Quantitative magnetic resonance imaging of estradiol-induced pituitary hyperplasia in rats.

Magnetic resonance imaging (MRI) has been used for the determination in vivo of rat pituitary size. In midsagittal T2-weighted sections the pituitary, having a lower T2 value than the surrounding tissue, was visible with pronounced contrast. The size has been estimated by pixel counting. A close correlation (r = 0.96) with the pituitary weights determined postmortem has been obtained, demonstrating the reliability of the in vivo method. Using MRI the effects of Sandostatin, a somatostatin analog, on the pituitary size have been monitored in a rat model of prolactinoma (estradiol-induced hyperplasia of the pituitary). Treatment with Sandostatin over 4 weeks resulted in a 40% reduction of the hyperplastic pituitaries. These results have been confirmed by determination of pituitary weights postmortem. However, due to a large interindividual variation in size of hyperplastic pituitaries, more animals are required to reach statistical significance when only endpoints of treatment can be measured. In contrast, MRI allows one to monitor individually the drug effects over a long period of time, eliminating interindividual variations.

The effect of a somatostatin analogue (SMS 201-995, Sandostatin) on the concentration of phosphoribosyl pyrophosphate and the activity of the pentose phosphate pathway in the early renal hypertrophy of experimental diabetes in the rat.

The effect of a long-acting somatostatin analogue on the acute renal hypertrophy following induction of experimental diabetes in the rat has been studied. The kidney weight increase occurring at 2 and 7 days after alloxan injection was significantly lower in the diabetic group receiving somatostatin. Similarly, the previously reported increase in glucose-6-phosphate dehydrogenase (EC 1.1.1.49) and 6-phosphogluconate dehydrogenase (EC 1.1.1.44) found in the kidney at 2 and 7 days of diabetes was less marked in the group receiving SMS 201-995. The fall in renal phosphoribosyl pyrophosphate associated with early diabetic renal hypertrophy (7) was also lessened by administration of SMS 201-995. No effects of the drug were found in the normal rat on the same regimen of treatment. These observations indicate involvement of glucagon and/or growth hormone in the initiation of kidney growth in diabetes.

Chemistry and pharmacology of SMS 201-995, a long-acting octapeptide analogue of somatostatin.

Starting from a hypothetical conformation of natural somatostatin and a knowledge of the minimal fragment needed for biological activity, a process of rational design and lead optimization has led to the potent, selective, and long-acting analogue SMS 201-995, (formula: see text) which selectively inhibits growth hormone secretion in several animal species for up to 6 h after subcutaneous application. In the rat, SMS inhibits GH, insulin, and glucagon 70, 3, and 23 times more potently than SRIF, resulting in GH/insulin and GH/glucagon selectivities of 20 and 3, respectively. The compound has been shown to inhibit growth of transplantable insulinomas in hamsters and to label selectively a subset of somatostatin receptors in the rat cortex. A radioactively labelled analogue has been used to visualize somatostatin receptors in a GRF-secreting human tumour. The stability and duration of action of SMS 201-995 after subcutaneous injection enable for the first time extended investigations of the clinical utility of somatostatin in various diseases.

SMS 201-995: a very potent and selective octapeptide analogue of somatostatin with prolonged action.

Stepwise modification of a conformationally stabilised analogue of the fragment of somatostatin which had been thought to be essential biologically active moiety has enabled us to synthesise the analogue H-(D) Phe-Cys-Phe-(D) Trp-Lys-Thr-Cys-Thr(ol) code-named SMS 201-995, which in vitro is three times more potent than the native hormone in inhibiting the secretion of growth hormone, which is highly resistant to degradation by pure enzymes and by tissue homogenates, which in vivo in rat and rhesus monkey is (depending on test system) at least 20 times more active than somatostatin, which is much longer acting, and which moreover in both species is much more selective in inhibiting the secretion of growth hormone than that of insulin. The compound is active by several routes of administration including the oral, is well tolerated both in laboratory animals and in man, and is currently undergoing preliminary clinical trial.

Two novel prolactin release-inhibiting 8 alpha-amino-ergolines.

Prolactin secretion inhibition and changes in striatal dopamine metabolism in rats were compared after the administration of 8 alpha-amino-ergoline CH 29-717 and 2 derivates. CQ 32-084 was similar to but less potent than CH 29-717, while 32-085, the l-methyl derivative, showed delayed dopaminomimetic effects.

Adrenergic and dopaminergic control of growth hormone secretion in urethan anesthetized adult male rats.

The effects of drugs which interfere with alpha-adrenergic and dopaminergic mechanisms, involved in GH and PRL secretion, have been analyzed in urethane anesthetized rats. Clonidine induced a dose-dependent release of GH (0.0032--0.1 mg/kg i.v.) as well as of PRL (0.032--1.0 mg/kg i.v.). The lowest dose of clonidine, when given into the third ventricle, provoked a very pronounced release of GH. Phentolamine, given intravenously, inhibited the clonidine-induced GH release in a dose-dependnet manner. L-Dopa administered intravenously and apomorphine administered intravenously or intraventricularly did not affect basal secretion of GH bu- produced a dose-dependnet inhibition of clonidine-induced GH release. Pimozide did not change basal GH secretion. Furthermore pimozide did not attenuate the inhibition of clonidine-induced GH secretion seen after apomorphine administration, however, it completely reversed apomorphine-induced PRL inhibition. These findings demonstrate that an alpha-adrenoceptor-mediated stimulatory mechanism is involved in GH and PRL secretion. An inhibitory dopaminergic mechanism is confirmed for PRL secretion and suggested for GH secretion.

Alpha adrenergic control of growth hormone in adult male rats.

Intravenous injection of 0.1 mg/kg clonidine into rats under urethane anaesthesia induced a prompt and long-lasting release of growth hormone, estimated by radioimmunoassay (IRGH), which could be abolished by 0.2 mg/kg phentolamine given into the 3rd ventricle. Injection of 3 mug/kg clonidine into the 3rd ventricle stimulated also the release of IRGH significantly. Intravenous administration of 0.32 mg/kg phenylephrine caused a small and transient release of IRGH only. These results provide evidence that central alpha-adrenergic stimulation resulting in an increased GH secretion is one important mechanism in the regulation of this hormone in the rat.

Effects of synthetic salmon calcitonin on gastric secretion and ulcer formation in conscious cats and rats.

In conscious and unrestrained cats the gastric secretion and ulcer formation induced by i.v. infusion of pentagastrin can be inhibited by synthetic salmon calcitonin given simultaneously. The volume and various constituents of gastric juice are proportionally diminished. Pepsin alone is definitely more inhibited, which may be of significance in respect to the mode of action of calcitonin. These effects are dose dependent in the range of 0.01 mug - 1.0 mug/kg/h salmon calcitonin, corresponding to 0.05 - 5.0 MRC units. Based on the finding that such minute doses have effects, it may be speculated that calcitonin has a regulatory function in gastric secretion of cats. In Shay-rats a dose dependent inhibitory effect of salmon calcitonin on ulcer formation and gastric secretion is demonstrated. Besides the volume, the acid concentration of gastric juice is reduced, which may explain the high efficacy of salmon calcitonin to prevent ulcer formation in this species. Ulcerations induced by pylorus ligation, stress and phenylbutazone can be inhibited to a similar degree by calcitonin, suggesting interference with a basal mechanism common to all three types of ulcerogenesis.