Effects of opioid substances on cAMP response to the beta-adrenergic agonist isoproterenol in human mononuclear leukocytes.

The effects of different opioid substances on isoproterenol and forskolin-stimulated cyclic AMP (cAMP) intracellular accumulation, and on the binding of 125I-pindodol (IPIN) to beta 2-adrenoceptors were studied in human mononuclear leukocytes (MNL). The opioids used were alpha-endorphin, beta-endorphin, tau-endorphin, DAGO (a mu receptor agonist), dermenkephalin (a delta receptor agonist and morphine. Only morphine was able to increase the cAMP response to isoproterenol. The EC50 of isoproterenol for cAMP accumulation was shifted leftward by morphine; this effect was blocked by naloxone. On the contrary, the cAMP response to forskolin, direct activator of adenylate cyclase, was similar in the control test with respect to the experiments with morphine. The five opioid peptides induced no changes in the dose-response curves with isoproterenol and forskolin. Furthermore, none of the opioids induced changes in the IPIN binding. Our data show that morphine is able to exert a significant enhancement of the response of beta 2-adrenergic receptors to isoproterenol in human mononuclear leukocytes. This effect seems to be mediated by mu opioid receptors and seems to involve G protein.

Evidence for interactions between HLA system class I and beta-adrenergic receptors in human mononuclear leukocytes.

In order to determine the possible interactions between histocompatibility leukocyte antigen (HLA) -class I antigens and beta-adrenergic receptors, we evaluated the effects of anti-HLA class I monoclonal antibodies on beta-adrenoceptor-mediated intracellular production of cAMP in human mononuclear leukocytes. Moreover, we studied whether anti-HLA class I monoclonal antibodies inhibit the binding of a specific radioligand to the beta-adrenoceptors, and, conversely, whether both isoproterenol and propranolol interfere with the binding (evaluated by a cytofluorometric assay) of the anti-HLA class I monoclonal antibodies to the cell membrane. Our results showed that anti-HLA class I monoclonal antibodies induced a significant beta-adrenergic-dependent increase in intracellular cAMP whereas anti-HLA class II and antimelanoma monoclonal antibodies were ineffective. Moreover anti-HLA class I monoclonal antibodies inhibited, in part, the specific binding of a beta-adrenergic radioligand, although they did not induce the internalization of the beta-adrenoceptors. On the other hand, both isoproterenol and propranolol induced a significant decrease in the peripheral blood mononuclear cell expression of HLA-class I molecules. Our data suggest that important interactions between major histocompatibility complex gene products and the beta-adrenergic receptors may occur in human cells.

Norepinephrine-induced plasma dopamine decrease in man: pharmacological evidence of the involvement of alpha 2-adrenoceptors.

OBJECTIVE: The purposes of this study were: (1) to test whether intravenous infusion of norepinephrine can affect plasma dopamine levels; and (2) to explore to what extent dopamine-2 or alpha 2-receptors play a role in this response. DESIGN: Norepinephrine infusion in man was performed to test whether the increase in norepinephrine during sympathetic stimulation can affect dopamine release. Specific antagonists of presynaptic dopamine-2 and alpha 2-receptors were administered to test the receptor(s) involved in this possible regulatory phenomenon. METHODS: Plasma catecholamine levels were investigated in seven normal subjects before and after administration of domperidone (dopamine-2 antagonist), yohimbine (alpha 2-antagonist) and norepinephrine. RESULTS: Both oral domperidone and yohimbine induced a significant increase in both plasma norepinephrine and plasma dopamine. Norepinephrine infusion induced a significant decrease in plasma dopamine. Pretreatment with domperidone only partially counteracted this inhibitory effect of norepinephrine infusion, whereas yohimbine fully counteracted it. CONCLUSIONS: Our data show that norepinephrine may act as a hormone at plasma concentrations as low as 450 pg/ml. The norepinephrine-induced plasma dopamine decrease seems to be alpha 2-adrenoceptor-mediated. This norepinephrine effect may be involved in the physiologic decrease in plasma dopamine that we demonstrated in the upright position in normal subjects.

Intraindividual variation of beta 2-adrenergic receptors on mononuclear leukocytes and their relationships with endogenous plasma catecholamines in man.

The interindividual and intraindividual variations of both MNL beta 2-adrenergic receptor density and dissociation constant of binding were evaluated in 19 healthy volunteers. In addition the possible relationships between catecholamine plasma levels and MNL beta 2-adrenergic receptor density were studied in 8 of these subjects. The volunteers were studied three times with ten days' interval. There was a significant inverse relationship between receptor density and norepinephrine plasma levels, only. Neither epinephrine nor dopamine were correlated with receptor density. Interindividual coefficient of variation was 29.57%. The mean value of the intraindividual coefficients of variation was 14.1%, while the mean value of the analytical coefficients of variation was 10%. Our results are at some variance with data in the literature and may contribute to elucidate the role of MNL beta 2-adrenergic receptors as an index of sympathetic function in man.

Absence of correlations between plasma catecholamine levels and mononuclear leukocyte beta 2-adrenergic receptors in the elderly.

To assess the effects of aging on catecholamine plasma levels and mononuclear leukocyte (NML) beta 2-adrenergic receptors and on the possible relationships between these two parameters, we evaluated two groups of human subjects: 18 elderly volunteers (age 65-70 years) and 13 young volunteers (age 21-35 years). Norepinephrine plasma levels were significantly higher in the elderly subjects compared to the younger ones (P less than 0.05), whereas plasma epinephrine levels were not different. Also MNL beta 2-adrenoceptor density was significantly higher in elderly subjects (P less than 0.05). The binding dissociation constants were not significantly different. In young subjects there was a significant (P less than 0.02), inverse relationship between receptor densities and plasma norepinephrine levels; this relationship was not present in elderly persons. Our data suggest that the increase in beta 2-adrenoceptors may be due to a compensatory phenomenon, owing to the reduced beta-adrenergic sensitivity observed in the elderly subjects; moreover, the regulation of beta-adrenoceptors by plasma catecholamines seems to be altered by aging.

Neuroendocrine effects of interferon alpha 2-a in healthy human subjects.

The acute effects of interferon alpha-2a (3 x 10 IU im) on catecholamine and immunoreactive beta endorphin plasma levels, cortisol serum levels and lymphocyte beta 2-adrenoceptor density were evaluated in ten healthy volunteers. Interferon induced a significant increase in plasma norepinephrine; there was an increased norepinephrine standing response, too. On the contrary, epinephrine standing response was reduced by interferon. Lymphocyte beta 2-adrenoceptors decreased significantly after interferon administration; dissociation constant of binding was unchanged. Cortisol serum levels increased significantly with respect to control test, whereas immunoreactive beta endorphin did not change. These results support the hypothesis of functional relationships between neuroendocrine and immune systems; moreover they may be useful in clinical trials given the administration of interferon alpha in an increasing number of diseases.