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L X Cubeddu

Publications and source records attributed to L X Cubeddu.

104 records · Page 6Linked to original sources
PubMed1982

Rate and duration of stimulation determine presynaptic effects of haloperidol on dopaminergic neurons.

Superfused rabbit neostriatal slices prelabeled with [3H]dopamine ([3H]DA) were polarized with electrical pulses (12 V, 1 ms). Although transmitter release showed a proportional increase with a greater number of pulses (30-360 pulses), flat frequency-release curves were obtained. Haloperidol (0.03-0.3 micro M) enhanced 3H overflow without affecting its metabolism or time course, and antagonized apomorphine-induced inhibition of transmitter release. Maximal enhancement of release by haloperidol was obtained with 30-60 pulses delivered at a rate of 3 Hz, whereas much less facilitation of release was seen at 0.3 and 1 Hz (30-90 pulses) or with 360 pulses at either of the three frequencies. Therefore, the slope of the frequency-release curve was markedly increased by haloperidol. These results indicate that activation of presynaptic DA receptors, and thus facilitation of release by haloperidol was highly dependent on the rate and duration of stimulation of striatal dopaminergic terminals. In these neurons the feedback loop seems to act physiologically to depress the slope of the frequency-release curve.

Animals↗
PubMed1982

Effects of chemical sympathectomy on the increases in plasma catecholamines and dopamine-beta-hydroxylase induced by forced immobilization and insulin-induced hypoglycemia: origin and fate of plasma dopamine-beta-hydroxylase.

The effect of acute stresses on plasma norepinephrine, epinephrine and dopamine-beta-hydroxylase (DBH) were evaluated in control and 6-hydroxydopamine-treated, awake cannulated guinea pigs. Forced immobolization for 1 hr caused a 3- and 5-fold increase in plasma DBH and norepinephrine, respectively. Pretreatment with 6-hydroxydopamine (23 mg/kg b.wt.i.a., 72 and 48 hr before stress) reduced by 70% the increase in plasma DBH and totally prevented the rise in plasma catecholamines evoked by the restraining stress. Injection of insulin (5 U/kg b.wt.i.a.) induced a 60% decrease in blood glucose, a 1-fold increase in plasma DBH and a selective 4-fold increase in plasma epinephrine; these effects were not modified by chemical sympathectomy. Our results indicate that forced immobilization and hypoglycemia produce a preferential activation of the sympathetic postganglionic nerves and of the adrenal medulla, respectively, and that in guinea pigs both stresses increase plasma DBH. The kinetics of disappearance of plasma DBH were studied after subjecting the guinea pigs for 1 hr to forced immobilization. Although 7 of 12 animals showed a biphasic rate of fall of plasma DBH, in each case there was a rapid initial fall possibly due to the "distribution" of the enzyme with a T1/2 of 1.65 hr. Similar findings were observed in 6-hydroxydopamine-treated guinea pigs. These results suggest that the distribution of DBH is the most important process in reducing the augmented plasma DBH levels elicited by a short-term stress and that this process is not dependent on the integrity of the sympathetic nerves nor on the adrenal or sympathetic origin of the enzyme. This study supports the view that the ratio, content of releasable DBH present in sympathetic nerves and adrenal glands/total circulating pool of DBH, is the factor that determines whether an increase in plasma DBH would occur in animals exposed to an acute stress.

Animals↗
PubMed1980

Presynaptic effects of 2-aminotetralins on striatal dopaminergic neurons.

The present study evaluated whether 2-amino-5,6-dihydroxy-1,2,3,4,-tetrahydronaphthalene (A-5,6 DTN) and its 6,7-dihydroxy isomer (A-6,7 DTN) had effects on striatal dopaminergic terminals in addition to their well known action as agonists on postsynaptic dopamine (DA)-receptors. The presynaptic effects of 2-aminotetralins were evaluated on rat striatal tissue slices prelabeled with [3H]DA. Both, A-5,6 and A-6,7 DTN enhanced the basal efflux of radioactive products in a concentration-dependent fashion. Benztropine (1 microM) antagonized the releasing effects of low concentrations of both drugs (0.1-3.0 microM). Apomorphine and A-5,6 DTN (alpha rotamers, trans conformation) were 3 to 5 times more potent than A-6,7 DTN (beta rotamer, trans conformation) in inhibiting rat striatal monamine oxidase. This effect could account for the 50-fold greater potency of A-6,7 than A-5,6 DTN in enhancing the efflux of [3H]dihydroxyphenylacetic acid. A-5,6 DTN, A-6,7 DTN and apomorphine (0.3 microM each), reduced by 30% the depolarization elicited overflow of radioactive products. In summary, A-5,6 and A-6,7 DTN seem to enter DA-terminals and storage vesicles to accelerate the efflux of [3H]DA and 3H-dihydroxyphenylacetic acid and act upon presynapatic receptors to inhibit transmitter release. A greater selectivity for monamine oxidase inhibition was found with the alpha rotameric agents. The present study indicates that A-5,6 and A-6,7 DTN have marked presynaptic effects on rat striatal DA-containing neurons in addition to their well known effects as agonists on postsynaptic DA receptors.

2-Naphthylamine↗
PubMed1975

Release of norepinephrine and dopamine-beta-hydroxylase by nerve stimulation. V. Enhanced release associated with a granular effect of a benzoquinolizine derivative with reserpine-like properties.

A reserpine-like agent, 2-hydroxy-2-ethyl-3-isobutyl-9,10-dimethoxy-1,2,3,4,6,7,-hexa-hydro-11b-H-benzo[a]quinolizine (BQZ), at concentrations that do not inhibit phosphodiesterase activity, produces a marked increase in the outflow of 3-H-dihydroxyphenyl-ethyleneglycol from the isolated, perfused cat slpeen prelabeled with 3-H-norepinephrine (3-H-NE). The increased intraneuronal levels of catechols probably account for the inhibition of the conversion of 1-minus14C-L-tyrosine to 1-minus14C-L-dopa which is observed in the presence of the drug. In addition, in the presence of 0.9 muM BQZ, there is a 2.5- to 3-fold increase in the nerve stimulation-mediated overflow of NE, 3-H-NE, total 3-H and dopamine-beta-hydroxylase activity. A highly significant positive correlation was observed between the increase in the spontaneous release of 3-H and the enhanced exocytotic release of transmitter by nerve stimulation. These results suggest that either a primary alteration of the storage granule membrane or the subsequent enhanced intraneuronal levels of NE or NE metabolites may be responsible for the enhanced exocytotic release by nerve stimulation. In the presence of 0.9 muM BQZ, addition of 3 muM cocaine produces an increase in the nerve stimulation-mediated overflow of NE and an inhibition of the formation of 3-H-dihydroxyphenylethyleneglycol. In addition, there is a 20 to 30% decrease in the overflow of 3-H and dopamine-beta-hydroxylase activity and a marked delay in the outflow of the enzyme elicited by nerve stimulation. These results suggested that, in the presence of BQZ, a large fraction of the NE released during nerve stimulation is recaptured into the nerve terminals where it is subsequently metabolized to 3-H-dihydroxyphenylethyleneglycol. The enhanced exocytotic release of NE, the extensive presynaptic metabolism of the recaptured transmitter subsequent to release by nerve stimulation, and inhibition of norepinephrine synthesis all appear to contribute to the accelerated depletion of tissue NE which is observed when the splenic nerves are stimulated in the presence of 0.9 muM BQZ. These results provide an explanation for the accelerated depletion of tissue NE in animals treated with reserpine-like compounds when the sympathetic innervation is intact.

2H-Benzo(a)quinolizin-2-ol, 2-Ethyl-1,3,4,6,7,11b-↗
PubMedDate not supplied

Ondansetron for nausea and vomiting associated with moderately emetogenic cancer chemotherapy.

This multicenter, randomized, double-blind study compared the efficacy and tolerability of ondansetron 8 mg twice daily for 3 days with placebo in preventing nausea and vomiting in 81 patients receiving cyclophosphamide-doxorubicin-based chemotherapy. The first dose of study drug was administered 30 minutes before the initiation of chemotherapy. Patients received a rescue antiemetic if the investigator deemed it necessary or if the patient experienced more than two emetic episodes during the 3-day study. Sixty-one percent of patients treated with ondansetron compared with 6% of patients receiving placebo (P < 0.001) had no emetic episodes during the 3-day study. Among patients with at least one emetic episode, the mean time to emesis was 24 hours 18 minutes in the ondansetron group compared with 8 hours 1 minute in the placebo group (P < 0.001). In the intent-to-treat analysis, 78% of patients in the ondansetron group and 29% of patients in the placebo group completed the study with no need for rescue therapy. Clinical laboratory and adverse-event profiles were similar between groups. The most common adverse event was headache, occurring in 23% of ondansetron patients and 24% of placebo patients. This study is the first double-blind, placebo-controlled trial to demonstrate that ondansetron 8 mg twice daily is effective in the prevention of nausea and vomiting associated with cyclophosphamide-doxorubicin-based chemotherapy. The twice-daily regimen may encourage patient compliance and may be more cost-effective than regimens that need to be given three times daily.

Antibiotics, Antineoplastic↗
PubMedDate not supplied

Cerebrospinal fluid and plasma dopamine-beta-hydroxylase activity in human hypertension.

Cerebrospinal fluid (CSF) and plasma dopamine-beta-hydroxylase (DBH) activity was measured in 22 normotensive (NT), 31 essential hypertensive (EH), and 11 renal hypertensive (RH) patients. Although no differences were observed in their plasma DBH, the mean CSF-DBH activity and specific activity of EH were significantly lower than those of NT and RH patients. Very low CSF-DBH (less than 0.15 units/ml of CFS or less than 0.5 units/mg of CSF protein) was found only in EH (26% of EH). Of the 31 EH patients, 19(60%) had CSF-DHB activities lower than 0.5 units/ml, whereas only 5 of 22 NT (23%) and no RH fell within this range. Nevertheless, 20% of EH, 55% of NT, and 40% of RH patients had CSF-DBH activities above the mean value for NT (less than 0.9 units/ml). NT subjects with very low plasma DBH (less than 50 units/ml) had CSF-DBH activities that fell within normal range. With the exception of these subjects, the specific activity of CSF-DBH was always lower than that of the plasma enzyme. The concentration of albumin, alpha 1, beta, and gamma globulins was measured in plasma and CSF obtained from the last five NT, four EH, and two RH patients. A positive linear relationship was obtained when the log of the plasma/CSF concentration ratio for these proteins was plotted against their molecular weight. Similar slopes and intercepts were obtained for these patients, suggesting that no major differences seem to exist in their blood-brain-barrier permeability to proteins. The results suggest that measurements of CSF-DBH could be of help in the differential diagnosis of human hypertension and in the neurochemical characterization of EH. If CSF-DBH reflects central noradrenergic activity, its reduction might indicate the existence of a central catecholaminergic defect in a subgroup of EH patients.

Adolescent↗
PubMedDate not supplied

A comparison of verapamil and propranolol for the initial treatment of hypertension. Racial differences in response.

We compared verapamil and propranolol hydrochloride for monotherapy of hypertension. Verapamil lowered blood pressure (BP) more effectively than propranolol in black and white patients. Verapamil was equally effective in blacks and whites, whereas propranolol was more effective in whites. Heart rate was reduced by 6.0 beats per minute by verapamil, and by 13.6 beats per minute by propranolol. In blacks, verapamil lowered systolic BP 16.9 vs 8.1 mm Hg for propranolol; verapamil reduced diastolic BP 12.8 vs 8.6 mm Hg for propranolol. In whites, verapamil lowered systolic BP 19.0 vs 12.7 mm Hg for propranolol; verapamil reduced diastolic BP 16.7 vs 12.3 mm Hg for propranolol. Increases in systolic BP were observed in 22% and 3.4% of patients receiving propranolol and verapamil, respectively. The PR interval was increased from 163.5 to 174.9 ms for verapamil vs 160.3 to 164.4 ms for propranolol. Constipation (15%) and headaches (10%) were most frequent complaints for verapamil vs fatigue (18%) and dizziness (7%) for propranolol. Changes in blood biochemistry values were of small magnitude. We conclude that verapamil monotherapy is a safe and effective means of achieving BP control in patients with essential hypertension.

Adult↗
PubMedDate not supplied

Urinary excretion of nitric oxide metabolites in runners, sedentary individuals and patients with coronary artery disease: effects of 42 km marathon, 15 km race and a cardiac rehabilitation program.

BACKGROUND: The mechanisms by which regular exercise is associated with decreases in all-cause and cardiovascular mortality are unknown. Nitric oxide (NO) may have a role, as it is known to be an important factor in cardiovascular regulation. The relationships between physical activity and systemic formation of NO were evaluated in healthy volunteers and in patients with coronary artery disease (CAD). METHODS: Urinary excretion of NO metabolites (nitrates + nitrites) was measured in 50 men. Group 1 comprised 14 highly trained runners (90 km/week) who were tested before and after a marathon race of 42.2 km. Group 2 comprised 11 well trained men (64 km/week) who were tested before and after a 15 km race. Group 3 comprised 12 sedentary individuals who gave a single urine sample. Group 4 comprised 13 patients with CAD who were tested before and after a 6 km walk. RESULTS: Group 1 showed the highest basal levels of urinary NO metabolites: 10.10 mmol/g creatinine; they were followed by group 2, with 5.60 mmol/g creatinine, group 3 with 1.59 mmol/g creatinine and patients with CAD (group 4), who had 0.35 mmol/g creatinine. After the marathon, those in group 1 showed a significant (P=0.0001) reduction of 80% in the excretion of NO metabolites. The 15 km race (group 2 and the 6 km walk (group 4), produced nonsignificant reductions in NO excretion. Patients with CAD were prospectively evaluated before and after a 12-week cardiac rehabilitation program. Their urinary excretion of NO metabolites (mmol/g creatinine) at the end of the program was 157% higher than at baseline (P=0.034). A positive, significant correlation (P=0.006) was observed between the increases in exercise capacity [in METs (one MET is equal to the body's oxygen consumption at rest, and corresponds to 3.5 ml/Kg/min)] and in NO metabolite excretion induced by the 12-week program. CONCLUSIONS: The baseline urinary excretion of NO metabolites increases with increasing levels of physical activity (chronic aerobic exercise). Patients with CAD had lowest levels of urinary NO metabolites and these increased in direct proportion with the gain in functional capacity. These findings suggest that increased NO production may be a major adaptive mechanism by which chronic aerobic exercise training benefits the cardiovascular system. The marked increase in NO production induced by long-term, high levels of aerobic exercise may be protective in athletes undertaking strenuous levels of exercise.

Coronary Disease↗