Biomedical subjects

A Conti

Publications and source records attributed to A Conti.

At least 163 records · Page 9Linked to original sources

PubMed1994

Colony-stimulating activity and hematopoietic rescue from cancer chemotherapy compounds are induced by melatonin via endogenous interleukin 4.

We have reported that melatonin may rescue bone marrow cells from apoptosis induced either in vivo or in vitro by cancer chemotherapy compounds via bone marrow T-cells and endogenous release of granulocyte-macrophage colony-stimulating factor. Here we show that the number of granulocyte/macrophage colony-forming units cultured with suboptimal concentrations of colony-stimulating factor was higher in the presence of melatonin both at physiological and pharmacological concentrations. CD4+,Thy-1.2+ cell depletion or addition of anti-mouse interleukin 4 monoclonal antibodies prevented both effects of melatonin. Upon incubation with etoposide, the concentration of myeloid precursors was 43 +/- 8 per 10(5) cells. The melatonin+etoposide value was 68 +/- 7, whereas that of melatonin+etoposide+anti-interleukin 4 was 38 +/- 6. Melatonin was also ineffective when bone marrow cells were separated in adherent and nonadherent populations. Supernatants from nonadherent cells incubated with melatonin proved to contain interleukin 4 activity which, however, showed its influence on unseparated bone marrow and adherent cells but not on nonadherent cells. It is proposed that melatonin represents a neuroendocrine regulator of interleukin 4 production in bone marrow T-helper cells. Interleukin 4 may then stimulate adherent stromal cells to produce granulocyte/macrophage colony-stimulating factor. Such a neuroendocrine-cytokine mechanism may explain the hematopoietic rescue of melatonin as well as its antitumoral and immunoenhancing properties.

Animals↗

PubMed1994

2-Alkynyl derivatives of adenosine-5'-N-ethyluronamide: selective A2 adenosine receptor agonists with potent inhibitory activity on platelet aggregation.

A series of new 2-alkynyl and 2-cycloalkynyl derivatives of adenosine-5'-N-ethyluronamide (NECA) and of N-ethyl-1'-deoxy-1'-(6-amino-2-hexynyl-9H-purin-9-yl)-beta-D- ribofuranuronamide (1, HE-NECA), bearing hydroxy, amino, chloro, and cyano groups in the side chain, were synthesized. The compounds were studied in binding and functional assays to assess their potency for the A2 compared to A1 adenosine receptor. The presence of an alpha-hydroxyl group in the alkynyl chain of NECA derivatives accounts for the A2 agonist potency, leading to compounds endowed with sub-nanomolar affinity in binding studies. However, these analogues also possess good A1 receptor affinity resulting in low A2 selectivity. From functional experiments the 4-hydroxy-1-butynyl (6) and the 4-(2-tetrahydro-2H-pyranyloxy)-1-butynyl (16) derivatives appear to be very potent in inducing vasorelaxation without appreciable effect on heart rate. The new compounds were also tested as inhibitors of platelet aggregation induced by ADP. Introduction of an alpha-hydroxyl group in the alkynyl side chain caused a greater increase in antiaggregatory activity than either NECA or HE-NECA, resulting in the most potent inhibitors of platelet aggregation so far known in the nucleoside series. The presence of an alpha-quaternary carbon such as the 3-hydroxy-3,5-dimethyl-1-hexynyl (12) and the 3-hydroxy-3-phenyl-1-butynyl (15) derivatives markedly reduced the antiaggregatory potency without affecting the A2 affinity. The hydrophobicity index (k') of the new nucleosides barely correlated with the binding data, whereas high k' values were associated with increased A2 vs A1 selectivity but with reduced activity in all functional assays. Some of the compounds synthesized possess interesting pharmacological properties. Compounds having an appropriate balance between vasorelaxation and antiplatelet activity, if confirmed in vivo, deserve further development for the treatments of cardiovascular disorders.

Adenosine↗

PubMed1994

Hematopoietic rescue via T-cell-dependent, endogenous granulocyte-macrophage colony-stimulating factor induced by the pineal neurohormone melatonin in tumor-bearing mice.

We investigated whether melatonin can affect tumor growth and/or hematopoiesis in mice transplanted with Lewis lung carcinoma and treated with cyclophosphamide or etoposide. These agents were injected i.p. for 5 days at two different cumulative doses (cyclophosphamide, 40 and 160 mg/kg body weight; etoposide, 20 and 40 mg/kg body weight) from day 8 through day 12 after tumor transplantation. Melatonin was injected s.c. at a dose of 1 mg/kg body weight/day, from day 8 throughout the experiments and from days 8 through 12 or from day 13 onwards. Melatonin did not influence tumor growth but selectively counteracted bone marrow toxicity when administered together with the cancer chemotherapy compounds without interfering with their anticancer action. In vitro, melatonin proved to counteract apoptosis in bone marrow cells incubated with etoposide. Such protection was reflected by an increased frequency of granulocyte/macrophage-colony forming units but not of the pluripotent spleen-colony forming units. The effect of melatonin was neutralized by anti-granulocyte/macrophage-colony-stimulating factor monoclonal antibodies. When athymic, T-cell-deficient mice were used as bone marrow donors, melatonin did not exert any protective effect. This suggested that melatonin is able to stimulate the endogenous production of granulocyte/macrophage-colony-stimulating factor via bone marrow T-cells. Due to the well known lack of toxic and undesirable side effects of melatonin, these findings might have a straightforward clinical application.

Animals↗

PubMed1994

A randomized study with the pineal hormone melatonin versus supportive care alone in patients with brain metastases due to solid neoplasms.

BACKGROUND: Unresectable brain metastases remain an untreatable disease. Because of its antitumor cytostatic action and its anticonvulsant effect, the pineal hormone melatonin could constitute a new effective agent in the treatment of brain metastases. The current study was performed to evaluate the effect of melatonin on the survival time in patients with brain metastases due to solid neoplasms. METHODS: The study included 50 patients, who were randomized to be treated with supportive care alone (steroids plus anticonvulsant agents) or with supportive care plus melatonin (20 mg/day at 8:00 p.m. orally). RESULTS: The survival at 1 year, free-from-brain-progression period, and mean survival time were significantly higher in patients treated with melatonin than in those who received the supportive care alone. Conversely, steroid-induced metabolic and infective complications were significantly more frequent in patients treated with supportive care alone than in those concomitantly treated with melatonin. CONCLUSIONS: The pineal hormone melatonin may be able to improve the survival time and the quality of life in patients with brain metastases due to solid tumors.

Adult↗

PubMed1994

Prevalence of anti-HCV in institutionalised mentally handicapped subjects.

Data on the prevalence of antibody to hepatitis C virus among 278 subjects in an institution for the mentally handicapped were analysed by risk factors. A prevalence of 4% was found, higher than blood donors belonging to the same area (1.4%). No differences in prevalence with regard the length of residence, age, sex, degree of retardation or for presence of HBV markers were observed.

Adolescent↗

PubMed1994

Noradrenergic modulation of lymphohematopoiesis.

Adrenergic agents can affect hematopoiesis after syngeneic bone marrow transplantation (BMT) in mice. In particular, chemical sympathectomy by 6-hydroxydopamine and/or administration of various doses of the alpha 1-adrenergic antagonist prazosin were shown to increase the concentration of blood granulocytes, platelets and bone marrow granulocyte--macrophage-colony forming units (GM-CFU), and to induce a granulocytic hyperplasia of the spleen. Here we show that while enhancing myelopoiesis, prazosin decreased the number of spleen B- and T-lymphocytes as well as the number of thymocytes after BMT. The relative proportion of thymocyte subpopulations was not affected, suggesting a non-corticosteroid related mechanism. Furthermore, NK activity and primary cytotoxic T-lymphocyte (CTL) response to Lancy vaxinia virus was impaired in mice treated with prazosin after BMT. When noradrenaline was added in bone marrow cultures, it decreased the number of GM-CFU and such an effect was counteracted by prazosin. These findings suggest that hematopoiesis is under an alpha-adrenergic control.

Animals↗

PubMed1994

Low-dose interleukin-2 subcutaneous immunotherapy in association with the pineal hormone melatonin as a first-line therapy in locally advanced or metastatic hepatocellular carcinoma.

Experimental studies have showed that hepatocellular carcinoma (HCC) cells are susceptible to cytolysis of interleukin (IL)-2-activated lymphocytes. Moreover, our previous studies demonstrated that the pineal neurohormone melatonin (MLT) may enhance IL-2 efficacy. On this basis, a study was started with low-dose IL-2 (3 million U/day subcutaneously for 6 days/week for 4 weeks) plus MLT (50 mg/day orally every day given in the evening) as a first-line therapy of unresectable HCC. The study included 14 patients. Objective tumour regressions were obtained in 5/14 (36%) patients (one complete response, four partial responses), with a median duration of 7+ months. 6 patients had stable disease, while the other 3 progressed. Toxicity was low in all cases. This study shows that the neuroimmunotherapy with low-dose IL-2 plus MLT is a new well-tolerated and effective therapy of advanced HCC.

Adult↗

PubMed1994

Effects of the new A2 adenosine receptor antagonist 8FB-PTP, an 8 substituted pyrazolo-triazolo-pyrimidine, on in vitro functional models.

1. We have characterized the in vitro pharmacological profile of putative A2 adenosine antagonists, two non-xanthine compounds, 5-amino-8-(4-fluorobenzyl)-2-(2-furyl)-pyrazolo [4,3-e]-1,2,4-triazolo[1,5-c] pyrimidine (8FB-PTP) and 5-amino-9-chloro-2-(2-furyl 1,2,4-triazolo [1,5-c] quinazoline (CGS 15943), and the xanthine derivative (E)7-methyl-8-(3,4-dimethoxystyryl)-1,3-dipropyl- xanthine (KF 17837). 2. In binding studies on bovine brain, 8FB-PTP was the most potent (Ki = 0.074 nM) and selective (28 fold) drug on A2 receptors, whereas CGS 15943 and KF 17837 exhibited affinity in the low and high nanomolar range, respectively, and showed little selectivity. 3. In functional studies, 8FB-PTP antagonized 5'-N-ethyl-carboxamidoadenosine (NECA)-induced vasorelaxation of bovine coronary artery (pA2 = 7.98) and NECA-induced inhibition of rabbit platelet aggregation (pA2 = 8.20). CGS 15943 showed weak activity in the platelet aggregation model (pA2 = 7.43) and failed to antagonize NECA-induced vasodilatation. KF 17837 was ineffective in both models up to micromolar concentrations. 4. Antagonism of A1-mediated responses was tested versus 2-chloro-N6-cyclopentyladenosine (CCPA) in rat atria. 8FB-PTP and CGS 15943 also antagonized competitively the negative chronotropic response induced by CCPA. Conversely, KF 17837 was unable to reverse A1-mediated responses. 5. 8FB-PTP is a potent and competitive antagonist of responses mediated by A2 adenosine receptors. The data provided a basis to reduce, by further chemical modifications, the affinity at A1 receptor and therefore enhance A2 receptor selectivity.

Adenosine↗

PubMed1994

Adrenal medulla secretion in Cushing's syndrome.

To investigate whether chronic endogenous hypercortisolism might alter adrenomedullary phenylethanolamine N-methyltransferase activity, we measured epinephrine/norepinephrine (E/NE) ratios in the adrenal venous blood of 8 patients undergoing surgery for Cushing's syndrome and in 12 control subjects undergoing surgery for left kidney diseases. To investigate the adrenomedullary secretory activity in Cushing's syndrome, we measured basal E plasma levels in 24 patients and 32 age- and sex-matched normal control subjects, and we evaluated the adrenomedullary response to glucagon in 9 patients and in 22 age- and sex-matched normal subjects. Last, to clarify whether chronic endogenous hypercortisolism might modify E plasma levels through a modification of E metabolism, we measured the E MCR in four patients and four age-matched controls. Mean (+/- SEM) E/NE ratio in adrenal venous blood was similar in patients with Cushing's syndrome (4.61 +/- 0.78) and in the control group (4.71 +/- 0.74). Mean (+/- SEM) basal plasma E was significantly lower in patients with Cushing's syndrome (98.2 +/- 10.9 vs. 184 +/- 25.1 pmol/L, P < 0.01) than in the control group. Similarly, plasma NE also was reduced (0.75 +/- 0.09 vs. 1.10 +/- 0.07 nmol/L, P < 0.01). In patients with Cushing's syndrome the E response to glucagon was significantly reduced (P < 0.01). E MCR was almost identical in patients with Cushing's syndrome (1.48 +/- 0.10 L/min.m2) and in control subjects (1.51 +/- 0.10 L/min.m2). Our data demonstrate that: 1) chronic endogenous hypercortisolism is not able to change adrenomedullary phenylethanolamine N-methyltransferase activity and therefore the quality of adrenomedullary secretion; and 2) chronic endogenous hypercortisolism causes a decrease in basal and stimulated adrenomedullary activity without altering E MCR significantly. Therefore the adrenal medulla does not seem to play a pathogenetic role in the hypertension of Cushing's syndrome.

Adrenal Medulla↗

PubMed1994

Human alpha S1-casein like protein: purification and N-terminal sequence determination.

Casein components of human milk are generally reported to belong to the beta- and kappa-groups. In this research human casein fraction was obtained from pooled mature milk, either by ultracentrifugation or by acid precipitation. In both cases a minor component with a slightly higher mobility in SDS-PAGE than beta-casein was identified. The protein was purified to homogeneity, the N-terminal sequence of the first 14 amino acid residues of this new human casein subunit shows a high degree of homology with the alpha s1-casein sequences from other species.

Amino Acid Sequence↗

PubMed1994

Housestaff coverage in a nonteaching community hospital.

In August 1992, a project team of senior medical and administrative personnel was formed (Housestaff Coverage Project Team) at the Park Ridge Health System, Rochester, N.Y.. The team was given a mandate to address housestaff coverage, primarily from an economic standpoint. Through total quality management (TQM), the project team sought to develop a house coverage plan that was sustainable, efficient, and effective. A plan was developed that includes three layers of service. A minimum "standard hospital coverage" would be available to all physicians and their patients and cover the basic needs of admission, crisis intervention, and issues of length of stay. A complete level of service would be available under the title of "case management" and would consist of total patient management, under the direction of the attending physician, from admission through discharge. The third level of service available to both "standard" and "case managed" patients would be a "consultative service." The latter would function as a traditional in-house medical service and would bill for its services. Park Ridge Hospital believes it has developed a system of housestaff coverage that is sustainable, efficient, and effective. An evaluation mechanism, primarily addressed at length of stay, will tell if we are correct in this assumption.

Hospitals, Community↗

PubMed1994

Analysis of human hematopoietic stem cell populations.

Purification of human hematopoietic stem cells (HSC) may be useful clinically for preparation of tumor-free grafts to be used for autologous transplantation and as targets for gene therapy. To analyze the phenotype of the human HSC, assays were used that measure the unique properties of stem cells, i.e., their long-term repopulating ability and their multilineage potential. These assays include: (1) an in vitro long-term hematopoietic culture system, using the murine bone marrow stromal cell line SyS1, which supports both B lymphopoiesis and myelopoiesis; (2) fetal human bone grafts implanted in SCID-hu mice, in which maintenance of CD34+ cells and B and myeloid differentiative capacity of candidate stem cell populations may be measured; (3) fetal human thymus grafts in SCID-hu mice, which allow the analysis of in vivo T-cell potential of a candidate stem cell population. Stem cells in adult bone marrow (ABM) or cytokine-mobilized peripheral blood (MPB) are thought to express CD34 but lack expression of markers indicating lineage commitment. This CD34+ Lineage- (Lin-) subpopulation has been isolated by fluorescence-activated cell sorting and tested for activity in the assays described here. CD34+ Lin- cells from both ABM and MPB demonstrated long-term engraftment in the SCID-hu bone model. This CD34+ Lin- population can be subfractionated further using an antibody to Thy-1. The Thy-1+ subset of CD34+Lin- cells is enriched for both long-term culture-initiating cells (LTC-1C) and has the ability to engraft in vivo.

Animals↗

PubMed1994

[Serum levels of the carboxyterminal telopeptide of type I collagen in patients with thyroid disorders].

Serum carboxyterminal cross-linked telopeptide of type I collagen (ICTP) levels, marker of bone resorption, were evaluated in 35 patients with hyperthyroidism (age range: 21-68 years) and in 35 with hypothyroidism (age range: 28-69 years). Data obtained were compared with those recorded in an age and sex matched control group. In patients with hyperthyroidism, serum ICTP levels were significantly higher than in controls (mean +/- SE: 9.1 +/- 0.7 vs 4.1 +/- 0.3 ng/ml; p < 0.0001). In patients with untreated hypothyroidism ICTP levels were significantly reduced (2.5 +/- 0.2 ng/ml, p < 0.0001); seven patients with hypothyroidism, evaluated after substitutive L-thyroxine treatment, showed a significant increase of ICTP levels (6th month: 5.9 +/- 0.7 ng/ml, p < 0.02). Taking into consideration all the data recorded in patients with both hyper- and hypothyroidism, serum ICTP levels were positively correlated with those of free T3 and free T4 and negatively correlated with those of TSH. In conclusion, our data show that repeated determinations of ICTP levels, which directly reflect the bone resorption activity, might be usefully employed in the evaluation of bone turnover in patients with thyroid disorders.

Adult↗

PubMed1994

Long-term follow-up of in situ carcinoma of the breast.

Eighty cases of duct carcinoma in situ (DCIS) of the breast have been investigated by a cohort-retrospective study. These consisted of 8.5 per 1,000 of 9,446 breast biopsies originally diagnosed as benign, between 1964 and 1976, with a mean follow-up of 17.5 years. There were forty-one cases (51%) of DCIS of clinging type (CC); 30 cases (37.%) of CC associated with other types of DCIS; nine cases of DCIS other than CC two of which were DCIS of comedo-type. Invasive duct carcinoma (IDC) subsequently developed in 11 patients (14%), whereas DCIS recurred in 5 (6%). The recurrence was ipsilateral in 12 of these 16 patients. IDC appeared more frequently, with high statistical significance, when the lesion present in the original biopsy showed pleomorphic (P) nuclei (ie, poorly differentiated cyto-nuclear morphology). The Standardized Morbidity Ratio (SMR) was 8.0 (95% CI; 2.9-17.5) with the general population as reference. IDC that developed following a lesion displaying P nuclei also showed a statistically significantly more aggressive behavior. It is suggested that when cases of DCIS are followed-up for a considerable length of time, a two-wave pattern of aggressiveness becomes apparent. IDC that develops after a poorly differentiated DCIS leads to death more precociously than that appearing after other types of DCIS, especially those showing more bland nuclear cytology.

Adult↗

PubMed1994

Pharmacology of the new selective A2a adenosine receptor agonist 2-hexynyl-5'-N-ethylcarboxamidoadenosine.

The pharmacological profile of 2-hexynyl-5'-N-ethylcarboxamidoadenosine (2HE-NECA, CAS 141018-30-6), a new selective A2a adenosine receptor agonist, was characterized. In binding studies on both rat and bovine brain, 2HE-NECA was more potent on A2a receptors (Ki = 2.2 and 1.5 nmol/l, respectively) than the reference A2a agonist, 2-[4-(2-carboxyethyl)-phenethylamino]-5'-N-ethylcarboxamidoaden osi ne (CPEC) or the non-selective adenosine agonist 5'-N-ethylcarboxamidoadenosine (NECA). The drug displayed a good A2a vs A1 receptor selectivity in brain tissues of both animal species (60- and 160-fold, respectively). In functional studies, 2HE-NECA showed marked vasodilating properties in rat aorta, bovine and porcine coronary arteries. The vasodilatory response in the porcine coronary preparation was greater for 2HE-NECA (EC50 = 23.3 nmol/l) than for CPEC (EC50 = 58.7 nmol/l) or NECA (EC50 = 76.6 nmol/l). In the rat Langendorff model, in which global ischemia was induced, 2HE-NECA (100 nmol/l) significantly prevented the risk of diastolic pressure and coronary perfusion pressure occurring during postischemic reperfusion. The in vitro antiaggregatory activity of 2HE-NECA (IC50 = 0.07 mumol/l), as tested in rabbit platelets, was higher than that found with NECA (IC50 = 0.2 mumol/l) or CPEC (IC50 = 2.16 mumol/l). In spontaneously beating rat atria, which are responsive to A1-receptor stimulation, 2HE-NECA did not show any negative chronotropic activity up to micromolar concentrations. In conscious spontaneously hypertensive rats, 2HE-NECA administered intraperitoneally caused a dose-dependent reduction in systolic blood pressure (ED30 = 0.005 mg/kg) with minimal reflex tachycardia.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenosine↗

PubMed1994

Pharmacology of the highly selective A1 adenosine receptor agonist 2-chloro-N6-cyclopentyladenosine.

The pharmacological profile of 2-chloro-N6-cyclopentyladenosine (CCPA, CAS 37739-05-2), a highly selective A1 adenosine receptor agonist, was characterized. Its effects were compared with those of the non-selective adenosine receptor agonist 5'-N-ethylcarboxamidoadenosine (NECA). In binding studies on both rat and bovine brain, CCPA was highly potent on A1 receptors (Ki = 1.3 and 0.5 nmol/l, respectively) and displayed good A1 vs A2a receptor selectivity (500- and 920-fold, respectively). In functional studies, CCPA showed marked negative chronotropic activity in spontaneously beating rat atria (EC50 = 8.2 nmol/l). This effect was antagonized dose-dependently by the A1 selective antagonist 8-cyclopentyl-1,3-dipropylxanthine (DPCPX). In the rat Langendorff model, in which global ischemia was induced, CCPA (3 nmol/l) prevented significantly the rise of diastolic pressure and coronary perfusion pressure during postischemic reperfusion. In vascular preparations, a functional activity responsive to A2a adenosine receptor stimulation, CCPA did not show any vasodilating properties up to micromolar concentrations, whereas NECA had a good relaxing activity in bovine coronary arteries (EC50 = 167 nmol/l). In rabbit platelets, a model sensitive only to A2a-receptor stimulation, CCPA did not elicit any relevant antiaggregatory properties, whereas NECA was found to be effective (IC50 = 200 nmol/l). Likewise, in an in vivo model of platelet aggregation in the rabbit using a non-invasive radioisotopic technique, CCPA (100 micrograms/kg, 30 min i.v. infusion) did not influence platelet function, whereas NECA (10 micrograms/kg, 30 min i.v. infusion) decreased peak value for platelet accumulation by 35%.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenosine↗

PubMed1994

[The adult patient with a congenital GH deficiency. Cholesterol-lowering effects of therapy with biosynthetic GH].

In adults with childhood onset GH deficiency, serum total and LDL cholesterol levels were significantly higher (p < 0.05 and < 0.01, respectively), while serum HDL cholesterol levels were significantly lower (p < 0.05) than those recorded in an age and sex matched control group. These biochemical alterations determined the presence of a marked increase of coronary risk indexes (total/HDL cholesterol and LDL/HDL cholesterol) which were significantly higher (p < 0.0001) than in controls. Serum VLDL and triglycerides levels were similar to those found in controls. After recombinant GH treatment (0.5 IU/kg/week, sc), serum total and LDL cholesterol levels were significantly reduced, becoming similar to those recorded in controls after six months' therapy. Serum HDL cholesterol levels, which were slightly reduced after 3 months, significantly increased after 6 months of GH treatment, becoming similar to those recorded in controls; no significant modifications were observed in VLDL cholesterol and triglycerides levels during treatment. The coronary risk indexes fell during GH treatment, but still remained higher than in controls. On the basis of these promising data, it is tempting to speculate that more prolonged GH treatment might be able to ameliorate the risk for cardiovascular diseases in adults with GH deficiency. Although further additional studies with a larger number of patients are needed to confirm these preliminary observations, adults with GH deficiency should be recommended to take into great consideration the control of other risk factors involved in the genesis of coronary disease.

Adult↗

PubMed1994

Modulation of hematopoiesis via alpha 1-adrenergic receptors on bone marrow cells.

We have recently demonstrated that adrenergic agents can affect hematopoiesis after syngeneic bone marrow transplantation in mice. In particular, chemical sympathectomy by 6-hydroxydopamine (6-OHDA) and/or administration of the alpha 1-adrenergic antagonist prazosin were shown to increase the concentration of blood granulocytes, platelets, and bone marrow colony-forming units-granulocyte/macrophage (CFU-GM), and to induce a granulocytic hyperplasia of the spleen. Here we show that prazosin can also enhance myelopoiesis and platelet formation in normal mice. Furthermore, noradrenaline and the alpha 1-adrenergic agonist methoxamine could directly inhibit the in vitro growth of GM-CFU. The effect of noradrenaline was counteracted by prazosin and by other alpha-adrenergic antagonists such as phentolamine and yohimbine, in the following order of potency: prazosin > phentolamine > yohimbine. In line with these results, we were able to demonstrate that 3H-prazosin binds specifically to both bone marrow cell membranes and intact bone marrow cells. Scatchard analysis of the binding to intact cells revealed the presence of two binding sites. A kd of 0.98 +/- 0.32 nM and a B max of 5 +/- 2.9 fM/2 x 10(6) cells characterized the higher affinity site, while the lower affinity site displayed a kd of 55.9 +/- 8.2 nM and a B max of 44 +/- 7.7 fM/mg protein. These saturation studies, together with competition experiments to evaluate the ability of various adrenergic compounds to displace 3H-prazosin binding, classified the higher affinity site as an alpha 1-adrenergic receptor. The remaining low affinity binding site remains to be characterized. Furthermore, separation of bone marrow cells by counterflow centrifugal elutriation (CCE) showed that the high-affinity binding is due to a lymphoid/stem cell fraction with no blasts and no GM-CFU progenitors. The low-affinity site was apparent on the rotor-off fraction, which was enriched with GM-CFU progenitor cells. These findings demonstrate that alpha-adrenergic receptors are present on bone marrow cells and participate in the regulation of hematopoiesis.

Animals↗