Renal blood flow during acute ischaemic heart failure in dogs: effects of dopamine and high doses of insulin

The effects of acute ischaemic heart failure on renal blood flow and the influence of dopamine at low dose range and high doses of insulin were examined. Acute left ventricular (LV) failure was induced in dogs by injection of 50-micron plastic microspheres into the left main coronary artery. The dogs showed signs of severely depressed LV function. Cardiac output was decreased to a significantly greater extent than renal blood flow, and while total peripheral resistance was significantly increased, there were no significant changes in renal vascular resistance. The results indicate different sympathetic discharge to the various vascular beds during acute ischaemic heart failure. Dopamine at low dose range and high doses of insulin were found to improve myocardial contractility and to reduce renal vascular resistance and increase renal blood flow.     

Comparison of the effects of the isomers of amphetamine, methylphenidate and deoxypipradrol on the uptake of l-[3H]norepinephrine and [3H]dopamine by synaptic vesicles from rat whole brain, striatum and hypothalamus.

The ATP-Mg++-dependent uptake of [3H]dopamine and l-[3H]norepinephrine into purified synaptic vesicles of whole rat brain, rat striatum and rat hypothalamus was inhibited 10-fold more effectively by S-(+)-amphetamine as compared to its corresponding (R-(-)-enantiomer. In contrast, S-(+)-deoxypipradrol and its R-(-)-enantiomer were approximately equipotent inhibitors of 3H-amine uptake into these synaptic vesicular preparations. The 1R:2R-methylphenidate was twice as potent as its 1R:2S-enantiomer as an inhibitor of 3H-catecholamine uptake. These data suggest that the receptor sites on the amine pumps present in the membranes of all three vesicular preparations are similar in so far as they are all sensitive to the stereochemical configuration around the alpha-carbon of amphetamine but are not sensitive to the stereochemical configuration around the analogous carbon of deoxypipradrol and methylphenidate. These observations are the reverse of those previously observed for the phenethylamine pumps present in peripheral and central neuronal membranes.     

Electrophysiological effects of cocaine in the mesoaccumbens dopamine system: repeated administration

Behavioral evidence indicates that the potent rewarding effects of cocaine are mediated, in part, by the mesoaccumbens dopamine (DA) system projecting from A10 DA cells in the ventral tegmental area (VTA) to the nucleus accumbens (NAc). Previous electrophysiological studies from our laboratory have indicated that cocaine (i.v.) exerts inhibitory effects on A10 DA neurons, due to enhanced stimulation by DA at DA autoreceptors are well as by activation of NAc-VTA feedback pathways. In the present experiments, extracellular single-unit recording and microiontophoretic techniques were used to determine the possible alterations in the mesoaccumbens DA system after repeated cocaine administration. Twice daily injections of cocaine (10 mg/kg i.p., 14 days) caused significant subsensitivity to the inhibitory effects of low i.v. doses of the DA agonist apomorphine in comparison to rats receiving similar treatments with saline or procaine. Iontophoretic application of DA to A10 DA neurons in rats treated repeatedly with cocaine (2X10 mg/kg, 14 days) also produced significantly less inhibition as compared to control rats. Cell population analysis of the VTA revealed that autoreceptor subsensitivity in cocaine-treated rats resulted in a significantly greater number of spontaneously active A10 DA neurons, and a significantly higher firing rate as compared to A10 DA neurons in control rats. In striking contrast to A10 DA cells, recordings from NAc neurons in cocaine-treated rats (2X10 mg/kg, 14 days) indicated that these cells were supersensitive to the inhibitory effects of iontophoretic DA. Although the mechanism underlying such supersensitivity remains unclear, the increased sensitivity of postsynaptic NAc DA receptors combined with the subsensitivity of A10 DA autoreceptors could lead to greatly enhanced DA transmission and may help to explain some aspects of cocaine-induced behavioral sensitization.     

Nicotine and morphine differentially activate brain dopamine in prefrontocortical and subcortical terminal fields: effects of acute and repeated injections.

Acute systemic injections of nicotine and morphine produce increased locomotion and repeating these injections produces an enhanced locomotor effect. Different lines of evidence suggest that both the acute and sensitized locomotion elicited by morphine are linked to activity in the mesolimbic dopamine (DA) system. The present experiments assessed the effect of acute and repeated injections of nicotine on DA utilization [3,4-dihydroxyphenylacetic acid (DOPAC)/DA] in subcortical and prefrontocortical DA terminal fields and compared these to the effects of morphine. Acute nicotine produced substantial increases in the DOPAC/DA ratio in the nucleus accumbens (N. Acc.) and the antero-medial striatum but not in the dorso-lateral striatum or the medial prefrontal cortex (mPFC). Repeated injections greatly reduced or abolished the drug's effects in the first two terminal fields and produced an increase in DA utilization in the mPFC. In contrast, acute morphine produced large increases in the DOPAC/DA ratio in both the N.Acc. and the mPFC. Consistent with previous findings, repeated morphine increased its effects further in the N. Acc. and produced a small decrease in the mPFC. Neither nicotine nor morphine produced changes in baseline DA utilization in any site. Finally, repeated exposure to nicotine did not enhance the locomotor response to a subsequent injection of morphine. These findings suggest that nicotine differs from morphine in the way it elicits locomotion following repeated injection and possibly in its relation to DA as a mediator of reward. They are also consistent with evidence for a functional interaction between the effects of DA in subcortical and prefrontocortical sites.     

Direct comparison of cerebrovascular effects of norepinephrine and dopamine in head-injured patients

OBJECTIVE: To directly compare the cerebrovascular effects of norepinephrine and dopamine in patients with acute traumatic brain injury. DESIGN: Prospective randomized crossover trial. SETTING: Neurosciences critical care unit of a university hospital. PATIENTS: Ten acutely head-injured patients requiring vasoactive drugs to maintain a cerebral perfusion pressure of 65 mm Hg. INTERVENTIONS: Patients were randomized to start the protocol with either norepinephrine or dopamine. Using an infusion of the allocated drug, cerebral perfusion pressure was adjusted to 65 mm Hg. After 20 mins of data collection, cerebral perfusion pressure was increased to 75 mm Hg by increasing the infusion rate of the vasoactive agent. After 20 mins of data collection, cerebral perfusion pressure was increased to 85 mm Hg and again data were collected for 20 mins. Subsequently, the infusion rate of the vasoactive drug was reduced until a cerebral perfusion pressure of 65 mm Hg was reached and the drug was exchanged against the other agent. The protocol was then repeated. MEASUREMENTS AND MAIN RESULTS: Mean arterial pressure and intracranial pressure were monitored and cerebral blood flow was estimated with transcranial Doppler. Norepinephrine led to predictable and significant increases in flow velocity for each step increase in cerebral perfusion pressure (57.5+/-19.9 cm x sec, 61.3+/-22.3 cm x sec, and 68.4+/-24.8 cm x sec at 65, 75, and 85 mm Hg, respectively; p <.05 for all three comparisons), but changes with dopamine were variable and inconsistent. There were no differences between absolute values of flow velocity or intracranial pressure between the two drugs at any cerebral perfusion pressure level. CONCLUSIONS: Norepinephrine may be more predictable and efficient to augment cerebral perfusion in patients with traumatic brain injury.     

Comparative effects of amphetamine, phenylethylamine and related drugs on dopamine efflux, dopamine uptake and mazindol binding

We quantified the effects amphetamine (AMPH), phenylethylamine (PEA), tyramine (TYR), octopamine (OCT) and DA, on initial rates of DA uptake (striatal minces), binding of [3H]mazindol to the neuronal uptake (NU) site (striatal membranes) and on DA and dihydroxyphenylacetic acid (DOPAC) efflux (striatal slices). In general, the order of potency for the three paradigms was: AMPH less than DA = TYR = PEA less than OCT. The Km values for uptake were positively correlated with the Ki values for inhibition of mazindol binding (r = 0.91; P less than .01) and with the potencies to induce DA efflux (r = 0.96; P less than .005). Potencies for inhibition of mazindol binding and for eliciting DA efflux also were highly correlated (r = 0.92; P less than .01). Correlations were lost if data for nomifensine (NOM), a NU inhibitor, were included in the analysis. Despite the significant correlations, AMPH, TYR, PEA and OCT Despite the significant correlations, AMPH, TYR, PEA, and OCT were 10 to 20 times more potent in inhibiting NU than in eliciting efflux or inhibiting mazindol binding. Conversely, the potency of NOM to inhibit mazindol binding was 10 and 800 times greater than that required to inhibit NU or to elicit DA release, respectively. NOM inhibited competitively AMPH-induced DA release. These results suggest that: 1) AMPH-like drugs bind to and are likely to be transported by the NU carrier, and 2) inward transport of these agents appears to have multiple effects (e.g., an increase in intracellular Na+ and Cl-) that act cooperatively to increase Vmax and reduce Km for the outward, carrier-mediated DA transport. AMPH, TYR, PEA and OCT had qualitatively similar effects on endogenous DA and [3H]DA release. Monoamine oxidase inhibition potentiated these effects. All these agents released more endogenous DA from control than from reserpine-treated slices. In control slices, TYR and OCT increased DA and DOPAC efflux; whereas AMPH and PEA increased DA and reduced DOPAC efflux, except at high concentrations in which DOPAC efflux also was increased. After reserpine, these agents reduced DOPAC efflux in proportion to the increased DA efflux. In summary, we propose that AMPH-like drugs increase DA efflux from a single cytoplasmic pool maintained by DA synthesis and spontaneous and drug-induced efflux of DA from storage vesicles.(ABSTRACT TRUNCATED AT 400 WORDS)     

Comparison of the cerebral effects of dopamine and norepinephrine in severely head-injured patients

OBJECTIVE: To compare the cerebral effects of dopamine and norepinephrine after severe head injury. DESIGN: Prospective, clinical study. SETTING: Surgical intensive care unit in a university hospital. PATIENTS: Nineteen patients with severe head-injuries already requiring vasopressor therapy. Group 1: patients receiving dopamine (n = 9); group 2: patients receiving norepinephrine (n = 10). INTERVENTION: Vasopressor therapy was switched from dopamine to norepinephrine in group 1 and from norepinephrine to dopamine in group 2, maintaining the same mean arterial pressure (MAP). MEASUREMENTS AND RESULTS: MAP, intracranial pressure (ICP), jugular venous oxygen saturation (SjvO2), transcranial Doppler mean velocity in the middle cerebral artery (Vm), and transoesophagal Doppler aortic output (AO) were evaluated under dopamine and norepinephrine. Means for each group were compared with the paired Student's t-test. For the same MAP, ICP was significantly higher with dopamine than norepinephrine in both groups (respectively, group 1: 26 +/- 11 vs 23 +/- 11 mmHg, P < 0.005; group 2: 39 +/- 13 vs 31 +/- 9 mmHg, P < 0.005). SjvO2, Vm, and AO did not change significantly between treatments. The ICP variation between treatments was not correlated with the variation of any other measured parameter. The ICP variation between treatments was significantly higher in group 2 than group 1, which could be explained by autoregulation mechanisms. CONCLUSIONS: For the same MAP, ICP was significantly higher with dopamine than norepinephrine with no argument supporting an increase of cerebral blood flow.     

Hemodynamic effects of isoproterenol and norepinephrine in acute cardiac tamponade

The hemodynamic effects of isoproterenol infusion, 0.5 μg/kg per min were evaluated in eight intact anesthetized dogs during cardiac tamponade. During tamponade, the mean of pericardial pressures was increased from — 1.5 to 12.5 mm Hg, and the mean of right atrial pressures was increased from 1 to 12.4 mm Hg. Mean cardiac output fell from 144.8 to 44.8 ml/kg per min (P < 0.001), and rose to 105.6 ml/kg per min (P < 0.001) with isoproterenol. Mean cardiac stroke volume fell from 20.3 to 6.1 ml during tamponade (P < 0.001) and rose to 12.1 ml with isoproterenol (P < 0.001). The heart rate increased from 193.3 beats/min during tamponade to 217.5 beats/min with isoproterenol (P < 0.05). During isoproterenol infusion, the mean right atrial pressure and mean pericardial pressure decreased significantly. With cardiac tamponade, the mean blood pressure fell from 157.5 to 126.1 mm Hg (P < 0.01) and did not change significantly with isoproterenol, 11 additional animals were studied with norepinephrine infusion during tamponade. There were no consistent hemodynamic effects with infusions of 0.5 and 1 μg/kg per min. With norepinephrine 2, 5, and 10 μg/kg per min cardiac output rose in some experiments. Isoproterenol infusion increased the cardiac output during tamponade principally by increasing cardiac stroke volume and to a lesser degree by increasing the heart rate. It is postulated that the increased stroke volume resulted from an increased ejection fraction with greater decrease in end-systolic than end-diastolic ventricular volume. These effects are consistent with the known positive inotropic, peripheral vasodilator, and positive chronotropic effects of isoproterenol.     

Regulation of the human norepinephrine transporter by cocaine and amphetamine

Certain antidepressant and psychostimulant drugs block the uptake of norepinephrine from the synaptic cleft by inhibiting norepinephrine transporter (NET) function. The effects of chronic occupation of the NET by these drugs on NET expression are poorly understood. We previously described down-regulation of the NET in cultured cells after continuous exposure to the tricyclic antidepressant desipramine. Here, the effects of structurally unrelated NET ligands, cocaine and amphetamine, on levels of NET and on NET function in HEK-293 cells transfected with human NET cDNA were investigated. All drug exposures were followed by incubation in drug-free media before harvesting and assays. Exposure of intact cells to cocaine for 3 days did not significantly affect the B(max) or K(D) of [(3)H]nisoxetine binding to NET in membrane homogenates, and did not alter levels of NET immunoreactivity or NET mRNA. In contrast, incubation of cells with amphetamine significantly reduced [(3)H]nisoxetine binding to NET and levels of NET immunoreactivity in a time-dependent manner, although levels of NET mRNA appeared to be unaffected. Exposures to cocaine or amphetamine resulted in significant reductions of [(3)H]norepinephrine uptake, although the magnitude of the reduction produced by amphetamine was much greater than cocaine. [(3)H]Nisoxetine binding to NET and NET protein levels were also reduced by exposure of cells to high concentrations of norepinephrine, although norepinephrine exposures were accompanied by changes indicative of cellular toxicity. Cocaine and amphetamine have distinctly different effects on NET expression after continuous exposure. The ability of only certain drugs to down-regulate the NET may provide clues to the unique therapeutic effects of antidepressants that are NET ligands.     

Venous responsiveness to norepinephrine in healthy subjects: effects of single doses of 325 mg aspirin

BACKGROUND: Antithrombotic doses of aspirin, which are widely used in patients with cardiovascular disease, may inhibit prostaglandin synthesis but the physiologic significance with regard to vascular tone is not well defined. We hypothesized that inhibition of vasodilator prostaglandin synthesis by aspirin would significantly increase sympathetic-mediated venoconstriction. METHODS: Twelve healthy volunteers (mean age, 24.5 +/- 0.8 years; age range, 19 to 30 years) were studied on two mornings approximately 7 days apart and not less than 90 minutes after a randomized single dose of 325 mg aspirin or matching placebo. Distension of dorsal hand veins was measured with use of the linear variable differential transformer technique during local infusions of exogenous norepinephrine (0.125 to 1,024 ng/min) and during release of endogenous norepinephrine from sympathetic activation by a forehead cold pressor test. Hemodynamic parameters and venous plasma catecholamine levels were measured. Antiplatelet activity of the dose of aspirin was confirmed in three subjects. RESULTS: Aspirin increased venoconstriction to norepinephrine, causing a significant shift to the left (P < .03) of the norepinephrine dose-response curve and a significant decrease in logED50 (P < .03), representing a decrease in the dose of norepinephrine required to reduce vein distension by 50% from 50 to 25 ng/min. Venoconstriction to the cold pressor test was significantly increased by aspirin (10% +/- 3% versus 3% +/- 1% for placebo; P < .02). Cold pressor-induced increases in mean arterial pressure were significantly larger with aspirin compared with placebo (18 +/- 1 versus 14 +/- 1 mm Hg, respectively; P < .03). Baseline levels and stress-induced increases in plasma norepinephrine were not different between days. CONCLUSIONS: The results suggest that aspirin inhibits the role of vasodilator prostaglandins in modulating peripheral venoconstriction and increases vascular resistance during physiologic stress in young healthy subjects.     

Acute administration of amphetamine: differential regulation of dopamine synthesis in dopamine projection fields.

In order to study the inhibitory mechanisms regulating dopamine (DA) synthesis in vivo, the effect of amphetamine in the presence and absence of selective D1 and D2-DA receptor antagonists was examined in various brain regions. In response to amphetamine (3 mg/kg s.c.) administration, DA synthesis in the striatum, but not the nucleus accumbens or the medial prefrontal cortex, exhibited a biphasic response (increased followed by decreased). The D1 selective antagonist, SCH 23390 (0.5 mg/kg s.c., 60 min), modestly increased DA synthesis (30%) in the striatum but not in the nucleus accumbens or the prefrontal cortex. However, pretreatment with the D1 DA receptor antagonist did not prevent the amphetamine-induced elevation of striatal DA synthesis 45 min after amphetamine administration. The D2 selective antagonist, eticlopride (2 mg/kg s.c., 60 min), increased DA synthesis in both the striatum and the nucleus accumbens but not in the prefrontal cortex. Although amphetamine alone increased DA synthesis only in the striatum, in the presence of D2-DA receptor blockade, amphetamine increased DA synthesis in the striatum, the nucleus accumbens and the medial prefrontal cortex. The results support the hypothesis that DA synthesis is differentially regulated by distinct inhibitory mechanisms depending on the projection field. The apparent differences in regulatory mechanisms may allow selective alteration of DA synthesis in one particular projection field, while other areas remain unaffected.     

The effects of acute and repeated doses of suriclone on subjective sleep, psychomotor performance and cognitive function in young and elderly volunteers

Suriclone is a new anxiolytic drug belonging to the family of cyclopyrrolones. The effects of acute and repeated doses of suriclone on subjective sleep, psychomotor performance and cognitive function were compared to those of placebo in young and elderly volunteers. Young volunteers randomly received suriclone 0.2 mg, 0.3 mg, 0.4 mg or placebo tid, and the elderly received suriclone 0.1 mg, 0.2 mg or placebo tid. After the first single dose and after a three-day treatment, subjects completed at 1, 2, 4, 12 and 24 h after drug administration the following battery of psychomotor and cognitive tests: critical flicker fusion threshold, choice reaction time, simulated car tracking test, the stroop test and the Sternberg memory scanning task. Visual analogue scales and the Leeds sleep evaluation questionnaire were also administered during the study. No significant effects of suriclone compared to placebo were seen on the psychomotor tests both in young and elderly volunteers. The only significant result was an improvement of the ease of getting to sleep in the young with 0.4 mg suriclone tid. In conclusion, there is little evidence to suggest that suriclone produces any measurable behavioural toxicity, so often seen with many of the benzodiazepines, in either young or elderly subjects.     

Effects of norepinephrine alone and norepinephrine plus dopamine on human intestinal mucosal perfusion

Objectives To evaluate the effect of norepinephrine alone and norepinephrine combined with dopamine on jejunal mucosal perfusion, gastric-arterial pCO₂ gradient, and global splanchnic oxygen demand-supply relationship after cardiac surgery.Design A prospective interventional study.Setting A university cardiothoracic intensive care unit.Patients Eighteen patients were studied during propofol sedation and mechanical ventilation after uncomplicated coronary artery bypass surgery.Interventions After control measurements, each patient received norepinephrine (50±26 ng·kg·min) to increase mean arterial blood pressure by 30% followed by addition of low-dose dopamine (2.6±0.3 µg·kg·min). Postdrug control measurements were performed 120 min after discontinuation of the catecholamines.Measurements and results Norepinephrine induced a 32% increase in systemic vascular resistance with no change in cardiac index. Neither jejunal mucosal perfusion, assessed by laser Doppler flowmetry, nor gastric-arterial pCO₂ gradient (tonometry) was affected by norepinephrine. Splanchnic O₂-extraction increased (P<0.05) and this increase was positively correlated to the individual dose of norepinephrine (r = 0.78, P<0.0001). Splanchnic lactate extraction was increased by norepinephrine (P<0.05). None of the patients had splanchnic lactate production during norepinephrine infusion. The addition of dopamine increased cardiac index by 27% (P<0.001) and decreased splanchnic O₂ extraction. Dopamine increased jejunal mucosal perfusion by 32% (P<0.001) while the gastric-arterial pCO₂ gradient remained unchanged.Conclusions Vasopressor therapy with norepinephrine after cardiac surgery did not jeopardize intestinal mucosal perfusion in spite of a dose-dependent increase of the global splanchnic oxygen demand-supply relationship. The addition of dopamine increased intestinal mucosal perfusion.This study was supported by grants from the Swedish Medical Research Council (no. 13156), Medical Faculty of Göteborg (LUA), Scandinavian Heart Center Research Foundations, and Göteborg Medical Society. The study was presented at the Annual Meeting of the European Association of Cardiothoracic Anaesthesiologists May 2002, Dublin, Ireland.     

Differential effects of amphetamine and dopamine uptake blockers (cocaine, nomifensine) on caudate and accumbens dialysate dopamine and 3-methoxytyramine.

Evidence suggests that some amphetamine-like stimulants may enhance accumbens dialysate dopamine to the greater extent than caudate dopamine. To test our hypothesis that the difference in transmitter response may derive, in part, from the degree to which released dopamine in the two regions is metabolized to 3-methoxytyramine, we compared the effects of amphetamine with the uptake blockers, nomifensine and cocaine, on caudate and accumbens dialysate concentrations of dopamine, its acid metabolites and 3-methoxytyramine. The percentage increases in accumbens dopamine were significantly greater than in caudate only after the uptake blockers. All three drugs promoted dose-dependent increases in dialysate 3-methoxytyramine which, although temporally delayed, generally paralleled the increases in dopamine. However, after the administration of uptake blockers, the ratio of dialysate 3-methoxytyramine to dopamine was greater in caudate than in accumbens. In addition, the acid metabolite patterns were the same in the two regions after amphetamine, but were qualitatively different after the uptake blockers. These results indicate that the relative degree of metabolism of released dopamine to 3-methoxytyramine in caudate and accumbens may contribute to the regional differences in dopamine response to uptake blockers.     

Inhibitory effects of amphetamine on potassium-stimulated release of [3H]dopamine from striatal slices and synaptosomes

Amphetamine, 10(-7) M or greater, evoked the release of [3H]dopamine ([3H]DA) and inhibited subsequent K+-evoked [3H]DA release from striatal synaptosomes superfused at a flow rate (1 ml/min) that prevented reuptake. Amphetamine inhibited the K+-evoked release of [3H]DA to a lesser extent in striatal slices or in synaptosomes superfused at a flow rate (0.35 ml/min) that allowed reuptake. The observed decrease in amphetamine inhibition of K+-evoked release was primarily due to amphetamine blocking [3H]DA reuptake. Interneuronal interactions may account for some of the inhibitory effects of amphetamine on K+-evoked release in the slice. Inhibition of K+-evoked release from either slices or synaptosomes was still evident when 10(-6) M amphetamine was removed from the superfusion buffer and the spontaneous release had returned to control levels. The presence of Ca++ during amphetamine exposure was required for subsequent inhibition of K+-evoked release in synaptosomes. Amphetamine in the presence of Ca++ did not affect the subsequent release of [3H]DA evoked by the Ca++ ionophore, A23187. Therefore, amphetamine inhibition of the K+-evoked release of [3H]DA cannot be explained by prior depletion of Ca++-releasable pools. Nifedipine, 1 microM, failed to block either the Ca++-dependent release of [3H]DA or the inhibition of K+-evoked release by amphetamine. However, 1 mM cobalt inhibited the Ca++-dependent release of [3H]DA by amphetamine and antagonized the inhibition of K+-evoked release after amphetamine exposure. This suggests that amphetamine may open voltage-dependent Ca++ channels sensitive to cobalt but not nifedipine. Amphetamine may desensitize these voltage-dependent Ca++ channels and inhibit their activation by K+ depolarization.