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SUMMARY
The monoamine oxidase inhibitor mebanazine (Actomol) was found to reduce the growth of cartilage, and the normal increase in body weight and pituitary weight in growing male rats. The inhibitory effect of mebanazine on cartilage growth is only partially overcome by concomitant injection of growth hormone. The inhibitory effect on growth is much greater when mebanazine is injected together with hydrocortisone; it exceeds by far the sum of the effects of mebanazine or hydrocortisone alone (augmentative synergism).
Mebanazine also inhibits cartilage growth in normal rats receiving metyrapone (Metopirone—which inhibits corticosteroid production) and in adrenalectomized animals receiving hydrocortisone. Mebanazine stimulates involution of the thymus and depletion of ascorbic acid from the adrenal glands of rats. This shows that mebanazine releases adrenocorticotrophic hormone in normal rats and in rats receiving high doses of hydrocortisone.
Our results thus suggest that the inhibitory effect of mebanazine on growth is twofold: it potentiates a corticosteroid which itself is a growth inhibitor and in addition blocks the release of growth hormone from the pituitary by a specific mechanism inherent in the action of mebanazine as an enzyme blocker.
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SUMMARY
A large number of monoamine oxidase (MAO) inhibitors: pivhydrazine (Tersavide), nialamide (Niamide), isocarboxazid (Marplan), mebanazine (Actomol), phenelzine (Nardil), pheniprazine (Catron) and tranylcypromine (Parnate), decrease cartilage growth in normal rats. This inhibition is not directly due to their properties as MAO inhibitors. Thus, for example, iproniazid (Marsilid), 2,5-dichlorophenylhydrazine, etryptamine (Monase) and amphetamine (Benzedrine) did not decrease epiphysial growth of the tibia in immature female rats. MAO inhibitors with a methyl residue on the α-carbon atom inhibited growth to a greater extent than those with a hydrogen in place of the methyl group.
Pargyline (Eutonyl) did not depress cartilage growth in adrenalectomized rats, even when they received large doses of adrenaline. However, pargyline inhibited cartilage growth in adrenalectomized animals receiving hydrocortisone and in normal rats. Thus the growth-inhibiting effect of pargyline seems to be mediated by its potentiating effect on corticosteroids.
Growth hormone prevented the inhibitory effect of pargyline on cartilage growth. Pargyline alone given to normal young male or female rats decreased weight gain for 2 weeks. Later the experimental animals caught up with the controls. It is assumed that the transient weight loss is due to the sympathomimetic effect of the MAO inhibitor, which depresses hypothalamic centres concerned with appetite, weight gain and growth.
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The mechanism by which combined treatment with monoamine oxidase inhibitors and a corticosteroid reduces the weight of the accessory sex glands in intact rats by about one half has been studied. Phenelzine sulphate in combination with hydrocortisone acetate given for 30 days to ovariectomized rats reduced the pituitary stores of luteinizing hormone (LH) by 33%. Similar reductions in somatotrophic hormone, corticotrophin and thyroid-stimulating hormone content were found after comparable treatment, whereas luteotrophic hormone increased.
The increase of weight of the seminal vesicles and prostate gland produced by human chorionic gonadotrophin could be partly antagonized by the simultaneous administration of mebanazine and dexamethasone, but the action of testosterone on these glands in castrated animals was not inhibited. Interference with the production and effectiveness of LH is therefore the most likely mode of action by which these drugs effect the reduction of the weight of the accessory sex glands.
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Follicle-stimulating hormone (FSH) preparations from various species stimulate the rate of formation of cyclic AMP by ovarian tissue, but there has been doubt whether this effect is due to an inherent property of FSH or to contamination of the FSH preparations with luteinizing hormone (LH) (Marsh, Mills & Lemaire, 1972). To answer this question we have made use of an antiserum directed against the β-subunit of ovine LH. Such antisera neutralize LH, but unlike antisera raised with intact LH do not cross-react with FSH and thyroid-stimulating hormone (TSH) which have a similar α-subunit (Pierce, Liao, Howard, Shome & Cornell, 1971).
Ovine LH (NIH-LH-S18) purified on Sephadex G-100 was dissociated and separated into its α- and β-subunits as described by Reichert, Rasco, Ward, Niswender & Midgley (1969). The concentrated β-subunit fraction was emulsified with Freund's complete adjuvant and used for immunizing rabbits (twice 200 μg antigen/rabbit by multiple intradermal injections, 2
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SUMMARY
The actions of luteinizing hormone (LH) and of prostaglandin E2 (PGE2) on the intact ovary or isolated components of the ovary from adult or prepubertal rats were studied in vitro with respect to (1) the rate of incorporation of [3H]adenine via ATP into cyclic adenosine-3′,5′-monophosphate (cAMP), or the level of cAMP measured by a competitive protein-binding assay; (2) protein kinase activity in the 27000 g supernatant, with calf thymus histone as the substrate; and (3) rate of oxidation of d-[6-14C]glucose. In addition, ornithine decarboxylase activity was assayed in the ovary in vitro after hormone treatment in vivo.
When ovaries from adult or pubertal rats were incubated in Krebs—Ringer bicarbonate buffer, addition of PGE2 to the medium resulted within 1 min in a doubling of the rate of cAMP formation; the rate was about fourfold after 5 min. PGE2 was 25 times more potent in this respect than prostaglandin F2α. Both isolated Graafian follicles and corpora lutea responded to either PGE2 or LH with increased cAMP production. During the perinatal period and until the age of 10 days the ovaries were unresponsive to LH, but responded to PGE2 with increased cAMP formation. Follicles cultured with LH for 18 h and then washed were refractory to subsequent stimulation by LH, yet remained fully responsive to PGE2.
A prostaglandin analogue, 7-oxa-13-prostynoic acid, did not inhibit LH-stimulated or PGE2-stimulated cAMP formation in vitro in whole ovaries. Indomethacin, a substance reported to inhibit prostaglandin synthesis in other tissues, likewise failed to inhibit this action of LH. Simultaneous addition of LH and PGE2 to the incubation medium augmented cAMP production to a significantly greater extent than did either agonist when added at maximally effective concentrations on their own, though this augmentation was short of a full additive effect. The latter finding provides presumptive evidence against the view that PGE2 is an obligatory mediator of LH action on the ovary, but this question remains open.
PGE2 mimicked the action of LH in stimulating glucose oxidation by ovaries in vitro, and in causing a 15-fold increase in ovarian ornithine decarboxylase activity within 4 h of injection into prepubertal rats.
Ovarian protein kinase activity in pubescent (28-day-old) rats was markedly enhanced by incubation of intact ovaries with LH or PGE2 or by exogenous cAMP added to the 27000 g supernatant. The stimulatory action of LH or PGE2 on the enzyme was attended by a significant decrease (to 10% of control value) in the binding of exogenous cyclic [3H]AMP to protein in the 2000 g supernatant fraction of the ovary, presumably reflecting saturation of the cAMP-binding regulatory subunit of protein kinase by enhanced endogenous generation of the cyclic nucleotide.
Stimulation of ovarian protein kinase by exogenous cAMP was demonstrable in 12-day-old rats, but insignificant at the age of 7 days. It thus appears that the competence of ovarian protein kinase to respond to cAMP, and of ovarian adenylate cyclase to respond to LH, are both acquired during the 2nd week of postnatal development.
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SUMMARY
Five monoamine oxidase inhibitors (MAOI) were tested for a correlation between MAO blocking potency, the effect on somatotrophic hormone (STH) production and metabolic effects on the pituitary.
Mebanazine, N-acetyl-mebanazine and pargyline inhibited STH production, body weight gain and glucose-6-phosphate (G-6-P) dehydrogenase activity. MAOI which contain a hydrazine group (mebanazine and N-acetyl-mebanazine) also inhibited alkaline phosphatase activity as well as DNA and RNA formation in the pituitary, while pargyline, which contains an amino group, was inactive in these respects.
Iproniazid and norpargyline were inactive with regard to STH production, body-weight gain and metabolic activities of the pituitary: alkaline phosphatase activity, G-6-P dehydrogenase activity, and DNA and RNA content. This suggests a relation between the ability of an MAOI to inhibit STH production and inhibition of the phosphogluconate oxidative pathway.
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SUMMARY
Paracetamol (N-acetyl-p-aminophenol) given i.p. in doses of 3–20 mg./kg./24 hr. stimulated epiphysial cartilage growth in intact female rats. This stimulation was not a result of increased food intake. It may be mediated by the adrenal gland, since paracetamol stimulated cartilage growth in thyroidectomized but not in adrenalectomized rats. Of 12 paracetamol derivatives tested, most did not affect cartilage growth or were less active than paracetamol. A structure-activity relationship could be established. Our results suggest that the mechanism of the stimulatory effect of paracetamol on growth may be twofold: the drug probably stimulates somatotrophin (STH) production and/or potentiates STH action on growth.
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It has been shown previously (Zor, Dikstein & Sulman, 1965a, b) that the monoamine oxidase inhibitor mebanazine inhibits the release of somatotrophin (STH). This could be demonstrated in rats by the marked decrease in the width of the epiphysial cartilage and by showing that the release of corticotrophin (ACTH), the natural antagonist of STH, was stimulated. This effect is greatly potentiated by corticosteroids.
The aim of the present study was to investigate to which of the enzyme systems involved in growth the ability of mebanazine to inhibit growth is related.
Immature male rats of the 'Sabra' strain of the Hebrew University, 5 weeks old, weighing 60 ± 5 g., received i.p. injections of mebanazine resinate (which contains only 35% of the base), 30 mg./kg./24 hr., for 20 days (six injections weekly). They were killed on the day after the last injection.
DNA was separated from RNA by the method
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SUMMARY
The effect of hormones on the 'tibia test' in intact immature female rats has been studied. It was found that corticotrophin, hydrocortisone, dexamethasone, oestradiol, thyroidectomy and pancreatectomy inhibit the growth of epiphysial cartilage, while somatotrophic hormone (STH) and, to a lesser extent, insulin, testosterone, thyroxine, triiodothyronine and aldosterone stimulate it. Dehydroepiandrosterone, progesterone, deoxycorticosterone and prolactin did not affect cartilage growth. Consequently, the 'tibia test' in intact immature female rats can only be considered specific for STH if interference with cartilage growth by the above mentioned hormones can be excluded. This does not detract from the usefulness of the 'tibia test' in intact female rats for studies of growth-promoting or growthinhibiting substances.
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The aim of this study was to search for direct biochemical effects of highly purified FSH on isolated ovarian follicular theca in vitro. Granulosa cells (GC; approximately 1 × 105 cells per follicle) were flushed from isolated follicles of pro-oestrous rats. The remaining theca layer and the isolated GC were incubated with highly purified ovine FSH. Prostaglandin E (PGE) accumulation was measured by radioimmunoassay. Follicle-stimulating hormone induced a 15-fold increase in PGE accumulation over the basal level in the follicular theca, the stimulated rate exceeding threefold that observed in the GC fraction derived from the same follicle. Follicle-stimulating hormone caused no significant increase in cyclic AMP level or steroidogenesis in the theca layer, but was active on these parameters in the GC. In contrast, LH increased the accumulation of cyclic AMP, progesterone and testosterone, as well as of PGE, in follicular theca. Exogenous 8-bromo cyclic AMP or cyclic GMP also stimulated PGE production in follicular theca or GC, but FSH was without any effect on the level of endogenous cyclic GMP in GC or follicular theca. Antibodies to FSH prevented the effect of FSH (but not that of LH) on PGE formation by follicular theca and GC, while antibodies to the β-subunit of LH blocked the effect of LH but not of FSH. We conclude that highly purified FSH has a stimulatory effect on PGE formation by the follicular theca.
