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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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SUMMARY
Treatment of intact adult male rats with 10 mg. perphenazine (Trilafon)/kg. resulted in a decrease in the prolactin content of the pituitary within 1 hr. This decrease was probably due to suppression of the hypothalamic prolactin-inhibiting factor (PIF). Subsequent intracarotid infusion of neutralized acid extracts of rat hypothalamus restored the pituitary prolactin content. This effect was dose-dependent within a range of ½-2 hypothalami. Infusion of extracts of cerebral cortex failed to increase pituitary prolactin. The response to the hypothalamic extracts is considered to be specific for PIF and is proposed as an assay method for PIF.
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In a previous paper an attempt was made to minimize the effect of random variations during routine toxicological screening in female rats, by using all the previously accumulated control experiments for comparison (Dikstein, Kaplanski, Koch, Locker & Sulman, 1967). The method is based on comparison of organ weights of the treated animals with computer-drawn curves showing the standard weight of organs as a function of body weight in control animals. This method allows the use of as few as six rats for each treatment and six control rats. The method obviates misinterpretation of body weight changes caused either by the treatment or by uncontrollable changes in experimental conditions. In this communication we describe a method developed for use in male rats.
The basic approach is as follows. Using all the data accumulated in previous control experiments, a regression line between a certain measurable parameter (usually the weight of a specific
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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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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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SUMMARY
Promethazine and promethazine sulphoxide selectively inhibited gonadotrophin secretion in female rats. The effects obtained were: decrease in ovarian weight, reduction in the number of follicles and corpora lutea in the ovary, prolongation of the oestrous cycle and reduced amounts of gonadotrophin-releasing factors in the hypothalamus.
Very small doses of clomiphene citrate (1–100 ng/kg) increased gonadotrophin secretion in female rats, as shown by an increase in ovarian weight, increase in the number of corpora lutea, shortening of the oestrous cycle and increased amounts of gonadotrophin-releasing factors in the hypothalamus. Higher doses of clomiphene citrate (1 μg—2 mg/kg) produced the well-known inhibition of gonadotrophin secretion.
The possible mechanism of action of these drugs is discussed.
