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Disappearance of LHRH and D-Leu⁶-Des Gly NH₂¹⁰ LHRM Ethylamide in Ewes¹

Washington State University, Pullman 99164³

Abstract

The in vivo disappearance of biological activity of luteinizing hormone-releasing hormone/follicle stimulating hormone-releasing hormone (LHRH) and a structural analog, D-Leu⁶-des Gly NH₂¹⁰ LHRH ethylamide (D-Leu⁶) were compared in intact ewes. Nine ewes were in the luteal phase of an estrus cycle when randomly divided into three equal treatment groups. Ewes were infused with either saline (5 ml/hr), LHRH (1 mg/5 ml/hr), or D-Leu⁶ (.1 mg/5 ml/hr) for 16.5 hours. Jugular blood was drawn every 30 min during infusion and for 6 hr thereafter to determine serum luteinizing hormone (LH). One milliliter of each blood sample collected following cessation of infusion was injected (iv, within 5 to 10 sec of collection) into an estrogen-progesterone treated ovariectomized (EPO) rat. The EPO rats were bled at 0, 15, 30, 60, 120, 240, 360 min after injection of sheep blood. LH released from each rat was used as an index of biologically active LHRH or D-Leu⁶ remaining in sheep blood at the time of collection. Mean serum LH concentrations in ewes treated with D-Leu⁶ or LHRH were not different (P>.05) indicating similar bioactivities of the two different doses of peptide used. Ewes had serum LH concentrations of less than 5 ng/ml at the time their blood was injected into the bioassay rats. Serum LH was not increased in blood of rats compared to pretreatment levels when injected with blood from sheep given saline (P>.05). Regression lines were fit to the means of the disappearance curves of each treatment. Analysis of regression coefficients showed the LH-releasing activity of LHRH and the D-Leu⁶ treated ewes decreased at a similar rate (P>.05). Since the two treatments were not different, they were pooled and a half-life of 185 min or 3.07 hr was calculated. Biological activity of LHRH and D-Leu⁶ was not detectable after 4.0 hr post-infusion. These data indicate that the greater biological potency of the analog D-Leu⁶ relative to synthetic LHRH is not attributable to a longer circulating time in the blood.

¹ Scientific Paper No. 4846. College of Agriculture Research Center, Washington State University. Project 0137.

² The authors wish to thank Dr. R. Ripple of Abbott Laboratories for the synthetic LHRH, D-Leu⁶ and a grant for conducting this study; Dr. G. D. Niswender for antiovine LH; Dr. L. E. Reichart forovine LH for iodination; the National Institute of Arthritis, Metabolic and Digestive Diseases Pituitary Hormone Distribution Program for NIH-LH-S17 usedfor standards.

³ Department of Animal Sciences.