Direct Effect Of Bromocriptine Research Articles

Inhibitory effects of bromocriptine on vascular smooth muscle cell proliferation

Bromocriptine (BC), an ergot alkaloid with wide therapeutic use in humans, has been shown to inhibit proliferation of several abnormally hyperproliferative cells in vivo and in vitro. In the present study, direct effects of BC on mitogen-stimulated proliferation of rat vascular smooth muscle cells (VSMC) (A7r5 cells) and human aortic smooth muscle cells (HAOSMC) were examined in vitro. Twenty-four hour proliferative responses of quiescent A7r5 cells and HAOSMC to a variety of mitogens in the presence or absence of BC were determined by quantifying the incorporation of 3H-thymidine into DNA. BC at 1 μM inhibited the responses of A7r5 cells to various concentrations of fetal calf serum (FCS) by 50–70% without affecting the ED 50 of FCS (2%). BC dose dependently inhibited the proliferation of A7r5 cells and HAOSMC stimulated by 2% FCS, with 52% inhibition at 1 and 0.1 μM, respectively. BC at 1 μM also completely inhibited the maximal mitogenic responses of A7r5 cells to prolactin, platelet-derived growth factor, insulin-like growth factor, and phorbol mysterate acetate (PMA), and BC at 1 μM completely inhibited the mitogenic response of HAOSMC to PMA. BC is a dopamine D 2 agonist, a noradrenergic α 2 agonist, and an α 1 antagonist, but the inhibitory effects of BC on A7r5 cell proliferation could not be mimicked by the specific D 2 agonists, LY162502 and LY171555; the α 2 agonist, clonidine; or the α 1 antagonist, WB-4101. Neither dopamine nor the D 2 agonist, LY162502, could inhibit HAOSMC proliferation induced by FCS. The PMA-induced stimulation of protein kinase C (PKC), a positive regulator of mitogenesis, could be completely blocked in A7r5 cells and HAOSMC by 1 and 0.1 μM BC, respectively. However, FPCS (2%)-induced activation of PKC in A7r5 cells and HAOSMC could only be blocked by 61 and 19% by BC (1 μM for A7r5 cells and 0.1 μM for HAOSMC), respectively. Given the existing evidence that BC reduces the severity of several other pathological conditions, such as insulin resistance, inflammation, and hyperlipidemia, which potentiate vascular disease, the current findings further suggest that BC use in the treatment of atherosclerosis and/or restenosis deserves further investigation.

Direct effects of bromocriptine on the steroidogenic capability of porcine granulosa cells.

The direct effects of bromocriptine on steroidogenesis were examined in cultured porcine granulosa cells. The following observations were made with bromocriptine: (1) It significantly increased the basal or FSH-stimulated secretion of progesterone in cultured porcine granulosa cells at concentrations exceeding 10(-7) mol/l; (2) its inhibitory effect on basal estradiol secretion was demonstrated; (3) it did not influence cell number in cultured porcine granulosa cells; (4) it increased the extracellular accumulation of cAMP in a concentration-dependent manner; and (5) it did not induce a change in cytosolic free Ca2+ concentration. These findings suggest that bromocriptine exerts a direct effect on steroidogenesis in ovarian granulosa cells.

Effect of bromocriptine on secretion and morphology of human prolactin cell adenomas in vitro.

The direct effect of short-term bromocriptine administration on human prolactin cell adenomas in vitro was studied by light and electron microscopy and correlated with the effect on hormone release. The light microscopic and, for the first time, ultrastructural characteristics of adenomatous prolactin cells in control and treated cultures were analyzed morphometrically and the changes induced by bromocriptine were quantified. Following 72 h treatment which lowered levels of prolactin release, there was a marked reduction in cell size, cytoplasmic volume and cytoplasmic volume densities of endoplasmic reticulum and Golgi apparatus. In contrast, the percentage of cytoplasm occupied by lysosomes increased. There was no consistent change in number and diameter of secretory granules. These findings indicate that prolactin cell involution is a direct effect of bromocriptine and suggest that reduction in endoplasmic reticulum and Golgi complex is largely responsible for the decreased cell size. Lysosomal degradation of cytoplasmic components may play a role in this process.

Effect of bromocriptine treatment on circulating somatomedins in tall adolescents.

Somatomedin and bromocriptine levels were measured before and after 3 months of bromocriptine treatment (5 mg/day) in the sera of 16 tall adolescents with excessive adult height prediction. Somatomedins were measured by RIA for somatomedin C and IgFII and by measuring thymidine incorporation into human lectin-activated lymphocytes. Mean +/- SEM levels of bromocriptine after three months of treatment were 0.61 +/- 0.08 ng/ml. No changes in radioimmunoassayable somatomedin C were observed after bromocriptine intake respectively 1.34 +/- 0.17 U/ml before and 1.4 +/- 0.01 U/ml during treatment. On the opposite a significant decrease of thymidine activity (p less than 0.002) from 1.45 +/- 0.17 U/ml to 1.12 +/- 0.19 U/ml was observed. No changes of IgFII levels were observed in the sera of the 8 patients where they were measured. In order to test a possible direct effect of bromocriptine on peripheral tissues bromocriptine mesylate was added in somatomedin bioassays. Inhibitory effect of bromocriptine in vitro is seen at higher levels (1 microM) compared to the circulating one (1 nM). This study demonstrates that the major effect of bromocriptine which is the acceleration of bone maturation is not related to changes in somatomedin C.

Evidence for dopaminergic control of circadian variations in thyrotropin secretion.

This study examines the influence of dopamine of recumbent circadian secretory patterns of plasma TSH. Seven euthyroid men were studied during a control (no medication) and a bromocriptine period (2.5 mg bromocriptine three times a day for 5 days). In the control period, a clear daily pattern in plasma TSH was evidenced, with highest levels occurring during the late evening presleep period and the fist few hours after the onset of nocturnal sleep. During the control period, recumbent 24-h plasma TSH was linearly correlated (gamma = 0.41; P less than 0.05) with clock time. Bromocriptine lowered the mean 24-h TSH from a control level of 2.1 +/- 0.2 to 1.1 microunits/ml. Further, bromocriptine eliminated the early nocturnal TSH surge and the correlation of plasma TSH with clock time. Thus, circadian variations in plasma TSH levels may be modulated, in part, by a dopaminergic mechanism. However, we cannot rule out a direct effect of bromocriptine on the anterior pituitary resulting in decreased late evening rises in plasma TSH.

Bromocriptine for an Acromegalic Patient

A 64-year-old woman with active acromegaly of 33 years' duration, severe carpal tunnel syndrome, and subclinical heart disease was treated with bromocriptine mesylate. Within eight months of therapy, basal growth hormone (GH) levels decreased from 90.0 to 7.0 ng/mL, and hand volume was reduced from 375 to 295 mL. Concomitantly, echocardiographic studies showed normal left ventricular size and function. Electromyographic studies demonstrated normal function in both median nerves. Bromocriptine may correct cardiac dysfunction and carpal tunnel syndrome in acromegaly either by reduction of GH oversecretion or by a direct effect of bromocriptine on dopamine receptors in the heart and peripheral nerve endings. (<i>JAMA</i>244:1825-1827, 1980)

The mechanism of the suppressive action of bromocriptine on adrenocorticotropin secretion in patients with Cushing's disease and Nelson's syndrome.

The oral administration of 2.5 mg bromocriptine elicited a significant suppression of plasma ACTH and cortisol in 6 of 13 patients with untreated Cushing′s disease. In the responding patients, mean plasma ACTH levels were higher and pituitary tumor size was larger than in the nonresponders. In two patients with Nelson′s syndrome, plasma ACTH was diminished by 70% and 30%, respectively, from 4-6 h after 2.5 mg bromocriptine. In one patient with ectopic ACTH secretion from a bronchial carcinoid, plasma ACTH was suppressed by 32% from 3-5 h after 2.5 mg bromocriptine. The effects of bromocriptine and cyproheptadine on the secretion of ACTH from trypsin-dispersed tumor cells prepared from the ACTH-secreting rat pituitary tumor 7315a were investigated in vitro. Bromocriptine (1 µM) inhibited ACTH secretion by 40% (P < 0.01), while 1 JUM cyproheptadine inhibited ACTH secretion by 25% (P < 0.01). On the basis of 1) the direct effects of bromocriptine and cyproheptadine on ACTH secretion by rat pituitary tumor cells, 2) the suppressive effect of bromocriptine in a patient with ectopic ACTH secretion, and 3) the increasing sensitivity of ACTH secretion to bromocriptine with increasing pituitary tumor size, we suggest that one mechanism of action of bromocriptine is a direct effect on the ACTH-secreting pituitary microadenoma n patients with Cushing′s disease and Nelson′s syndrome.

Bomocriptine treatment of patients with acromegaly resistant to conventional therapy.

Eleven patients with active acromegaly resistant to conventional therapy were treated with bromocriptine for 15 (12--22) months by increasing the daily dose stepwise from 5 to 10--60 mg. A satisfactory response was achieved in all but one of the eight patients, in whom the mean diurnal level of serum GH was less than 50 ng/ml, whereas patients with grossly elevated serum GH levels responded poorly. In the longterm, no overall effects on glucose tolerance or plasma insulin (IRI) levels were observed but the chemical diabetes of three patients ameliorated in two. On the other hand, a dose-dependent acute suppressive effect of bromocriptine on plasma IRI response to oral glucose was observed, suggesting a direct effect of bromocriptine on the release of insulin from beta cells. Bromocriptine seems to be a good alternative in the treatment of patients with acromegaly who have not responded to conventional therapy.

Prolactin Suppression in the Treatment of Premenstrual Syndrome

Abnormal secretion of prolactin is amongst the many disorders of hormone secretion which have been proposed as potential causes for the common syndrome of premenstrual tension. Eight women suffering from this disorder participated in a five-month double-blind crossover trial of bromocriptine (5 mg per day) given in the luteal phase of the cycle. Significant improvement in most symptoms occurred during active as opposed to placebo therapy, together with objective evidence of a decrease in premenstrual weight gain and breast enlargement. This corresponds with the results of other studies which used bromocriptine in this dosage. The effect may be mediated by suppression of prolactin secretion, but could equally be a direct effect of bromocriptine.