonary artery pressure and vascular resistance. Resting and exercise stroke volume and cardiac output rose in response to the fall in vascular resistances. Heart rate was not altered at rest or during exercise. The first dose of the alpha₁ blocker indoramin elicits a significant reduction in ventricular preload and afterload and augmentation of ventricular performance in patients with congestive heart failure.     

Ultrastructural localization of nicorandil in the heart of rats

To examine the intracellular localization of nicorandil in the heart, [14C]nicorandil and [3H]nicorandil (3 mg kg(-1)) were given orally to rats. The maximum concentration (Cmax) of nicorandil in the myocardium was reached 15 min after the oral dosing. At this time subcellular localization of nicorandil was examined. Nicorandil and its denitrated metabolite, SG-86 were found in mitochondrial fractions and in cytosolic and microsomal fractions of the heart. Electron-microscopic autoradiograms recorded 15min after oral dosing of 3 mg kg(-1) [3H]nicorandil to rats also showed the presence of silver grains generated by the radioactive nicorandil or its metabolites in the mitochondria of the heart. We conclude that nicorandil given orally to rats is distributed in mitochondria of the heart.     

Milrinone. A preliminary review of its pharmacological properties and therapeutic use

Milrinone is a bipyridine derivative of amrinone, with approximately 10 to 75 times greater positive inotropic potency, and separate direct vasodilatory properties. As with amrinone, the relative importance of these properties to treatment of congestive heart failure still remain controversial. The mode of action of milrinone appears to be due in part to selective inhibition of a specific cardiac phosphodiesterase with a subsequent increase in intracellular cyclic adenosine monophosphate and alteration in intracellular and extracellular calcium transport. Clinical experience has involved both short and long term treatment of a limited number of patients with moderate to severe congestive heart failure refractory to conventional therapy. Milrinone has usually been administered as intravenous bolus doses (12.5 to 75 micrograms/kg) and/or continuous intravenous infusion (0.5 microgram/kg/min), or orally (30 to 40 mg/day in divided doses). Milrinone rapidly improves cardiac performance by enhancing myocardial contractility, and by decreasing systemic vascular resistance (afterload), left ventricular filling pressure (preload), and pulmonary arterial pressure. Exercise performance improvement occurs with enhancement of left ventricular performance but without a significant increase in myocardial oxygen consumption or significant decrease in mean arterial pressure. Milrinone has been compared with dobutamine, nitroprusside and captopril in preliminary short term studies in patients with severe congestive heart failure. Milrinone significantly increased stroke work index and decreased left ventricular filling pressure compared to nitroprusside. When compared with dobutamine, both drugs improved cardiac index (to a similar degree), but milrinone significantly reduced right atrial pressure, pulmonary capillary wedge pressure and left ventricular end-diastolic pressure. One small study suggests that short term effects of intravenous milrinone may be superior to those of oral captopril, and it appears that the addition of captopril to milrinone therapy may produce a synergistic haemodynamic effect. Preliminary long term studies suggest that tolerance to the haemodynamic effects of milrinone does not occur, and that the drug is well tolerated and without the thrombocytopenic effects, fever and gastrointestinal complications observed with amrinone. However, it has not been demonstrated that milrinone improves the prognosis of the disease or the overall mortality and its propensity to produce arrhythmias has not been fully agreed upon.(ABSTRACT TRUNCATED AT 400 WORDS)     

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.     

CARDIOVASCULAR EFFECTS OF ISOSORBIDE DINITRATE INFUSED INTRAVENOUSLY INTO ANAESTHETIZED DOGS

The cardiohaemodynamic response and the development of tolerance to isosorbide dinitrate (ISDN) were examined in anaesthetized, open-chest dogs. ISDN, infused intravenously (i.v.) for 2 h at a rate of 10 or 30 micrograms/kg per min, decreased systemic blood pressure (systolic, mean and diastolic; SBP), left ventricular (LV) systolic and end-diastolic pressure, LVdP/dt max, pressure-rate product and coronary blood flow. No significant changes in heart rate (HR) and coronary vascular resistance were observed. Intravenous ISDN significantly attenuated the vasodilator effect of bolus intracoronary (i.a.) glyceryl trinitrate (GTN, 1 micrograms), and ISDN (30 micrograms), whereas that of bolus i.a. nicorandil (mononitrate, 20 micrograms) remained unaffected. Just after acute tolerance towards i.a. ISDN was provoked 1 h after starting ISDN infusion (30 micrograms/kg per min, i.v.), the combined infusion of ISDN (i.v.) and nicorandil (30 micrograms/kg per min) was instigated for a further hour. Also, 1 h after the onset of vehicle infusion (i.v.), the combined infusion of vehicle and nicorandil (30 micrograms/kg per min, i.v.) was started. There were essentially no significant differences between the corresponding values concerning the coronary vascular responses obtained from the two combined infusion groups.     

Pimobendane (UD-CG 115 BS) in the treatment of severe congestive heart failure. An acute haemodynamic cross-over and double-blind study with two different doses.

1. We compared the effects of two doses (5 and 10 mg) of oral pimobendane (UD-CG 115) on haemodynamics in eight patients suffering from chronic congestive heart failure. The two doses were given according to a randomized cross-over double-blind protocol; haemodynamics and plasma levels of pimobendane and its main metabolite UD-CG 212, were determined 1, 2, 3, 5, 7, 9, 11 and 12 h after each dose. 2. Both doses significantly improved the left and right ventricular functions of these patients, with a peak action 3 h after drug intake and long duration (more than 12 h). A significant dose-effect relationship was observed only for pulmonary wedge pressure and right atrial pressure. Significant correlations were found between UD-CG 212 plasma levels and cardiac index (r = 0.54, P less than 0.05), and pulmonary wedge pressure (r = 0.74, P less than 0.001); no correlation was found between these haemodynamic variables and pimobendane plasma levels. 3. One patient developed a transient drop in blood platelets together with a cutaneous rash, while three others had a transient and mild decrease of thrombocytes. 4. In conclusion, pimobendane improved right and left ventricular functions in severe heart failure. Both doses (5 and 10 mg) were effective. The higher dose induced marked improvement of the haemodynamic variables but the difference between doses was only significant for right atrial and pulmonary wedge pressures.     

Rapid and brief tolerance to (+)- and (-)-nicotine in unanesthetized rats

When given intravenously to unanesthetized rats as a bolus dose, (-)-nicotine produced a dose-related rise in blood pressure and fall in heart rate in the dose range of 5-40 micrograms/kg. Tolerance did not develop when doses were given at 30 min intervals. At the highest dose, the effects on heart rate persisted. In addition, severe arrhythmias and apnea were observed. (+)-Nicotine at 100 micrograms/kg produced effects similar to 10 micrograms/kg of (-)-nicotine. When given at 1 min intervals, tolerance quickly developed after only 6 injections at 5 micrograms/kg and after 4 injections at 10 micrograms/kg. Tolerance to (+)-nicotine also developed rapidly and was no longer evident at 5 min. The results suggest the tolerance is related to frequency of administration and dose. The implication of these results are discussed with regard to cardiovascular disease and dependence. In addition, we postulate that the relatively low degree of biological stereoselectivity of the optical isomers of nicotine, compared with that of the enantiomers of morphine, is due to the simplicity and flexibility of the nicotine molecule. It can be shown using Dreiding models that the nitrogen atoms in the enantiomers are nearly superimposable.     

The acute hemodynamic, hormonal, and pharmacokinetic properties of oral spirapril in patients with moderate to severe heart failure.

The acute hemodynamic, hormonal, and pharmacokinetic responses to the oral angiotensin-converting enzyme (ACE) inhibitor spirapril were studied in 15 patients with moderate to severe congestive heart failure in a baseline controlled dose-ranging study. Doses of 0.3, 1.0, 1.5, 3.125, and 6.25 mg were investigated for 24 h in three groups of five patients each. All doses demonstrated a significant reduction in serum ACE, even after 24 h. Significant reductions in mean arterial pressure, systemic vascular resistance, and pulmonary capillary wedge pressure were observed with doses greater than 1.0 mg spirapril. Maximal significant hemodynamic effects occurred approximately 4-6 h after drug administration. The plasma concentrations of spirapril and its metabolite spiraprilate were dose-dependent. After administration of spirapril, the quick rise to the peak level of spiraprilate suggests rapid metabolism of spirapril into spiraprilate and a slow elimination of this metabolite. No severe hypotension or other serious side effects occurred in the patients studied. The results indicate that spirapril may be expected to be an effective drug in the treatment of congestive heart failure. From our findings we conclude that 1.5 mg spirapril is an optimal starting dose in patients with moderate to severe congestive heart failure.