DA Dose Research Articles

Gender Differences in Impulse Control Disorders and Related Behaviors in Patients with Parkinson's Disease and its Impact on Quality of Life.

Background:Dopaminergic medications administered to remedy motor symptoms in Parkinson’s disease are associated with an enhanced risk for impulse control disorders (ICD) and related compulsive behaviors (ICD-RB). Thus, the present study focuses on investigating the gender difference in the prevalence of ICD-RBs in Indian PD patients on dopamine replacement therapy (DRT), its impact on quality of life and to identify ICDs relevant in Indian scenario apart from the criteria set in QUIP-RS.Method:This was a hospital-based observational cross-sectional study in which Parkinson’s disease patients attending neurology clinic were included. Complete details of anti-parkinsonian therapy along with demographic and clinical variables were recorded on a predesigned Performa. Questionnaire for Impulsive-Compulsive Disorders in Parkinson’s disease (QUIP), which is a validated quick screening tool, was used to detect ICD-RBs. The relative frequency and comparative impact of ICD on health-related quality of life (QOL) was studied using validated PDQ-39 Questionnaire.Results:Out of 102 patients, at least one ICD or ICD-RB was present in 41.19% and ≥2 ICD-RBs were present in 15.59%. At least one ICD was present in 16.67%, any ICD-related compulsive behaviors was present in 34.31% patients. The most common was punding and compulsive medication use (12.75% each), followed by hobbyism (7.84%), compulsive eating (6.86%), pathological gambling (3.92%), and hypersexuality, walkabout, and compulsive shopping (2.94% each). ICDs not classified elsewhere such as trichotillomania were found 3 patients (2.94%). ICD-RBs showed a trend to be more frequent in women (44.82% women vs. 39.39% men). As compared with patients without ICD-RBs, those with ICD-RBs were found to have higher dose of LD and DA and higher Hoehn and Yahr stage. ICD-RBs have a negative impact on the quality of life of Parkinson’s disease patients.Conclusion:ICDs and ICD-RBs have been included in the behavioral spectrum of nonmotor symptoms in PD. PD patients are at increased risk of developing ICD-RBs which interfere with important activities and have obligation in ordinary life, leading to legal and psychological consequences with a great impact on QOL.

A study on a dental device for the prevention of mucosal dose enhancement caused by backscatter radiation from dental alloy during external beam radiotherapy.

The changes in dose distribution caused by backscatter radiation from a common commercial dental alloy (Au–Ag–Pd dental alloy; DA) were investigated to identify the optimal material and thicknesses of a dental device (DD) for effective prevention of mucositis. To this end, 1 cm3 of DA was irradiated with a 6-MV X-ray beam (100 MU) in a field size of 10 × 10 cm2 using a Novalis TX linear accelerator. Ethylene vinyl acetate copolymer, polyolefin elastomer, and polyethylene terephthalate (PET) were selected as DD materials. The depth dose along the central axis was determined with respect to the presence/absence of DA and DDs at thicknesses of 1–10 mm using a parallel-plate ionization chamber. The dose in the absence of DDs showed the lowest value at a distance of 5 mm from the DA surface and gradually increased with distance between the measurement point and the DA surface for distances of ≥5 mm. Except for PET, no significant difference between the DA dose curves for the presence and absence of DDs was observed. In the dose curve, PET showed a slightly higher dose for DA with DD than for DA without DD for thicknesses of ≥4 mm. The findings herein suggest that the optimal DD material for preventing local dose enhancement of the mucosa caused by DA backscatter radiation should have a relatively low atomic number and physical density and that optimal DD thickness should be chosen considering backscatter radiation and percentage depth dose.

Accidental intrathecal injection of dopamine hydrochloride resulting in analgesic effects.

Accidental intrathecal injection of dopamine hydrochloride resulting in analgesic effects.

Dopamine enhances gastric motility through D1 dopaminergic receptors on cholinergic neurons in the myenteric plexus of rats

ObjectivesInvestigate the effect of dopamine on the gastric motility and the underlying mechanism.MethodsImmunofluorescence and gastric motility recording by organ bath study.ResultThe immunoreactivities of D1 and D2 were distributed in the choline acetyltransferase (ChAT)‐immunoreactive neurons in the myenteric plexus of rats. The gastric motility in vitro was enhanced from 8.2 to 10.8£g¡Ámin£©by DA in the concentrations of 1¡Á10–8mol/L (n=10, p<0.05). However, DA manifested inhibitory role at the higher concentrations of 3¡Á10–6mol/L. The excitatory effect of DA was mimicked by SKF‐38393, a selective agonist of D1‐like receptors in dose‐dependent manner, and blocked by neuronal sodium channel blocker, tetrodotoxin (TTX) in 1¡Á10–5mol/L and atropine (competitive nonselective antagonist of muscarinic acetylcholine receptors) in 1¡Á10–5mol/L (n=8, p<0.05). The selective D2‐like receptor antagonist sulpride and selective D2‐like agonist Quipirole did not affect both the excitatory and inhibitory effect of DA.ConclusionsThe present study demonstrates that dopamine is able to enhance gastric motility in lower concentration through D1 dopaminergic receptors activating acetylcholine release from myenteric nerve plexus. The higher dose of DA can inhibit gastric motility, but the mechanism needs to be further investigated.

De novo once-monthly darbepoetin alpha treatment for the anemia of chronic kidney disease using a computerized algorithmic approach

Anemia of chronic kidney disease (CKD) has been traditionally treated by erythropoiesis-stimulating agents (ESAs) and/or iron following manual determination of dose. We hypothesized that once-monthly (QM) algorithmically dosed darbepoetin α (DA) and iron administration would successfully treat anemia of CKD in ESA-naïve CKD subjects. QM DA and iron doses were determined via a computerized program targeting a hemoglobin (Hb) of 10.5 - 12.5 g/dl in anemic, ESA-naïve, CKD Stages 3 - 5 subjects. Six consecutive QM doses were administered. Hb, ferritin, and transferrin saturation were recorded. Data are presented as means ± standard deviation. Anemia was identified in 133 subjects, with a mean follow-up of 188 days. DA doses and Hb were significantly greater at Months 3 and 6 compared to baseline (p < 0.05); DA doses were 109 ± 68 μg and 118 ± 91, respectively, at Months 3 and 6. Hemoglobin levels were correspondingly 11.3 ± 1.1 g/dl and 11.3 ± 1.0. 78% of patients achieved the target Hb by 6 months of therapy. The elevation of Hb was greater in non-proteinuric than proteinuric subjects at 6 months of treatment (11.6 ± 0.8 g/dl vs. 11.0 ± 1.1; p < 0.05), despite lower DA dose (96 ± 76 μg vs. 139 ± 98; p < 0.05). Successful treatment of the anemia of CKD by QM DA based upon a computerized dosing program was achieved by 6 months in 78% of ESA-naïve, CKD subjects.

Impulse control disorders in Chinese Parkinson’s disease patients: The effect of ergot derived dopamine agonist

ObjectiveWe studied the prevalence and related risk factors of impulse control disorders in Chinese Parkinson’s disease patients. MethodWe screened all non-demented Parkinson’s disease patients attending our Parkinson’s disease clinic from August 2009 to March 2010. The clinical characteristics of patients with impulse control disorders and those without were compared. ResultsOf the 213 PD subjects screened, 15 (7.0%) with impulse control disorders were identified. Fourteen of these subjects were on both a dopamine agonist and Levodopa, and one was on Levodopa alone. Of the fourteen subjects on both a dopamine agonist and Levodopa, eleven were on bromocriptine and Levodopa; 10.5% of the subjects exposed to bromocriptine had impulse control disorder. Upon multivariate analysis, dose of dopamine agonist used, young age at onset of Parkinson’s disease and a history of anxiety or depression were independent predictors for developing impulse control disorders. Conclusions7% of our Chinese PD subjects had impulse control disorders. When young Parkinson’s disease patients with a history of anxiety or depression are treated with high dose of DA, they are at risk of developing impulse control disorders.

Timing of the administration of intravenous darbepoetin alfa during the dialysis session: Does it impact efficacy?

AbstractBACKGROUNDDarbepoetin alfa (DA) is an erythropoietin‐stimulating agent (ESA) preferably administered through intravenous (IV) route in hemodialysis (HD) patients. Although some in vitro studies suggest the possibility of partial adsorption of ESAs in dialysis membranes (Mb) and lines, these data are not clinically confirmed.METHODSThis 12‐month, prospective, single‐center cross‐over study assessed the impact of the time of IV DA injection during HD on hemoglobin (Hgb) level and ESA dosing. A total of 90 HD patients received IV DA once every other week (Q2W), delivered at 2 possible time points: the middle or end of the HD session. After 6 months, the injection time point was crossed over to the other timing modality for another 6 months.RESULTSDemographics for both groups of patients were similar. Mean Hgb level remained stable from baseline to month 6 (not significant) for both timing modality groups. The same was observed for DA dose. Hemodialysis session parameters, nutritional status, and Kt/V were similar and stable during the study. Mean transferrin saturation was 44% and serum ferritin was $100 mg/L in more than 92% of patients. Iron supplementation remained unchanged and there were no blood transfusions during the study.CONCLUSIONSQ2W DA maintained target Hgb concentrations. The lack of difference in Hgb levels and DA dosing between the 2 injection timings suggests a lack of clinically significant adsorption/interaction between DA and dialysis Mb/lines. Therefore, timing of IV DA administration can be flexible and adapted to the routine practice of each local dialysis unit.

Darbepoetin Alfa for the Treatment of Anemia in Patients with Myelofibrosis with Myeloid Metaplasia (MMM). Results from a Danish Multicenter Study.

Background: Treatment with recombinant human erythropoietin (rHuEPO) may increase the hemoglobin (Hb) concentration in patients with myelofibrosis with myeloid metaplasia (MMM). Only one study in this setting has used darbepoetin alfa (Aranesp®) (DA), an erythropoiesis-stimulating protein with a long half-life allowing less frequent administration.We report the largest series of patients with MMM being treated with DA so far.Methods: Twenty-eight patients were enrolled in a prospective Danish multicenter study. Median age was 71 years (range 50 – 86 years). Inclusion criteria were symptoms of anemia or a Hb concentration ≤ 10 g/dL. Response criteria: A major response (MAR) was defined as either a complete response (CR = no need for blood transfusions and a increase in the Hb-level > 11.5 g/dl), or a partial response (PR = a 50% reduction in the need of blood transfusions, compared to the average monthly need during the 6 months before the start of DA in combination with a stable Hb level > 10 g/dl. A minor response (MIR) was defined as a 50% reduction in the need for blood transfusions compared to the average monthly need the last 6 months preceding start of DA treatment. Non-responders (NRS) were defined as patients with no change or an increased need for blood transfusions.Treatment: All patients were scheduled to receive DA 300 μg sc. once-weekly for at least 12 weeks. In patients who achieved a normal Hb concentration at this dose, the DA dose was decreased to 300 μg every second week or even third week if possible. If the Hb concentration subsequently declined and the patient developed anemia in the subsequent weeks, the dose of DA was increased to a level that maintained a normal Hb concentration. Patients achieving a CR or a PR continued DA beyond 12 weeks. In NRS, the treatment was discontinued after 12 weeks of treatment.Results: The response rate was 65% (17 out of 26 evaluable patients), 6 patients achieving a CR (23%), 3 PR (12%) and 8 MIR (30%). Six of the patients received antibiotic treatment during the study period. Two of these were non-responders. One non-responder developed AML in week 9 and died one week later. Three patients discontinued DA due to possible side-effects (gastrointestinal complaints in 2 patients and in one, bone- and muscle pains, the latter symptoms also being related to disease activity). Four of 17 responders had a serum erythropoietin (s-EPO) > 125 IU/L (median 53 IU/L; range 4,9 – 520 IU/L, while 4 of 9 non-responders had a s-EPO >125 IU/L (median 103 IU/L ; range 11,9 – 730 IU/L. The median serum EPO level was significantly higher in NRS (103 IE/l; range 11, 9 – 730 IU/L) as compared to responding patients (57 IE/l; range 4, 9 – 520 IU/L).Conclusion: Darbepoetin alfa is a well tolerated drug with few side effects and a high response rate in patients with MMM, implying an increase in the Hb concentration and a decrease in the need for blood transfusions in about 50% of the patients. A serum EPO < 125 IU/L is a predictor of a favorable EPO-response, although responses may also be seen in patients with higher serum EPO levels.

In vivo Dilatation of the Postnatal Ductus Arteriosus by Atrial Natriuretic Peptide in the Rat

Background: α-Human atrial natriuretic peptide (hANP) reportedly increases in premature infants with patent ductus arteriosus (PDA). Objectives: To clarify a possible hANP effect to reopen the postnatal ductus, we studied in vivo reopening of the postnatal DA by a recombinant hANP, carperitide, in rats. Methods: Near-term rat pups were incubated at 33°C following caesarean section. The inner diameter of the ductus was measured with a microscope and a micrometer following rapid whole-body freezing. The DA constricted quickly after birth, and the inner diameter was 0.80 and 0.08 mm at 0 min (fetal state) and 60 min after birth. hANP concentration in the pup blood and the ductus-dilating effect of hANP were studied by subcutaneous injection of hANP at 60 min after birth, and by measurement 7, 15, 30 and 60 min later. Results: The peak hANP concentration was 790 pg/ml at 7 min with 1 mg/kg, which is similar to the level seen in preterm infants with symptomatic PDA. hANP dilated the postnatal ductus dose dependently and maximally at 7 min after injection. hANP dilated the postnatal constricted ductus completely to 0.79 mm in diameter with a large dose (10 mg/kg) and to 0.55 mm with 1 mg/kg. Conclusions: hANP reopens the constricted postnatal DA dose dependently in rats. The increased hANP, accompanying premature PDA, may delay closure of the DA.

Darbepoetin α for the treatment of anemia in patients with myelodysplastic syndromes

Anemia occurs as a comorbidity in from 80% to 85% of patients with myelodysplastic syndromes (MDS): It causes fatigue, increases transfusion needs, and reduces quality of life. Darbepoetin alpha (DA) is an erythropoiesis-stimulating protein (ESP) that is more highly glycosylated and has a longer half-life relative to recombinant human erythropoietin (rHuEPO), thus, allowing less frequent administration, increased convenience, and better compliance. This retrospective analysis included 81 patients with MDS who were enrolled at 9 Spanish centers and who received once-weekly, subcutaneous DA (75-300 microg) for 16 weeks. Fifty-five percent of all patients (38 of 69 evaluable patients) achieved responses; 30.4% of were major responses, and 24.6% were minor responses; 64.7% of rHuEPO-naive patients and 45.7% rHuEPO-treated patients responded; and 43.2% had received previous rHuEPO. Most responses (65.8%) occurred at or before Week 8. The median age at diagnosis was 70 years (range, 38-87 years), the median age at the initiation of DA treatment was 75 years (range, 39-91 years), and 56.8% of patients were women. The median time from last ESP dose to DA initiation was 16.8 weeks (range, 0.0-159.0 weeks; <1 week in 53.1% of patients). According to the French-American-British classification system (n = 81 patients), 39.5% had refractory anemia (RA), 46.9% had RA with ringed sideroblasts, 9.9% had RA with excess blasts (RAEB), 1.2% had RAEB in transformation, and 2.5% had chronic myelomonocytic leukemia. According to the International Prognostic Scoring System (n = 47 patients), 55.3% of patients were in the low-risk group, and 36.2% of patients were in the intermediate-1-risk group. The median baseline hemoglobin level was 8.9 g/dL (range, 8.4-9.1 g/dL). The Starting DA dose was 75 microg per week in 3.7% of patients, 150 microg per week in 65.4% of patients, and 300 microg per week in 29.6% of patients (the dose was increased in 18.5% of patients and reduced in 9.9% of patients; median time to dose adjustment, 8 weeks). Five patients received granulocyte colony-stimulating factors. No DA-related adverse reactions occurred. In the current study, 55% of evaluable patients with MDS safely achieved an erythroid response.

Correction/Maintenance Dosing (Front Loading) of Darbepoetin alfa: Final Results from a Randomized Phase 3 Active Controlled Trial.

Prior research with darbepoetin alfa (DA; Aranesp®) in patients with chemotherapy-induced anemia (CIA) has indicated the possibility of decreasing the time to response through the use of higher initial doses (4.5 mcg/kg once weekly [QW]) compared with standard dosing regimens (either of DA or epoetin alfa [Procrit®]). Research has also shown that an every 3 week (Q3W) dosing schedule of DA is effective in alleviating the symptoms of CIA. Pilot studies using a correction/maintenance approach (‘front loading') have combined these two potentially attractive clinical attributes. This active-controlled trial examined the efficacy of DA using a correction/maintenance dosing regimen in patients with nonmyeloid malignancies receiving chemotherapy. In this study, 727 anemic patients (hemoglobin [Hb] <11g/dL) were randomized 1:1 to receive a DA dose of either 2.25 mcg/kg QW for 16 weeks or 4.5 mcg/kg QW for weeks 1–4, followed by a Q3W maintenance regimen using the same dose (4.5 mcg/kg) for weeks 5–16. The primary endpoint was to demonstrate the non-inferiority of correction/maintenance dosing versus standard weekly dosing, with respect to the proportion of patients either requiring a transfusion or withdrawing from the study during the 16-week treatment period. The pre-specified, non-inferiority margin, based on the effect size observed in DA placebo-controlled trials, was 12.5%. The two treatment groups were well balanced for baseline characteristics: 32% had hematologic malignancies, 15% breast cancer and 13% lung cancer. Both groups had a mean (SD) baseline Hb of 9.6 (1.0) g/dL. Non-inferiority was demonstrated with respect to the primary endpoint with a mean (95% CL) difference between groups of 1% (−7, 9). No difference was observed for the proportion of patients receiving a RBC transfusion from week 5 to end of treatment [24% (19, 28) for the 2.25 mcg/kg QW group vs 25% (20, 30) for the correction/maintenance group]. Over the entire study period, 87% (83, 91) of patients in the DA 2.25 mcg/kg group achieved a hematopoietic response at the end of treatment compared with 68% (62, 73) in the correction/maintenance group, suggesting no additional benefit for correction/maintenance dosing compared with standard dosing. During the initial 7 weeks of study, no differences were observed between patients receiving 2.25 mcg/kg QW or 4.5 mcg/kg QW for any endpoint (eg, Hb change of 1.4 g/dL after 6 weeks in both groups); Q3W dosing at 4.5 mcg/kg was shown to be effective in maintaining Hb through the remainder of the treatment period. No difference in adverse events between the two groups was observed. DA 2.25 mcg/kg QW is highly effective with respect to the reduction of transfusion requirements and management of anemia symptoms in patients with CIA. In this study of anemic patients with nonmyeloid malignancies receiving chemotherapy, almost all patients in the 2.25 mcg/kg QW dose group achieved a hematopoietic response, offering little room for additional clinical benefit that may have been expected in the 4.5 mcg/kg QW group as a result of the increased dose. Q3W dosing with DA 4.5 mcg/kg was shown to effectively maintain Hb levels. The effectiveness of lower/less frequent doses cannot be determined from this trial.

Changes in plasma free and sulfoconjugated catecholamines during the perioperative period of cardiac surgery: effect of continuous infusion of dopamine.

In order to elucidate the pharmacological properties of the formation of sulfoconjugated catecholamines (CAs) in human plasma, we investigated the changes in the plasma levels of free and sulfoconjugated CA during the continuous infusion of dopamine (DA; 4-6 microg/kg/min for 24 h, followed by 3-4 microg/kg/min for 48 h) in patients who had undergone cardiac surgery. The plasma level of free DA increased immediately after the start of the infusion and reached a plateau within 1 h at a level of about 2000 times the basal value. In the control patients who had received non-cardiac surgery without DA infusion, plasma-free DA increased only 5-fold after their operation. The plasma level of DA sulfate increased linearly for 24 h, to 48-fold of the basal value by DA infusion, whereas it showed only a 2-fold increase in the control patients. After 24 h, due to reduction of the infused DA dose, the level of free DA gradually decreased, whereas the level of DA sulfate remained elevated. The plasma levels of free adrenaline (Ad) and noradrenaline (NA) also increased during the DA infusion, but their levels reached a plateau within 1-2 h. Sulfoconjugated Ad and NA increased progressively until the tapering off of DA infusion. In the control patients, both free and conjugated Ad and NA showed transient increases over 12 h after surgery. These results suggest that sulfoconjugation plays a role in regulating the plasma levels of excess free CA, thereby modifying the cardiovascular effects of circulating CA. Measurement of the increase in plasma conjugated CA may be useful as an index of the increase in free CA in plasma due to the administration of an exogenous form or release of endogenous CA from the tissues.

6-Hydroxydopamine induced impairment of Pavlovian conditioning in the rabbit.

This study employed bilateral, intraventricular injections of 6-hydroxydopamine (6-HDA) to examine the effects of monoamine depletion on Pavlovian conditioning of the rabbit's nictitating membrane response. 6-HDA produced dose-dependent and highly correlated decreases in the rate of acquisition of conditioned responses and in the telencephalic content of 5-HT, DA, and NE. At the highest dose of 6-HDA (1340 micrograms), 5-HT, DA, and NE were reduced by 42, 48, and 89%, respectively, and the number of trials required to achieve criterion acquisition was increased by 123%. Control experiments established that the highest dose of 6-HDA: 1) had no effect on the unconditioned nictitating membrane reflex; 2) had no effect on the threshold of the conditioned stimulus for eliciting conditioned responses; and 3) produced only a small, less than 5%, decrease in nonassociative responding. It was concluded that decreases in 5-HT, DA, and NE can impair associative learning without altering sensory or motor function.

The renal vasodilating effect of dopamine is mediated by calcium flux and prostacyclin release in man.

A low dose of dopamine (DA; 1 microgram/kg.min for 3 h) was infused into 10 normal subjects to determine whether vasodilator prostaglandins might be involved in the vascular action of this vasoactive hormone. Although this DA dose did not alter blood pressure, pulse, or cardiac index, it significantly increased renal blood flow (RBF), as estimated by para-amino-hippurate clearance [1.40 +/- 0.10 (+/- SE) to 1.93 +/- 0.18 L/min.1.73 m2; P less than 0.02]. This increase was due to DA receptor action since it was blocked by metoclopramide, a DA antagonist, and was not altered by prazosin, an alpha-adrenergic antagonist. DA simultaneously increased the urinary excretion rate of 6-keto-PGF1 alpha, a stable metabolite of prostacyclin [PGI2; 79 +/- 16 to 154 +/- 32 ng/g creatinine (2 +/- 0.40 to 3.88 +/- 0.78 pmol/mumol creatinine); P less than 0.02], but there was no change in PGE2 excretion. This dose of DA increased urinary Na+ and K+ excretion and slightly increased creatinine clearance from 0.12 +/- 0.01 to 0.16 +/- 0.02 L/min.1.73 m2 (P less than 0.05). Metoclopramide also blocked the increase in PGI2 excretion, indicating that this increase was due to DA. The relationship between RBF and PGI2 was supported by studies in which either indomethacin or ibuprofen, both cyclooxygenase inhibitors, blocked the increase in both RBF and PGI2 excretion rate. Since some DA actions may be mediated through calcium flux, we also administered nifedipine, a calcium channel-blocking drug, and found that the DA effect on RBF and PGI2 was significantly reduced. These studies suggest that the DA effect on RBF is mediated by calcium flux, which probably activates renal vascular phospholipase, leading to release of arachidonic acid and synthesis of PGI2, a potent vasodilator.

The relationship of relative gene dose to the complex phenotype of the daughterless locus in Drosophila.

The daughterless (da) gene provides an essential maternally supplied component for Drosophila sex determination and dosage compensation. In this connection, it is required as a positive regulator of a female-specific master regulatory gene, Sex-lethal (Sxl). In addition, zygotic da gene function is required for male and female viability. Thus, the phenotype da is complex; it includes both maternal and zygotic aspects, as well as both sex-specific and nonsex-specific aspects. Assessment of wild-type da function has relied on the characterization of only a single leaky mutant da allele. In order to better understand the nature of this allele and the relationships between the various aspects of its complex phenotype, tandem duplications of both the mutant and wild-type da alleles were isolated and used in a dose study of this gene's function. Three conclusions were reached: 1) by the most stringent genetic criteria, the mutant da allele is a simple hypomorph, an allele with reduced but non-zero levels of wild-type functions; 2) since increased dose of da+ had no effect on viability or progeny sex ratio, this gene seems not to be a dose-sensitive element of the X/A ratio sex determination signal; and 3) expression of the maternal da+ allele does make a contribution to the nonsex-specific developmental processes that require zygotic da+ function; however, that contribution is clearly minor. In contrast, the zygotic genotype with respect to da appears to have no effect on the expression of Sxl+ in the zygote, the sex-specific process that requires maternal da+ function.

EFFECTS OF INTRARENAL ADMINISTRATION OF DOPAMINE (DA) ON RENAL BLOOD FLOW (RBF) IN CONSCIOUS FETAL AND ADULT SHEEP IN VITRO DA RECEPTOR FINDINGS

Effects of intrarenal boluses of OA (0.125 to 16 ug/kg of body wt.) on RBF were studied in chronically catheterized fetal (F) lambs (129-137 days; term 145 days) and adult (A) sheep. Changes in RBF were continuously monitored by doppler flowmeter. Effects of DA alone and during α and β adrenergic blockade were studied. Blood pressure was unchanged during DA infusion. DA alone in F produced no change in RBF (%ΔRBF) at doses 2 ug/kg decreased RBF in a dose response relation (r=0.84). Decreased RBF in A was seen only at >8 ug/kg. F were less sensitive to DA than A when DA was corrected for RBF (ug/kg/ml RBF). Following adrenergic blockade (%ΔRBF-B), DA produced vasodilation in F and A; the DA dose required for vasodilation was 10 times greater in F than A. In vitro DA-receptor characterization was done using the opposite kidney removed at surgery. Similar DA receptor affinity between F (Kd 66.3±10.4 nM) and A (Kd 70.5±6.4 nM) as well as DA receptor density (1.08±0.13 and 0.90±0.22 pM/mg protein respectively) were found. Present results demonstrate that DA has less vasodilatory effect in F than A during adrenergic blockade but this effect is not secondary to a difference in receptor affinity or density, suggesting a post-receptor phenomenon.

Reversal of guanethidine- and diethyldithiocarbamate-induced amnesia by peripherally-administered catecholamines

The effect of peripherally-administered catecholamines on guanethidine- and diethyldithiocarbamate-induced amnesia of a PA training in mice was investigated. The amnesic effect of guanethidine could be blocked with 50 mg/kg DA, or 0.75 mg/kg NE when given either before, immediately, or 10 min after but not 90 min following PA. Epinephrine or a lower dose of DA could not attenuate the guanethidine-induced amnesia. The amnesic effect of diethyldithiocarbamate could be blocked with 50 mg/kg DA, 0.75 mg/kg NE or 0.5 mg/kg E when given either before, immediately or 10 min after but not 90 min following PA. The amnesic effects of these compounds were interpreted in terms of their peripheral antiadrenergic actions.

The role of peripheral catecholamines in reserpine-induced amnesia

The effect of peripherally administered catecholamines on reserpine-induced amnesia of a PA training in mice was investigated. The amnesic effect of reserpine could be blocked with 50 mg/kg DA or 0.1 or 0.75 mg/kg NE when given ip either before, immediately, or 10 min after but not 90 min following PA. Epinephrine or a lower dose of DA could not attentrate the reserpine-induced amnesia. Syrosingopine, the peripherally acting reserpine analogue also produced time-dependent retention impairments. The amnesic effects of these Rauwolfia alkaloids were interpreted in terms of their peripheral antiadrenergic actions.