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Biomedical subjects

R M MacLeod

Publications and source records attributed to R M MacLeod.

At least 109 records · Page 6Linked to original sources
PubMed1983

The inhibition of phosphatidylinositol turnover: a possible postreceptor mechanism for the prolactin secretion-inhibiting effect of dopamine.

We studied the association between the inhibition of phosphatidylinositol (PI) turnover and the inhibition of PRL secretion in the presence of dopamine. The incorporation of radiolabeled phosphate into anterior pituitary gland PI as well as serum PRL levels were significantly (P less than 0.01) greater in female than in male rats. No significant sex-related difference was found in the incorporation by pituitary tissue of 32P into phosphatidylcholine (PC) or phosphatidylethanolamine (PE). Dopamine decreased the incorporation of 32P into PI, but not into PC or PE, by female rat pituitary glands; this effect was reversed by two dopamine receptor-blocking agents, haloperidol and pimozide. After dopamine was removed from the incubation medium, basal 32P incorporation into PI was restored within 10 min. The administration of bromocriptine (500 micrograms/kg, ip, 4 h earlier) significantly reduced pituitary PI turnover. Conversely, in vivo injection of alpha-methyl-p-tyrosine (alpha MpT; 200 mg, ip, 2.5 h before death), an inhibitor of catecholamine biosynthesis, dramatically increased serum PRL levels. In vitro incorporation of 32P into PI, but not into PC or PE, increased (+130%) when these glands were incubated for 30 min with radiolabeled phosphate. The in vitro addition of 0.5 microM dopamine to glands from alpha MpT-treated rats counteracted the stimulation of 32P incorporation into PI produced by alph MpT treatment. In rats bearing the transplantable PRL-secreting tumor MtTW15, the hyperprolactinemia produced by the tumor stimulates hypothalamic turnover of dopamine, with a consequent inhibition of pituitary gland PRL secretion. 32P incorporation into PI, but not into PC or PE, was significantly (P less than 0.01) inhibited (-41%) in pituitary glands from these rats. The injection of alpha MpT (200 mg/kg, ip) or haloperidol (2 mg/kg, ip) 12 and 3 h before death into MtTW15 tumor-bearing rats abolished the inhibition of 32P incorporation into pituitary PI. Dopamine also decreased PI turnover in the 7315a PRL-secreting pituitary tumor. Our data indicate that the PI cycle may be an intracellular mechanism controlling PRL release in the rat and that the changes in its cleavage and turnover may be an early postreceptor event responsible for the inhibition of PRL secretion produced by factors such as dopamine.

Animals↗
PubMed1983

Intranasal administration of human pancreatic tumor GH-releasing factor-40 stimulates GH release in normal men.

Human pancreatic tumor GH releasing factor-40 (hpGRF-40) selectively stimulates GH secretion in normal men and in some adult patients with GH deficiency. As the latter finding suggests that some children with GH deficiency may benefit from therapy with hpGRF-40 or an analogue, we investigated the effect of hpGRF-40 administered intranasally on GH release. Six normal men were given hpGRF-40 (30 ug/kg; test day) or an equivalent volume of vehicle alone (control day) at 0900 h. Immunoreactive GH was measured in serum obtained at intervals between 0800-1200 h. Mean (+/- SEM) integrated serum levels of GH (ng/ml/h) prior to and following administration of vehicle were not different (1.27 +/- 0.57 vs 0.87 +/- 0.28; p = 0.54). However, following hpGRF-40 administration, GH levels increased significantly (0.53 +/- 0.03 vs 2.88 +/- 0.75; p = 0.022). Peak levels of serum GH were detected within 30 min following hpGRF-40. Except for mild burning of the nasal mucosa reported by one subject, no side effects were noted. We conclude that, if hpGRF-40 or an analogue is shown to be useful in the treatment of some children with GH deficiency, the intranasal route of administration may be utilized and will be more acceptable for chronic therapy than intravenous, intramuscular, or subcutaneous injection.

Administration, Intranasal↗
PubMed1983

Hyperprolactinaemia and DNA synthesis in the pituitary gland of the rat.

Hyperprolactinaemia produced in rats by the transplanted prolactin-secreting tumours MtTW15 and 7315a significantly (P less than 0.01) inhibited by 70% the incorporation of [3H]thymidine into the pituitary DNA of the host animals. The weight and the DNA content of the glands were significantly (P less than 0.01) reduced by 30%. The administration of haloperidol, a dopamine receptor blocking agent, to the tumour-bearing rats increased the suppressed DNA replication in the anterior pituitary glands by approximately 560% in the MtTW15-bearing rat and by 100% in the 7315a-bearing animals. Furthermore, injection of drugs which stimulate prolactin release either by blocking the synthesis of dopamine (alpha-methyl-p-tyrosine) or the re-uptake of dopamine (reserpine) stimulated DNA synthesis by 800 and 100% respectively in the anterior pituitary gland of rats bearing the MtTW15 tumour. In contrast, lisuride, a dopamine agonist, significantly inhibited the incorporation of [3H]thymidine into the DNA of the pituitary gland of normal but not hyperprolactinaemic rats. Chronically administered oestrogens to hyperprolactinaemic rats increased the weight (100%). DNA content (31%), incorporation of [3H]thymidine into DNA (680%) and synthesis and release of prolactin (300%) in the pituitary gland. The incorporation of [3H]thymidine into tumour DNA was several times higher than in the pituitary gland of the host animal and was not significantly modified by any of the above treatments. Likewise the hyperprolactinaemia of the tumour-bearing rats was not significantly changed. In conclusion, we have shown that hyperprolactinaemia inhibits DNA synthesis in the anterior pituitary gland and this inhibition can be reversed completely by a dopamine receptor blocking agent and by hypothalamic dopamine depleting drugs. We propose that dopamine regulates, either directly or indirectly, DNA synthesis in the lactotrophs of the pituitary gland, which may be responsive to negative feedback mechanisms.

Animals↗
PubMed1983

Neuroendocrine evidence that tetrabenazine is a dopamine antagonist.

Tetrabenazine is considered to be a reserpine-like drug because of its ability to block dopamine storage in presynaptic vesicles. We used two methods to determine that tetrabenazine is also a dopamine antagonist. Tetrabenazine displaced the specific [3H]spiperone binding to the dopamine receptors of the anterior pituitary, the corpus striatum, and a transplantable rat pituitary tumor with values for 50% displacement (IC50) of about 15 microM. Under in vitro conditions, 0.5 to 10 microM tetrabenazine blocked dopaminergic inhibition of prolactin secretion from rat anterior pituitary glands. One, four, and twenty-four hours after a single tetrabenazine injection (30 mg/kg, ip), the serum prolactin changed from 22 +/- 9 ng/ml initially, to 450 +/- 52, 254.7 +/- 10.4, and 9.3 +/- 1.1 ng/ml, respectively. Pituitary glands of the treated rats incubated in vitro were refractory to dopaminergic inhibition of prolactin release to an extent that was maximal at one hour but inapparent by 24 hours after injection. In vivo and in vitro, tetrabenazine induces biological responses characteristic of a dopamine antagonist. These actions are independent of the reserpine-like properties of tetrabenazine. The unusual ability of tetrabenazine both to antagonize dopamine and to block presynaptic dopamine storage may provide a new tool for understanding the physiology of dopaminergic systems.

Animals↗
PubMed1983

Pertussis toxin actions on the pituitary-derived 235-1 clone: effects of PGE1, cholera toxin, and forskolin on cyclic AMP metabolism and prolactin release.

Pertussis toxin (PT) modulation of the cyclic AMP (cAMP) accumulation induced by prostaglandin E1 (PGE1), cholera toxin (CT), and forskolin was used to study the role of cAMP in the regulation of prolactin release. The clonal cell line 235-1, derived from a rat anterior pituitary tumor, served as the major target tissue. While PT had no effect on basal cAMP levels, in the presence or absence of a phosphodiesterase inhibitor, this novel bacterial toxin potentiated the cAMP response to each stimulus. The PT enhancement of PGE1-stimulated cAMP production was maximal after 24 hr of PT exposure, whether the toxin was left in the medium or removed after as little as 30 sec. Although PGE1, CT, and forskolin are all secretagogues for prolactin, increasing release by about 50%, PT had no apparent effect on these responses. These data support the hypothesis that cAMP may facilitate prolactin release, but may not be the primary stimulus for secretion.

1-Methyl-3-isobutylxanthine↗
PubMed1982

Tetrabenazine has properties of a dopamine receptor antagonist.

Tetrabenazine is considered to act in a manner similar to reserpine to reduce the involuntary movements of tardive dyskinesia or Huntington's disease and to improve psychoses. We determined that tetrabenazine also has properties of a dopamine receptor antagonist by testing the ability of tetrabenazine to block the inhibitory effect of dopamine on prolactin secretion from rat anterior pituitary glands in vitro and to displace 3H-spiperone binding to dopamine receptors in the pituitary, corpus striatum, and a rat transplantable prolactin-secreting tumor. Under in vitro conditions, 0.5 to 10 microM tetrabenazine directly blocked dopaminergic inhibition of prolactin secretion. Furthermore, 1 hour after tetrabenazine injection (30 mg/kg intraperitoneally) in vivo, when the serum prolactin had increased from 22 +/- 9 to 450 +/- 52 ng/ml (p less than 0.01), pituitary glands of the treated rats examined in vitro were refractory to dopaminergic inhibition of prolactin release. Tetrabenazine apparently interacts with the dopamine receptor because this drug displaced the dopamine antagonist 3H-spiperone from dopamine receptors of the three different tissues with an apparent inhibitory constant of about 5 microM. We conclude that tetrabenazine has biological and pharmacological properties typical of a dopamine receptor antagonist. These observations should stimulate a reevaluation of the mechanisms for the actions of tetrabenazine previously attributed exclusively to a "reserpine-like" effect.

Animals↗
PubMed1982

Failure of dopamine and bromocriptine to affect prolactin release and cell growth in the dopamine receptor-deficient 235-1 clone.

The 235-1 clone was recently derived from the 7315a transplantable pituitary tumor and continues to secrete rat prolactin. The cells have a prominent Golgi apparatus which can be stained immunocytochemically for prolactin, but there were no 600-900 nm granules which are characteristic of normal mammotrophs. In a perfused cell-column apparatus, prolactin release from the clone was unchanged by dopaminergic agonists, thyrotropin-releasing hormone and estradiol but stimulated by dibutyryl cyclic AMP. Cellular cyclic AMP content was also not changed by dopamine but was dramatically enhanced by prostaglandin E1, indicating that at least one hormone-adenylate cyclase coupling mechanism was functional. In radioligand binding studies using the dopamine antagonist [3H]spiperone, no evidence of a dopamine receptor was obtained. The [3H]spiperone binding present was not stereoselective, and exceedingly high concentrations of other ligands were required to displace the binding. In addition, the induction of a prolactin-secreting hard tumor in rats by subcutaneous inoculation of the 235-1 cells failed to induce measurable dopamine receptors associated with the tumor cells. In order to address the possibility that there were functional dopamine receptors on these cells, but that they could not be resolved with either the cell column and cyclic AMP studies or the radioreceptor assay, the clone cells were incubated with 0.1-100 nM bromocriptine for up to 8 days. Bromocriptine had no effect on the growth rate or prolactin secretion of the 235-1 clone but inhibited prolactin release from anterior pituitary cells by over 73% in control studies. We conclude that the 235-1 clone does not express dopamine receptors and that the presence of dopamine receptors is obligatory for the typical inhibitory effects of bromocriptine on prolactin release and pituitary cell growth.

Animals↗
PubMed1982

Lisuride, a dopamine agonist, inhibits DNA synthesis in the pituitary gland.

We investigated the effects of lisuride, a potent dopaminergic agent, administered in vivo on the incorporation of 3H-thymidine into DNA and 3H-leucine into prolactin and its subsequent release by the rat anterior pituitary gland in vitro. The results demonstrated that daily injection of 100 micrograms of lisuride for 7 days significantly (p less than 0.05) diminished (about 35%) the incorporation of 3H-thymidine into DNA and reduced the stimulation of DNA synthesis produced by estrogens. The incorporation of 3H-leucine into prolactin was markedly inhibited by the administration of lisuride, and also significantly (p less than 0.05) reduced the stimulation of prolactin secretion produced by estrogens. In pituitary glands enlarged by the chronic administration of estrogens, lisuride treatment significantly (p less than 0.05) reduced the weight (26%), the content of DNA (35%) and the incorporation of 3H-thymidine (40%). The inhibitory effect of lisuride on DNA synthesis was present as early as 20 h after a single injection of the drug (about 27%). The same treatment with lisuride significantly (p less than 0.05) reduced the incorporation of 3H-leucine into prolactin. The results of these experiments are compatible with the concept of a relationship between prolactin release and DNA synthesis in the pituitary gland. They also suggest that lisuride, as with bromocriptine, may exert its antiproliferative effects on prolactin-secreting adenomas by decreasing their synthesis of DNA.

Animals↗
PubMed1982

Unremitting suppression of the postovariectomy rise in plasma LH by tumor-induced hyperprolactinemia.

The plasma LH response to ovariectomy was studied at different periods in the development of hyperprolactinemia in rats bearing the transplantable prolactin-secreting pituitary tumors 7315a or MtTW15. Rats were subcutaneously inoculated with tumor cells and ovariectomy was performed at 3 times during the subsequent growth of the solid tumor: (1) coincident with tumor cell implantation; (2) when solid tumors first became palpable, and (3) when solid tumors were large. The values for circulating prolactin and LH were serially determined following ovariectomy for 63, 35 and 28 days, respectively. In other studies, tumor cells were implanted into animals which had undergone ovariectomy 3 months earlier. In the presence of hyperprolactinemia caused by the prolactin secreting tumors, the plasma LH following ovariectomy was either reduced following an initial increase, prevented from increasing, or reduced from chronically elevated levels. Hyperprolactinemia of approximately 7-50 micrograms/ml caused marked suppression of LH secretion, while hyperprolactinemia in the range of 0.2-6 micrograms/ml resulted in significant but slower and lesser suppression of LH which did not reach noncastrate levels. The inhibitory effect of hyperprolactinemia on plasma LH after ovariectomy was persistent and unremitting for the duration of each experiment, and there was no tendency for suppressed LH to return to levels expected for the ovariectomized state. The model of hyperprolactinemia induced with transplantable prolactin-secreting tumors in the ovariectomized rat may prove to be valuable in understanding the mechanism of depression of gonadal function by hyperprolactinemia.

Animals↗
PubMed1982

A case of ectopic ACTH syndrome: diagnostic difficulties caused by intermittent hormone secretion.

A patient with a thymic carcinoid tumour causing ectopic ACTH syndrome is presented. The case illustrates the rapid development of the clinical and laboratory findings often associated with ectopic secretion of ACTH, including severe proximal myopathy, emotional lability, and hypokalaemic alkalosis. Interpretation of conventional tests of pituitary-adrenal function was complicated by intermittent secretion of ACTH by the tumour. The results of selective venous sampling for ACTH ruled out pituitary ACTH hypersecretion and were suggestive of a thymic source; computerized tomography of the chest localized the tumour. In vivo and in vitro investigations confirmed excessive ACTH production by the tumour, and surgical resection plus radiotherapy has resulted in resolution of the syndrome. The diagnostic problems created by intermittent secretion of ACTH by these tumours and the pre-operative and post-operative medical management of these patients are discussed.

17-Hydroxycorticosteroids↗
PubMed1981

The direct effect of reserpine in vitro on prolactin release from rat anterior pituitary glands.

Anterior pituitary glands from normal untreated rats synthesize and release the hormone prolactin (Prl) during incubation under in vitro conditions. Addition of dopamine (DA) greatly inhibits the release of Prl and to a lesser extent reduces Prl synthesis. When pituitary glands are incubated in the presence of reserpine, there is a similar significant dose-related inhibition of Prl release. This effect persists even in the presence of a DA antagonist (haloperidol) and after the depletion of hypothalamic amines by in vivo treatment with reserpine. Reserpine in vitro also inhibits release of newly synthesized growth hormone from the pituitary glands of male rats; however, this is not observed when female rats are studied. We conclude that the direct effect of reserpine to inhibit Prl release is apparently independent of any interaction with catecholamine systems and is mediated by other, presently undefined mechanisms.

Animals↗
PubMed1981

Restoration of pituitary prolactin synthesis and release by the administration of morphine to rats bearing a transplanted prolactin-secreting tumor.

Rats bearing transplanted prolactin-secreting tumors are known to have very high prolactin levels in the serum, reduced hypothalamic opiate concentrations, increasing hypothalamic dopamine synthesis and increased hypophyseal portal blood dopamine levels. Further, it has been shown that incubation in 3H-leucine of anterior pituitary glands from these tumor-bearing rats demonstrates a marked inhibition of 3H-prolactin synthesis and release. Using rats with the prolactin-secreting tumor MtTW15, we have found that 4 days of continuous administration of either morphine sulfate 1.44 mg daily or haloperidol 0.11 mg daily using and osmotic infusion pump caused a significant increase in the synthesis and release of 3H-prolactin from incubated pituitary gland compared to untreated tumor-bearing animals. Morphine may reduce hypothalamic dopamine release, whereas haloperidol is a direct dopamine receptor antagonist in achieving these effects.

Animals↗