FurtherANNUAL REVIEWS (7,(22)(23)(24). Rather, I attempt to provide a theoretical framework within which to construct novel insights into this rapidly developing area, and discuss certain pitfalls in opiate-cardiovascular studies. BRIEF REVIEW OF CENTRAL AUTONOMIC-CARDiOVASCULAR PATHWAYSInformation regarding peripheral hemodynamic changes is detected by mechanoreceptors in the major arteries and relayed via vagal afferents to the brainstem. Stimulation of chemoreceptors, such as pulmonary "J" receptors found in the alveoli of the lung adjacent to pulmonary capillaries (25), can also result in the detection of changes in cardiorespiratory vari ables, which are likewise relayed via the ninth and tenth cranial nerves to Annu. Rev. Pharmacol. Toxicol. 1983.23:541-541. Downloaded from www.annualreviews.org by University of Nebraska -Lincoln on 09/19/13. For personal use only. .... ----------------I /SPLANCHNIC � . D " ME . EPI. NOREPI, · ENKEPH.Figu re J Central and peripheral autonomic pathways are represented in this simplified schematic of the neuronal circuitry that regulates cardiovascular responses. Solid lines gener ally represent parasympathetic innervations; dashed lines indicate pathways with greater direct relevance to sympathetic integration. The hypothalamus alone contains at least nine different nuclei with different anatomical and functional relationships among each other and with other autonomic nuclei. For a complete reference, see (26). Abbreviations AMYG Amygdala NTS Nucleus tractus solitarius LRN Lateral reticular nucleus LC Locus coeruJeus HYP Hypothalamus (many nuclei) ILN Intermediolateral nucleus Ji-ENDOR Beta endorphin EPI Epinephrine ENKEPH Enkepha1in DVN Dorsal vagal nucleus NA Nucleus ambiguus X Vagus nerve IX Ninth cranial nerve DYNOR Dynorphin NOREPI Norepinephrine AD MED Adrenal medulla Annu. Rev. Pharmacol. Toxicol. 1983.23:541-541. Downloaded from www.annualreviews.org by University of Nebraska -Lincoln on 09/19/13. For personal use only.

Exposure to bacterial endotoxins has long been known to stimulate the release of anterior pituitary hormones; administration of endotoxin was at one time a common clinical test of anterior pituitary function. Endotoxin is a potent stimulus for production of the endogenous pyrogenic protein, interleukin-1 (IL-1), by macrophages and monocytes. The possibility that IL-1 has a direct effect on the secretion of hormones by rat pituitary cells in a monolayer culture was investigated. Recombinant human IL-1 beta stimulated the secretion of adrenocorticotropic hormone, luteinizing hormone, growth hormone, and thyroid-stimulating hormone. Increased hormone secretion into culture supernatants was found with IL-1 concentrations ranging from 10(-9) M to 10(-12) M. Prolactin secretion by the monolayers was inhibited by similar doses. These concentrations of IL-1 are within the range reported for IL-1 in serum, suggesting that IL-1 generated peripherally by mononuclear immune cells may act directly on anterior pituitary cells to modulate hormone secretion in vivo. Incubation of IL-1 solutions with antibody to IL-1 neutralized these actions. These pituitary effects of IL-1 suggest that this monokine may be an important regulator of the metabolic adaptations to infectious stressors.

The effects of prolactin on lactation and reproductive organs are well known. However, the other possible target organs and physiological consequences of altered levels of circulating prolactin remain poorly understood. In this study, mice were treated with bromocryptine, a dopamine receptor agonist that inhibits pituitary prolactin secretion. Bromocryptine treatment prevented T-cell-dependent induction of macrophage tumoricidal activity after the intraperitoneal injection of Listeria monocytogenes or Mycobacterium bovis. Coincident treatment with ovine prolactin reversed this effect. Of the multiple events leading to macrophage activation in vivo, the production by T-lymphocytes of gamma-interferon was the most impaired in bromocryptine-treated mice. Lymphocyte proliferation after stimulation with mitogens in vitro was also depressed in spleens of bromocryptine-treated mice, and coadministration of prolactin also reversed this effect. Bromocryptine treatment also reduced the number of deaths resulting from inoculation of mice with Listeria; exogenous prolactin significantly reversed this effect. The critical influence of pituitary prolactin release on maintenance of lymphocyte function and on lymphokine-dependent macrophage activation suggests that, in mice, lymphocytes are an important target tissue for circulating prolactin.

To our knowledge, this is the first report that PSA may function in tumors as an endogenous antiangiogenic protein. This function may explain, in part, the naturally slow progression of prostate cancer. Our findings call into question various strategies to inhibit the expression of PSA in the treatment of prostate cancer.

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