Effects of positive inotropic drugs on the frequency of contraction of the isolated atria: influence of dose regimen and age

The dose-activity relationship of various positive inotropic drugs has been investigated in the spontaneously beating right atria of the rat. The influence of dose regimen and age has been evaluated. There is a significant difference between the maximal response of single and cumulative dose experiments with amrinone (P less than 0.05) and dobutamine (P less than 0.001) in animals aged 2 months and in dopamine (P less than 0.001) in animals aged 4 months. The maximum response is lowered significantly with age for isoprenaline with single (P less than 0.05) and for dopamine and dobutamine with cumulative dosing (P less than 0.001). In the single dose study the response is achieved within 4 min. for isoprenaline, noradrenaline, dobutamine, xamoterol and amrinone, but not until after 14 min. for prenalterol. It is concluded that both age and methods used in the study of pharmacodynamics are important. Thus when comparing effects the use of the same method and tissue from rats of the same age is necessary.     

Myocardial pharmacodynamics of dopamine, dobutamine, amrinone and isoprenaline compared in the isolated rabbit heart

The isolated spontaneously beating rabbit heart was used for comparing the myocardial effects of isoprenaline, dobutamine, dopamine and amrinone. Both isoprenaline and dobutamine produced a progressive concentration-dependent increase in contractility from 100% to a maximum of about 200% (pD2 7.81 and 7.01, respectively) as measured by the increase in isotonic contraction rate. The simultaneous augmentations in contraction amplitude reached maxima of about 127 and 143% (pD2 7.83 and 7.05) for each of the drugs and the heart frequency rose to 202 and 162% (pD2 7.80 and 6.63), respectively. The accompanying oxygen consumption increased from 100 to 194% (pD2 7.70) for isoprenaline and to only 177% (pD2 6.36) for dobutamine. Coronary flow rate rose to 153 and 134%, respectively. Dopamine increased the contraction rate to 181% (pD2 6.26), contraction amplitude to about 122% (pD2 6.25) and heart rate to 162% (pD2, 5.85), while oxygen consumption rose to a maximum of 202% (pD2 5.69). Coronary flow rate rose to 156%. In contrast amrinone produced an unexpected slowly progressing decrease in contraction rate and contraction amplitude to about 66% (pD2 4.45 and 4.01, respectively). Oxygen consumption increased to 159% (pD2 4.10) and coronary flow rate to 210%. The positive inotropic effect of dobutamine thus equalled that of isoprenaline but with a distinct lower concomitant increase in heart frequency and oxygen consumption which may reflect a better myocardial efficiency during the action of dobutamine.     

复方丹参注射液联合多巴胺和多巴酚丁胺治疗新生儿硬肿症临床观察

目的：观察复方丹参注射液与多巴胺、多巴酚丁胺对新生儿硬肿症的临床疗效。方法：新生儿硬肿症患儿102例，治疗组52例，对照组50例。两组均采用常规治疗，治疗组加用复方丹参注射液与小剂量多巴胺、多巴酚丁胺治疗，比较两组治疗效果。结果：治疗组症状体征消失时间、住院时间均优于对照组（P均〈0.05）。总有效率治疗组94．2％，对照组74．0％，两组比较差异有统计学意义（P〈0．01）。结论：复方丹参注射液联合多巴胺和多巴酚丁胺可提高新生儿硬肿症的治疗效果，不良反应小，使用安全。     

Impaired vasodilatation response to amrinone in the forearm of patients with congestive heart failure: role of endothelium-derived nitric oxide

Recent in vitro experiments have shown that amrinone enhances the release of nitric oxide (NO) from the endothelium and induces NO mediated vasodilatation. This in vivo study examined whether amrinone causes vasodilatation mediated by endothelium-derived NO, and whether this effect is attenuated in patients with endothelial dysfunction. Eight patients with congestive heart failure and 10 age- and sex-matched healthy volunteers were studied. Forearm blood flow (FBF) was measured before and during infusion of drugs of acetylcholine, amrinone, and nitroglycerin in incremental doses. After the completion of these measurements, 100 micromol of N(G)-monomethyl-L-arginine (L-NMMA) was infused intraarterially. Thereafter, FBF measurement in response to incremental doses of amrinone was repeated. Infusion of incremental doses of amrinone caused a comparable increase in amrinone plasma concentration in both groups. Baseline FBF was 3.2+/-0.79 ml/min/100 ml in controls vs. 2.91+/-0.79 ml/min/100 ml in patients (p = 0.43). In both groups, FBF increased in response to acetylcholine, amrinone, and nitroglycerin. During infusion of the highest dose of nitroglycerin, FBF was not different between the two groups (p = 0.51); however, FBF during infusion of the highest doses of acetylcholine and amrinone was significantly less in patients than in controls: 9.75+/-2.69 vs. 24.87+/-8.65 ml/min/100 ml (p < 0.001) and 3.79+/-1.21 vs. 7.15+/-2.06 ml/min/100 ml (p < 0.001), respectively. L-NMMA significantly depressed the increase in FBF in response to amrinone in controls, but not in patients. In conclusion, the selective PDE III inhibitor, amrinone, has endothelium-derived NO-mediated vasodilating effects in addition to direct effects. This property may be impaired in patients with endothelial dysfunction.     

Comparison of the cardiovascular actions of Cordemcura, isoprenaline and dobutamine in cats

A comparative study was made of the closed-chest cardiovascular effects of Cordemcura (amrinone), isoprenaline, and dobutamine in anaesthetized cats (n = 17). The haemodynamic parameters used for this purpose include: maximum rate of both left ventricular pressure rise (dp/dtmax) and decline (dp/dtmin), heart frequency (HFR), arterial blood pressure, both systolic (Ps) and diastolic (Pd). The maximum changes of the haemodynamic parameters after increasing iv. bolus injections of the test substances were used to plot the dose-effect curves of the single parameters for each substance. All the 3 pharmaceuticals caused dp/dtmax to rise, with quantitative differences being found. Moreover, quantitatively different positive chronotropic effects have been found. The influence on the remaining haemodynamic parameters was different both in the quantitative and in the qualitative sense. The results were discussed with regard to comparing the cardiovascular effects of Cordemcura with isoprenaline and dobutamine.     

Increased tracheal responsiveness to beta-adrenergic agonist and antagonist in ovalbumin-sensitized guinea pigs

Despite the controversy of bronchial responsiveness to beta2-agonist drugs in asthma, in a previous study we have shown increased responsiveness of asthmatic tracheobronchial tree to isoprenaline. Therefore, in the present study, tracheal responsiveness to isoprenaline and also beta-adrenergic receptor blockade were studied in sensitized guinea pigs. An experimental model of asthma was induced in guinea pigs by sensitization of animals with injection and inhalation of ovalbumin (OA). The responses of tracheal chains of sensitized and control animals to cumulative concentrations of isoprenaline (I) in the absence and presence of 10 nmol/l propranolol were measured, and the effective concentration of I causing 50% of maximum response (EC50 I) was obtained. The propranolol blockade (CR - 1) was calculated by: (post-propranolol EC50 I/EC50 I) - 1. Tracheal responses of sensitized and control animals to cumulative concentrations of methacholine (M) were also measured and EC50 M were obtained. The tracheal responses of sensitized guinea pig to isoprenaline was significantly higher than that of the control animals (EC50 I for sensitized and control animals were 0.24 +/- 0.04 and 0.58 +/- 0.07 micromol/l, respectively; p < 0.001).The beta-adrenergic receptor blockade by propranolol (CR - 1) was also significantly higher in sensitized guinea pigs than that of the control animals (p < 0.001). The results of this study indicate an increased tracheal response to beta-adrenergic-stimulating drug and enhancement of beta-adrenergic blockade by propranolol in the sensitized guinea pig.     

Low dose anandamide affects food intake, cognitive function, neurotransmitter and corticosterone levels in diet-restricted mice

This investigation reports the possible role of the endocannabinoid anandamide on modulating the behavioral and neurochemical consequences of semi-starvation. We studied the effect of very low dose anandamide (0.001 mg/kg) administration on food intake, cognitive function and catecholaminergic and serotonergic pathways in two murine brain areas concerned with appetite (hypothalamus) and learning (hippocampus), and the peripheral corticosterone response to the stress of 40% diet restriction. Anandamide-treated mice consumed 44% more food (P<0.05) during 1 week of 2.5-h feeding each day. In the hypothalamus, there were significantly increased concentrations of norepinephrine (P<0.01), dopamine (P<0.05) and 5-hydroxytryptamine (5-HT) (P<0.001). In the hippocampus, anandamide increased significantly norepinephrine and dopamine, but decreased 5-HT (all at P<0.001). Diet restriction was accompanied in both areas by a significant decrease in all neurotransmitter concentrations that were partially restored by anandamide for dopamine and 5-HT, but not for norepinephrine. In animals on diet restriction, anandamide significantly improved impaired maze performance. Norepinephrine turnover and plasma corticosterone levels were also raised significantly by anandamide. The fact that low dose anandamide improved food intake, cognitive function and reversed some of the neurotransmitter changes caused by diet restriction, might have implications for the treatment of cachexia associated with acquired immunodeficiency syndrome (AIDS) and cancer, for mood changes sometimes associated with dieting, and in the extreme case, of patients with anorexia.     

Contribution of the vagus to the haemodynamic responses following intravenous boluses of isoprenaline.

1 Eight healthy subjects (six male, two female, aged 18-21 years) received graded intravenous bolus injections of isoprenaline sulphate. Heart rate and intra-arterial blood pressure were continuously monitored PRE- and POST-atropine (0.04 mg/kg). 2 PRE-atropine, an increase in heart rate of 25 beats/min was produced by 2.15 +/- 0.53 micrograms of isoprenaline and was associated with a fall in mean, systolic and diastolic pressures (18.9 +/- 2.8, 17.7 +/- 3.4 and 20.4 +/- 2.3 mm Hg respectively). 3 POST-atropine, the heart rate dose response curve was shifted to the right so that the dose of isoprenaline which increased heart rate 25 beats/min PRE-atropine, produced a significantly smaller heart rate rise of 20.3 +/- 1.7 beats/min (P less than 0.001). This was associated with a shift of the blood pressure dose-response curves to the left, and larger falls in mean, systolic and diastolic pressures (30.9 +/- 2.8, 31.8 +/- 3.3, 30.1 +/- 3.3 mm Hg respectively; P less than 0.01). 4 It is concluded that there is a significant contribution from a reflex withdrawal of cardiac vagal tone, to the tachycardia produced by a bolus of isoprenaline.     

Vascular responses to dopamine and dobutamine in the awake calf during constant aortic flow or constant aortic pressure.

We investigated vascular effects of dopamine and dobutamine infusions in awake calves implanted with the Penn State total artificial heart (TAH). This preparation uniquely permits independent servo-control of cardiac output (CO) and arterial blood pressure (BP). Thirty-two studies (22 with dopamine and 10 with dobutamine) were performed in four juvenile calves from 1 to 4 months after TAH implantation. Studies were performed in one of two TAH operating conditions: (a) constant aortic flow, in which the CO is fixed and aortic BP varies with systemic vascular resistance (SVR), or (b) constant pressure, in which the CO varies to maintain a constant BP when SVR changes. During both constant flow and constant pressure studies, dopamine caused a dose-dependent increase and dobutamine caused a dose-dependent decrease in SVR. There was no difference in the SVR response between constant flow or constant pressure conditions at any dose of dopamine or dobutamine (p greater than 0.05). The infusion doses of dopamine required to raise the SVR 20 and 50% during constant flow studies were 7.2 and 12.4 micrograms.kg-1.min-1, respectively. In constant pressure studies, these doses were 7.7 and 13.5 micrograms.kg-1.min-1. The infusion dose of dobutamine resulting in a 20% reduction in SVR was 27.2 micrograms.kg-1.min-1 in constant flow studies 26.2 micrograms.kg-1.min-1 in constant pressure studies. These data suggest that baroreflex and other indirect mechanisms are less important than direct vascular drug effects in this system.(ABSTRACT TRUNCATED AT 250 WORDS)     

Alpha-adrenergic effects of dopamine and dobutamine on the coronary circulation

After beta-adrenergic blockade, dopamine causes coronary vasoconstriction that is blocked by non-selective alpha-adrenergic antagonists. This study was carried out to determine the relative importance of alpha 1- and alpha 2-adrenoceptors in mediating coronary vasoconstriction in response to dopamine. Because dobutamine has been reported to cause alpha-adrenergic stimulation, the response to dobutamine was also examined. The circumflex coronary artery was cannulated and perfused at a constant blood flow rate in 14 dogs; coronary vasomotor responses were assessed from changes in perfusion pressure. Central effects were eliminated by vagotomy and stellate ganglionectomy; propranolol (1 mg/kg i.v.) was administered to block beta-adrenergic effects. The coronary responses to intracoronary bolus doses of dopamine and dobutamine were determined; the effects of selective alpha 1-blockade with prazosin (600 micrograms/kg i.v.) and selective alpha 2-blockade with idazoxan or rauwolscine (1-5 micrograms/kg per min intracoronary for 10 min) were examined. Dopamine produced dose-related coronary vasoconstriction; this response was not significantly altered by alpha 1-blockade with prazosin, but was abolished by the addition of alpha 2-adrenergic blockade with idazoxan or rauwolscine. Dobutamine did not produce coronary vasoconstriction at any dose tested. These data demonstrate that coronary vasoconstriction produced by dopamine is mediated through postjunctional alpha 2-adrenergic receptors.     

Effects of intraperitoneal administration of the GABA B receptor agonist baclofen on food intake in rats measured under different feeding conditions

The effects of intraperitoneal (i.p.) administration of the GABA(B) receptor agonist baclofen were assessed in rats under different feeding conditions. In Experiment 1, it was observed that baclofen (1-4 mg/kg) significantly (at least, P<0.05) increased cumulative food intake in non-deprived rats during the 120 min measurement period during the early light phase of the light-dark cycle. By contrast, during the early dark phase of the light-dark cycle in non-deprived rats, the 1mg/kg doses of baclofen significantly increased cumulative feeding at 30, 60 and 120 min (at least P<0.05), the 2mg/kg dose significantly increased feeding at 30 and 60 min (at least P<0.05) and the 4 mg/kg dose had no effects on feeding. In Experiment 2, baclofen (1-4 mg/kg) was found to produce no significant effects on food intake in rats that were food-deprived for 22 h. In Experiment 3, the effects of baclofen were investigated on food intake in 16 h food-deprived rats that had received an oral preload for 2h prior to drug administration. Baclofen (1-4 mg/kg) significantly increased cumulative food consumption (at least, P<0.05) only during the first 30 min after administration in these animals. The results of this study indicate that the effects of baclofen on food intake may be related to the state of hunger or satiety of the animals and the time during the light-dark cycle when the drug is administered.     

Comparative haemodynamic dose-response effects of dobutamine and amrinone in left ventricular failure complicating acute myocardial infarction

The comparative haemodynamic dose-response effects of intravenous (i.v.) amrinone and dobutamine were evaluated in 20 male patients with haemodynamic (pulmonary artery occluded pressure (PAOP) greater than 20 mm Hg) and radiographic left heart failure following a recent myocardial infarction. Following a 1-h control period, 10 patients were each randomised to amrinone (800, 1,600, or 3,200 micrograms/kg/h) or dobutamine (200, 400, or 800 micrograms/kg/h) sequentially infused for 30 min at each dose level; haemodynamic parameters were recorded at the end of each infusion period. Amrinone reduced systemic arterial blood pressure and vascular resistance index with a moderately increased heart rate; PAOP (-10 mm Hg; p less than 0.01) fell substantially without change in cardiac or stroke work indices. Dobutamine increased systemic arterial blood pressure, heart rate, and stroke work index at an unchanged PAOP; cardiac index (+0.7 L/min/m2; 25%; p less than 0.01) increased. Systemic vascular resistance index was significantly reduced by both drugs. Thus, dobutamine increased cardiac index at an unchanged PAOP; myocardial stroke work increased. Amrinone had lesser effect on cardiac pumping but reduced PAOP (preload) at an unchanged stroke work. The implications of these differential actions for the clinical therapy of myocardial infarction deserves further evaluation.     

Effect of amrinone in acute severe cardiac failure

5-Amino-(3,4'-bipyridine)-6(1H)-one (amrinone, WIN-40680, Wincoram) is a potent positive inotropic agent with vasodilator properties. Its positive inotropic effects are unaffected by propranolol and by pre-treatment with reserpine. The effect of intravenous amrinone was studied in 15 patients with acute severe cardiac failure (NYHA class IV) who had failed to respond adequately to treatment with cardiac glycosides, diuretics, vasodilators and catecholamines. Catecholamine dosage was held constant during the period of the study. This is the first report of standardised combination therapy with catecholamines and amrinone. Initially, a mean cumulative dose of 1.6 +/- 0.3 mg/kg of amrinone was administered during the 1st h. This was followed by a long-term infusion of 5-15 micrograms/kg.min. Hemodynamic parameters were monitored by invasive techniques for a minimum of 48 h. At the time of maximal effect, the cardiac index increased from 1.54 +/- 0.35 to 2.8 +/- 0.61 l/min.m2 (p less than 0.001), and the pulmonary arterial capillary pressure decreased from 31 +/- 7.1 to 23 +/- 7.6 mmHg (p less than 0.01). Heart rate and systemic mean arterial blood pressure showed no significant changes during treatment. These results indicate that amrinone may be effective in patients with acute severe cardiac failure refractory to catecholamines.     

Reduced contractile responses to forskolin and a cyclic AMP analogue in myocytes from failing human ventricle.

Myocytes were isolated from the right or left ventricles of failing and non-failing human hearts. Contractile responses to increasing concentrations of Ca2+, isoprenaline, forskolin and dibutyryl cyclic AMP (a lipophilic analogue of cyclic AMP) were determined. Responses were correlated with the age of the patient, and the severity of failure as defined by New York Heart Association class of symptoms (NYHA), left ventricular ejection fraction (LVEF), left ventricular end diastolic pressure (LVEDP) and dose of diuretics prescribed (diuretic class). The maximum contraction amplitude in high Ca2+ did not change with either age or severity of failure (n = 31-40 patients). Responses to isoprenaline (relative to Ca2+ in the same cell, isoprenaline/calcium ratio) decreased with increasing age (P < 0.001, n = 38), and increasing severity of disease (NYHA, P < 0.001, n = 38; LVEF, P < 0.001, n = 34; LVEDP, P < 0.001, n = 30; diuretic class, P < 0.01, n = 36). The decrease in forskolin/calcium ratio also correlated with age (n = 17, P < 0.005) and increasing severity (NYHA, P < 0.002, n = 17; LVEF, P < 0.05, n = 15; LVEDP, P < 0.02, n = 14; diuretic class, P < 0.05, n = 15). Multiple regression indicated that the contribution of age was greater than that of disease severity for both isoprenaline and forskolin responses. The dibutyryl cyclic AMP/calcium ratio did not change significantly with the age of the patient (P > 0.1, n = 13), or severity as defined by LVEDP (P = 0.05-0.1, n = 12) but did decrease with increasing NYHA class (P < 0.01, n = 13) or diuretics (P < 0.02, n = 12) or with low LVEF (P < 0.002, n = 12). Overall, neither forskolin nor dibutyryl cyclic AMP produced maximum responses greater than isoprenaline in myocytes from failing hearts. Where the response to isoprenaline was not limited by the appearance of arrhythmias, forskolin or dibutyryl cyclic AMP could give a significant (but small) increase in contraction over that with isoprenaline alone. These results provide evidence for a post-receptor defect in addition to beta-adrenoceptor desensitisation in myocytes from failing human heart.     

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

Amrinone is a bipyridine derivative with positive inotropic effects and vasodilatory properties. However, in the clinical setting of congestive heart failure, the relative contribution of these factors remains a matter of conjecture. Its mode of action appears to be related to alterations in extracellular and intracellular calcium balance, probably mediated by increased levels of tissue cyclic adenosine monophosphate and possibly involving a sodium-dependent pathway. Clinical experience has mostly been short term and is limited to a relatively small number of patients with severe congestive heart failure, refractory to conventional treatment. Amrinone rapidly improves cardiac performance by decreasing systemic vascular resistance (afterload), decreasing the determinants of left ventricular filling pressure (preload) and improving the cardiac contractility. Improvements in exercise performance and clinical symptomatology occur without an increase in heart rate or decrease in mean arterial pressure. Amrinone has been compared with dopamine, dobutamine, pirbuterol and prazosin in preliminary short terms studies in patients with severe congestive heart failure, although more studies are needed before any relative clinical advantages or disadvantages can be ascribed to amrinone. Initial experience suggests that the addition of vasodilators such as hydralazine and isosorbide dinitrate to amrinone therapy may confer additional haemodynamic benefits. Preliminary medium term studies suggest that tolerance to the haemodynamic effects of amrinone does not usually occur, but long term studies are needed to determine whether amrinone alters the normal progression of the disease and whether overall mortality is affected. Amrinone has usually been administered as intravenous bolus doses (totalling 1.5 to 3.6 mg/kg/day) and/or continuous intravenous infusion, with varied results. Generally, an oral dose greater than the intravenous dose is required to achieve an equivalent level of response. Reversible, usually asymptomatic, thrombocytopenia occurs in about 20% of patients treated with amrinone. Arrhythmias and gastrointestinal disturbances have been reported, but wider clinical experience is required to determine the side effect profile of the drug.     

Inotropic responses to human gene 2 (B29) relaxin in a rat model of myocardial infarction (MI): effect of pertussis toxin

Relaxin produces powerful inotropic and chronotropic responses in isolated atria. The effect of relaxin has been examined in a rat model of cardiac failure, induced by myocardial infarction (MI). Maximum inotropic responses to isoprenaline (sham 5.4+/-0.3 mN; MI 2.6+/-0.3 mN; P<0.001) and relaxin (sham 5.1+/-0.6 mN; MI 2.8+/-0.5 mN; P=0.013) were reduced in left atria following MI. No change in chronotropic responsiveness was observed in right atria. Pertussis toxin (PTX) treatment restored inotropic responses to isoprenaline (sham 5.5+/-1.3 mN; MI 5.8+/-1.0 mN; P=0.850) but not to relaxin. Instead, PTX reduced inotropic responses to relaxin in sham animals to the same level seen in the MI group (sham 3.2+/-1.7 mN; MI 2.8+/-0.6 mN; P=0.847). In right atria, PTX treatment did not affect the maximum chronotropic response to isoprenaline, but reduced responses to relaxin in both sham and MI animals. R3 relaxin and relaxin receptor (LGR7) mRNA was present in atria and left ventricle (LV) from sham and MI animals. R3 relaxin mRNA expression was increased in atria but not LV from MI animals. LGR7 mRNA expression was reduced in atria and LV from MI animals. PTX treatment in unoperated rats increased chronotropic responses (vehicle 184.3+/-5.3 beats min(-1); PTX 211.3+/-9.5 beats min(-1); P=0.029) and produced a rightward shift in the concentration-response curve to isoprenaline in left atria. PTX reduced inotropic (vehicle 3.3+/-0.7 mN; PTX 0.8+/-0.2 mN; P=0.005) and chronotropic (vehicle 130.2+/-8.1 beats min(-1); PTX 90.6+/-11.1 beats min(-1); P=0.012) responses to relaxin. 6 In left atria, relaxin produced a small increase in cAMP compared to those produced by isoprenaline and forskolin. However, PTX treatment significantly reduced relaxin-, isoprenaline- and forskolin-stimulated cAMP accumulation. Cardiac failure in MI animals caused a reduced inotropic response to both relaxin and (-)-isoprenaline. In non-MI animals, PTX treatment also reduced inotropic responses to relaxin. Differences between responses to (-)-isoprenaline and relaxin can be explained by changes in coupling efficiency occurring at the level of adenylate cyclase.     

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.     

Vasodilator responses to dopamine in rat perfused mesentery are age-dependent.

1. Dose-dependent vasodilator responses to dopamine, isoprenaline, noradrenaline, 3-isobutyl-1-methylxanthine (IBMX) and sodium nitroprusside were obtained in isolated perfused mesentery preparations, taken from reserpine-treated rats of different ages. The preparations were pretreated with phenoxybenzamine (1 microM) and perfused with physiological salt solution containing cocaine (10 microM), additional KCl (20 mM) and vasopressin (0.1 microM). 2. Vasodilator responses to dopamine were abolished by the dopamine1 (DA1)-selective antagonist SCH 23390 (10 nM) and those to isoprenaline by propranolol (1 microM), but the vasodilator responses to noradrenaline were abolished only when SCH 23390 and propranolol were used together. This indicated that dopamine was acting via DA1-receptors, isoprenaline via beta-adrenoceptors and that noradrenaline could act via DA1-receptors and beta-adrenoceptors in this preparation. 3. Responses to all the vasodilator drugs decreased in magnitude between the ages of 1 and 2 months. Responses to dopamine declined further in 4 month-old rats and were negligible at 6 or 22-24 months of age. Responses to isoprenaline were well maintained up to 6 months of age, but were negligible at 22-24 months. 4. It is concluded that, in the rat mesenteric vasculature, there is a non-specific decline in responses to vasodilator drugs during development (1 to 2 months). Subsequently there is a specific decline in DA1-receptor-mediated and beta-adrenoceptor-mediated responses; the former are lost at an earlier age than the latter. This different time course suggests that age influences receptor numbers, or their coupling to adenylate cyclase, rather than a post-receptor event in the adenylate cyclase/cyclic AMP pathway.     

The handling of five catecholamines by the extraneuronal O-methylating system of the rat heart

In a comparative study, the handling of five catecholamines by the extraneuronal O-methylating system of the rat heart was determined; all rats were pretreated with reserpine, monoamine oxidase and neuronal uptake were inhibited in all experiments. Hearts were perfused for 7 min with a tracer concentration of 3H-(+/-)-isoprenaline, either in the absence or in the presence of unlabelled catecholamines (which reduced the O-methylation of the tracer amine). IC50's were determined for unlabelled catecholamines and then converted to "half-saturating outside concentrations", i.e., to those concentrations in the perfusion fluid that half-saturate the intracellular catechol-O-methyl transferase (COMT). The values for the (-)-isomers of dobutamine, isoprenaline, adrenaline and noradrenaline and that for dopamine were low and rather similar (between 0.67 and 2.7 mumol/l). Stereoselectivity for isoprenaline probably reflected the preference of uptake2 for the (-)-isomer. The effects of (-)- and (+)-dobutamine indicated that both isomers are a) transported by uptake2 and b) good substrates of COMT. The Vmax for O-methylation [determined for 3H-(+/-)-isoprenaline, 3H-(+/-)-adrenaline, 3H-(+/-)-noradrenaline and 3H-dopamine] was rather similar for all four catecholamines. It is concluded that the extraneuronal O-methylating system of the rat heart handles the five catecholamines in a similar manner, although the Km for uptake2 had been found to increase substantially in the order: dobutamine less than isoprenaline less than adrenaline less than noradrenaline less than dopamine (Grohmann and Trendelenburg 1984b).     

Dopamine and dobutamine induce hypokalemia in anesthetized dogs

Epinephrine-induced hypokalemia appears to be mediated by beta 2-agonist activation of Na+/K+ ATPase. To determine whether dopamine and dobutamine induce hypokalemia, eight adult mongrel dogs were anesthetized and studied in random crossover fashion. Potassium [K+] was measured with an ion-selective microelectrode, and central hemodynamics were measured continuously. After stabilization, dopamine and dobutamine were infused at doses of 2, 4, 8, and 20 micrograms/kg/min (15-min increments/dose), and 0.9% NaCl was infused at equivalent volumes, with a 1-h washout between treatments. The mean change in [K+] at each infusion rate was compared between treatments among dogs with an adequate hemodynamic response. Among dopamine responders (n = 5), [K+] decreased from 3.74 +/- 0.42 mEq/L at baseline to 3.63 +/- 0.51 at 2 micrograms/kg/min (p less than 0.02) and was not significantly different at higher doses. Among dobutamine responders (n = 7), [K+] decreased from 3.52 +/- 0.74 at baseline to 3.31 +/- 0.87 at 8 micrograms/kg/min (p less than 0.02) and 3.25 +/- 0.86 at 20 micrograms/kg/min (p less than 0.02), and was not significantly different at lower doses. We conclude that dopamine and dobutamine induce significant hypokalemia, consistent with their adrenergic agonist activity, and this may be related to the known arrhythmogenicity of these agents.