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Increases in Circulating Insulin-Like Growth Factor I Levels by the Oral Growth Hormone Secretagogue MK-0677 in the Beagle Are Dependent upon Pituitary Mediation¹

Departments of Physiology and Biochemistry (K.-D.S., T.J., E.G.F., H.C., R.G.S., G.H.), Biometrics Research (D.Z.), and Laboratory Animal Resources (P.C., W.F.), Merck Research Laboratories, Rahway, New Jersey 07065; and University of Pennsylvania School of Veterinary Medicine (G.W.N.), Philadelphia, Pennsylvania 19104

Address all correspondence and requests for reprints to: Dr. K.-D. Schleim, Department of Physiology and Biochemistry, Merck Research Laboratories, P.O. Box 2000, Rahway, New Jersey 07065.

It has been well established that the spiroindoline sulfonamide MK-0677 stimulates GH secretion from the pituitary both in vitro and in vivo. MK-0677 has also been shown to increase serum insulin-like growth factor I (IGF-I) and cortisol levels in vivo; these increases are assumed to be driven by the increased serum GH and ACTH levels, respectively. However, such increases could also be due to a direct stimulatory action of MK-0677 at the level of the liver and adrenal cortex. To address this possibility, we investigated whether MK-0677 increased IGF-I and cortisol levels in hypophysectomized dogs.

Baseline GH, IGF-I, and cortisol responses to MK-0677 (1 mg/kg, orally) were initially determined. Hypophysectomy (hypox; n = 7) or sham surgery (sham; n = 5) was then carried out. Six days postsurgery, the GH and cortisol responses to MK-0677 were reevaluated in each dog. In addition, each dog was treated with porcine GH (PST; 0.1 IU/kg, sc) to confirm the responsiveness of the GH-IGF-I axis.

The mean peak GH increases in response to MK-0677 in the pre-sham dogs (83.7 ± 19.2 ng/ml), post-sham dogs (108 ± 26.2 ng/ml), and pre-hypox dogs (121.2 ± 13.6 ng/ml) were not significantly different. Mean peak GH levels were unchanged after MK-0677 administration in the hypox dogs (2.3 ± 0.7 ng/ml). Before surgery, serum IGF-I levels increased to 243 ± 27 and 224 ± 47 ng/ml in the sham and hypox groups, respectively, after MK-0677 administration. Surgery was associated with a marked (50%) decrease in serum IGF-I levels. MK-0677 administration increased IGF-I levels in the sham dogs from 78 ± 14 to 187 ± 31 ng/ml, whereas IGF-I levels remained unchanged (17.7 ± 2.4 ng/ml) in the hypox dogs. PST treatment increased IGF-I levels in the sham dogs from 162 ± 30 to 325 ± 32 ng/ml. In the hypox dogs PST treatment restored IGF-I to physiological levels (from 17.7 ± 2.4 to 199 ± 41 ng/ml).

Cortisol was increased after MK-0677 administration 3.7-fold in the pre-sham, 3.6-fold in the post-sham, and 3.6-fold in the pre-hypox dogs, but no increase was seen in the post-hypox dogs. ACTH GEL administration (2.2 U/kg, im) to hypox dogs returned cortisol to normal physiological levels, demonstrating the functional integrity of the adrenal cortex.

This study demonstrates that the GH secretagogue MK-0677 does not directly stimulate an increase in serum IGF-I or cortisol levels, but depends upon the presence of an intact pituitary.

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